AU2005202977A1 - Tankyrase2 Materials and Methods - Google Patents

Description

P/00/011 28/5/91 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Actual Inventors Address for service is: ICOS Corporation Erik CHRISTENSON Anthony J DEMAGGIO Phyllis S GOLDMAN David L MCELLIGOTT WRAY ASSOCIATES Level 4, The Quadrant 1 William Street Perth, WA 6000 Attorney code: WR Invention Title: "Tankyrase2 Materials and Methods" The following statement is a full description of this invention, including the best method of performing it known to me:- STANKYRASE2 MATERIALS AND METHODS SThis application claims the benefit of United States Provisional Application Serial No. 60/141,582, filed June 29, 1999.

The present invention relates generally to a novel tankyrase polypeptide having poly ADP-ribosylation activity, to polynucleotides encoding the polypeptide, S. and to methods of using such materials.

BACKGROUND OF THE INVENTION The ends of eukaryotic chromosomes (telomeres) are characterized by simple repeat DNA sequences. The length and sequence of the repeats varies from species to species but the importance of telomeres is universal in organisms with linear chromosomes. Telomeres protect the ends of the chromosomes and ostensibly function to prevent recombination of chromosome ends, which leads to chromosomal fusion and instability. In addition, there is considerable evidence that the length of the telomere repeats determines the ability of a cell to divide or perhaps even to survive: The telomeres of cultured primary human fibroblasts become progressively shorter with each cell division in the absence of an active mechanism to regenerate telomere length [Harley et al., Nature 345:458-60 (1990)]. At some critical stage of telomere shortening, these cells are no longer able to divide and enter a state known as cellular senescence. Thus, in human primary fibroblasts at least, telomere length functions as a biological clock to monitor cellular aging and regulate longevity.

The observation that telomere length regulates cellular aging prompted the hypothesis that telomere regulation may also be critical for organismal aging. Mice that are unable to replicate telomeres show characteristics of premature aging after the third generation. These characteristics include premature graying, decreased cell division capacity, impaired wound healing, and increased cancer incidence amongst others. Thus, regulation of telomere structure may be critical for some of the characteristics associated with aging. Drugs that modulate the regulation of telomere structure thus may have utility in treatment of age-related syndromes or in cases of genetically determined premature aging syndromes.

O Only recently has some of the machinery that replicates telomeres been described. This machinery, collectively referred to as the telomerase complex, consists of several proteins that replicate the telomeres and protect the telomere Sstructure from DNA repair, which otherwise might treat telomeres as damaged DNA and affect end joining or recombination thus destroying the integrity of the chromosome. Telomerase is the replicative component of the telomerase complex g and is a DNA polymerase that features an integral RNA molecule that serves as the template for the addition of the repetitive sequences [for a review, see Greider, Ann SRev Biochem 65:337-65 (1996)]. The observation that telomerase activity is essential C 10 for continued cell division suggests that inappropriate telomerase activity may be, in some instances, a contributing factor in the oncogenic transformation of cells. Forced expression of telomerase does not in and of itself cause oncogenic transformation but the fact that cells overexpressing telomerase have apparently unlimited capacity to replicate suggests that inappropriate expression of telomerase may be one step in a multi-step process of oncogenic transformation. In addition, numerous studies have shown that telomerase activity is higher in tumor tissue than most normal tissues suggesting that increased telomerase activity may be essential for tumor growth [for reviews, see Bacchetti, Cancer Surv 28:197-216 (1996); and Harley et al., Cold Spring Harbor Symp Quant Biol 59:307-15(1994)].

Two telomere-specific DNA binding proteins, designated TRF1 and TRF2 have also been shown to be important for maintenance of telomeres [Chong et al., Science 270:1663-7 (1995); van Steensel et al., Cell 92:401-13 (1998)]. TRF1 has a critical role in the regulation of telomere length while TRF2 seems to be important for protecting chromosome ends. Both molecules contain DNA binding domains and dimerization domains and both appear to function as homodimers. Binding of TRFI to telomere repeats inhibits the function of telomerase thus contributing to telomere shortening during replication [van Steensel and de Lange, Nature 385:740-3 (1997)].

An additional molecule, tankyrase, has been identified which modifies TRF1 by the addition of polymers of ADP-ribose [Smith et al., Science 282:1484-7 (1998)].

Tankyrase is structurally and functionally related to the Poly(ADP-Ribose) Polymerase (PARP) molecule, which modifies proteins by the addition of ADP-ribose -3- O polymers [for review see Alvarez-Gonzalez et al., Mol Cell Biochem 138:33-7 (1994)]. The structural relationship to PARP exists in a putative catalytic domain of tankyrase that has extensive amino acid sequence similarity to PARP. In addition, O tankyrase contains a sterile alpha motif (SAM) and 24 ankyrin repeats. These structures are typically involved in protein/protein interactions and at least a portion of the ankyrin repeat region in tankyrase has been shown to be responsible for the N- interaction with TRF1. Tankyrase has been shown to poly ADP-ribosylate TRFI in c vitro and it has been suggested that the role of tankyrase in vivo is to ADP-ribosylate STRFI causing dissociation of TRF1 from the telomere repeats and thus allowing N 10 telomerase to replicate the telomeres. Drugs that inhibit tankyrase activity then might be expected to inhibit the replication of telomeres and thus cause eventual senescence of dividing cell populations such as cancer cells or proliferating immune system cell as examples.

As tankyrase or tankyrase-related gene products might be attractive targets of drug design, there is a need in the art to identify additional molecules with related functions and/or structures. Such molecules might serve as specificity controls for tankyrase targeted drugs or may themselves be suitable targets for drug discovery programs.

In view of the above considerations, it is clear that existing knowledge is lacking with respect to cellular DNA repair mechanisms, signaling, and induction of cellular replication, mechanisms of tumorigenesis, and treatment of cancer disease states. Thus, there exists a need in the art for the identification of additional tankyrase-like molecules for use in determining the selectivity of therapeutics designed to modulate tankyrase function and as targets in their own right for therapeutic intervention in human diseases. The profiling oftankyrase inhibitors on additional tankyrase gene products may allow for the tankyrase-selective drugs, which could be beneficial for particular indications, the reduction of undesirable side effects, or the targeting of therapeutics to selected tissues. Other purposes and advantages of the invention will be readily apparent to the artisan having ordinary skill in the art.

-4- SUMMARY OF THE INVENTION SIt has now been discovered that these and other purposes can be achieved by the present invention, which, in one aspect, provides purified and isolated tankyrase2 Spolypeptides, preferably human tankyrase2 polypeptides. In particular the invention provides a purified and isolated tankyrase2 polypeptide comprising the amino acid sequence defined in SEQ ID NO:133 (designated "TANK2-LONG") or SEQ ID NO:135 (designated "TANK2-SHORT"). The invention also provides polynucleotides encoding the tankyrase2 polypeptides. For example, the polynucleotide may comprise the coding region of the nucleotide sequence defined in CN 10 SEQ ID NO:132 or SEQ ID NO: 134 The invention further provides polynucleotides that are complements to TANK2-encoding polynucleotides, as well as polynucleotides that hybridize under moderately stringent hybridization conditions to the coding or non-coding strand of the tankyrase2 polynucleotides. In a preferred case, the polynucleotide hybridizes to the complement of the polynucleotide defined in SEQ ID NO:132 or SEQ ID NO:134 under stringent hybridization conditions, and encodes a protein that: has poly(ADP) polymerase activity, interacts with damaged DNA, or binds to telomere repeat-binding factors and/or modulates their activity.

The polynucleotides may be DNA molecules or RNA molecules. Certain desirable polynucleotides of the invention, oligonucleotide probes, may further comprise a detectable label moiety.

In another aspect, the invention provides an expression construct, comprising a tankyrase2-encoding polynucleotide, as well as host cells transformed or transfected with the expression constructs. The polynucleotide can be operatively linked to a heterologous promoter.

In a further aspect, the invention provides a method for producing a tankyrase2 polypeptide in a host cell modified to express the tankyrase polypeptide, comprising the steps of: a) growing the host cell under conditions appropriate for expression of 0 the tankyrase2 polypeptide; and tn 5 b) isolating the tankyrase2 polypeptide from the host cell or the medium in which the host cell is grown.

In yet another aspect, the invention provides antibodies that are Simmunoreactive with a tankyrase2 polypeptide. For example, the antibodies may be selected from the group consisting of monoclonal antibodies, polyclonal antibodies, single chain antibodies (scFv antibodies), chimeric antibodies, bifunctional/bispecific N antibodies, humanized antibodies, human antibodies, CDR-grafted antibodies, Fab N fragments, Fab' fragments, fragments, and Fv fragments. Also provided are cell lines that produce such antibodies. There are also provided anti-idiotype antibodies that are immunoreactive with tankyrase2-specific antibodies.

In still another aspect, the invention provides a method for identifying a binding partner of a tankyrase2 polypeptide, comprising: a) contacting the tankyrase2 polypeptide with.a test compound under conditions that permit binding of the tankyrase2 polypeptide and the test compound; b) detecting binding of the test compound and the tankyrase2 polypeptide; and c) identifying the test compound as a binding partner of the tankyrase2 polypeptide.

For example, the method can be used to identify binding partners that selectively or specifically modulate, inhibit or enhance, a biological activity of the tankyrase2 polypeptide.

Also provided in another aspect is a method for identifying a binding partner of a tankyrase2 polynucleotide, comprising: a) contacting the tankyrase2 polynucleotide with a test compound under conditions that permit binding of the tankyrase2 polynucleotide and the test compound; b) detecting binding of the test compound and the tankyrase2 polynucleotide; and c) identifying the test compound as a binding partner of the tankyrase2 polynucleotide.

-6- O The method may be used to identify binding partners that selectively or specifically Smodulate, inhibit or enhance, expression of the tankyrase2 polypeptide.

There is also provided by the invention a method of treating a human or Sanimal subject having a medical condition mediated by poly(ADP-ribose) polymerase activity, comprising administering to the subject a tankyrase2 inhibitory compound in an amount effective for inhibiting tankyrase2 in the subject. In another aspect, the invention provides a method of treating a human or animal subject having a medical ,I condition mediated by poly(ADP-ribose) polymerase activity, comprising administering to the subject a compound that inhibits tankyrase2 expression or i 10 activity in an amount effective for inhibiting poly(ADP-ribose) polymerase activity in the subject. The method is of particular interest in treating medical conditions associated with growth of neoplastic tissue. For example, the method can be used to treat cancers such as carcinomas, sarcomas, leukemias, and lymphomas. More particularly, the method may be used to treat cancers selected from the group consisting of ACTH-producing tumor, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, and Wilm's tumor.

These and other features and advantages of the present invention will be appreciated from the detailed description and examples that are set forth herein. The detailed description and examples are provided to enhance the understanding of the invention, but are not intended to limit the scope of the invention.

in -7- O DETAILED DESCRIPTION OF THE PREFERRED

EMBODIMENTS

The present invention relates generally to a previously uncharacterized nucleic Sacid encoding a novel human protein designated "tankyrase2" (hereinafter also O referred to as "TANK2"). As illustrated herein tankyrase2 is distinct from known tankyrase proteins and other proteins sharing poly(ADP-ribose) polymerase activity.

The present invention is based on the discovery of novel gene encoding the tankyrase2 ,I protein, and nucleic acid sequences, oligonucleotides, fragments, and antisense C, molecules thereof.

The nucleotide sequence information provided by the invention makes C 10 possible large-scale expression of the encoded TANK2 polypeptide by techniques well known and routinely practiced in the art. The invention also permits identification and isolation ofpolynucleotides encoding related TANK2 polypeptides by well-known techniques including Southern (DNA) and/or northern (mRNA) hybridization, and amplification techniques such as polymerase chain reaction (PCR), ligase chain reaction (LCR), and the like. Examples of related polynucleotides include human and non-human tank2 genomic sequences, including allelic variants, as well as polynucleotides encoding polypeptides homologous to TANK2 and structurally related polypeptides sharing one or more biological, immunological, and/or physical properties of TANK2.

The invention includes both naturally occurring and non-naturally occurring tankyrase2 polynucleotides and polypeptide products thereof. Naturally occurring tankyrase2 products include distinct polynucleotide and polypeptide tankyrase2 species as they occur in humans. However, the invention includes other human tankyrase2 polynucleotide and polypeptide species defined through the analysis of sequence homology. The invention further comprises corresponding homologs of human TANK2 polypeptides and tank2 polynucleotides that are expressed in cells of other animal species, preferably mammalian homologs, and more preferably primate homologs. Within each tankyrase2 species, the invention further provides splice variants, which are encoded by the same genomic DNA but arise from distinct mRNA .0 transcripts. Non-naturally occurring tankyrase2 products include variants of the naturally occurring tankyrase2 products such as polynucleotide and polypeptide O analogs wherein one or more nucleotides or amino acids are added, substituted, or deleted). Non-naturally-occurring TANK2 polypeptide products also include TANK2 products that have been covalently modified, water-soluble polymer Smodifications, glycosylation variants, and the like.

The tankyrase2 polypeptides and the nucleic acids that encode the polypeptides provide a basis for diagnostic methods for the precise and accurate I detection and/or quantitation of TANK2 expression and medical conditions associated I with excessive or insufficient TANK2 activity. Furthermore, the nucleotide Ssequences disclosed herein may be used in the detection of aberrations, such as I 10 mutations and deletions, in the gene encoding TANK2. For example, the nucleotide sequences disclosed herein may be used to identify and isolate a genomic sequence for tank2. PCR primers can be designed from various portions of the introns and exons of a genomic tank2 nucleic acid sequence that will allow detection of aberrations in the genomic sequence.

The invention further provides methods of using TANK2 and genetically engineered host cells that express recombinant TANK2 to evaluate and screen for modulators of the poly(ADP-ribose) polymerase activity of the enzyme. Such screening methods may be used for the identification of allosteric agonists and antagonists of TANK2 activity as well as for the identification of direct competitive inhibitors) of such activity. TANK2 protein antagonists and inhibitors, such as anti-TANK2 antibodies and tank2 antisense molecules, will provide the basis for pharmaceutical compositions for the treatment and amelioration of symptoms associated with excessive poly(ADP-ribose) polymerase activity. Agonists of TANK2 will provide the basis of the treatment and amelioration of symptoms associated with insufficient poly(ADP-ribose) polymerase activity.

Tankvrase2 Polvnucleotides The present invention provides, inter alia, novel purified and isolated polynucleotides encoding human TANK2 polypeptides. The polynucleotides of the invention include DNA sequences and RNA transcripts, both sense and complementary antisense strands, and splice variants thereof. DNA sequences of the Sinvention include, without limitation, cDNA and genomic sequences. As used herein, Slower case "tank2" refers to a tankyrase2 nucleic acid sequence whereas upper case "TANK2" refers to a tankyrase2 amino acid sequence.

0 "Nucleic acid" as used herein refers to an oligonucleotide or polynucleotide sequence, and fragments or portions thereof, and to DNA or RNA ofgenomic or synthetic origin, which may be double-stranded or single-stranded, whether representing the sense or antisense strand. An exemplary double-stranded polynucleotide according to the invention can have a first strand a coding strand) Shaving a sequence encoding a TANK2 polypeptide, along with a second strand a C 10 "complementary" or "non-coding" strand) having a sequence deducible from the first strand according to the Watson-Crick base-pairing rules for DNA. Double-stranded or "duplex" structures may be DNA:DNA, DNA:RNA, or RNA:RNA nucleic acids.

A preferred double-stranded polynucleotide is a cDNA comprising the coding region of a nucleotide sequence defined by SEQ ID NO:132 or SEQ ID NO:134. An exemplary single-stranded polynucleotide according to the invention is a messenger RNA (mRNA) encoding a TANK2 polypeptide. Another exemplary single-stranded polynucleotide is an oligonucleotide probe or primer that hybridizes to the coding or non-coding strand of a polynucleotide selected from among the sequences defined by SEQ ID NO:132, and SEQ ID NO:134. Other alternative nucleic acid structures, e.g., triplex structures, are also contemplated.

Genomic DNA of the invention comprises the protein-coding region for a TANK2 polypeptide and includes allelic variants of the preferred polynucleotides of the invention, such as single nucleotide polymorphisms. Genomic DNA of the invention is distinguishable from genomic DNAs encoding polypeptides other than TANK2 in that it includes the TANK2-coding region found in tank2 cDNA of the invention. Genomic DNA can be transcribed into RNA, and the resulting

RNA

transcript may undergo one or more splicing events wherein one or more introns non-coding regions) of the transcript are removed, or "spliced out." RNA transcripts that can be spliced by alternative mechanisms and therefore be subjected to removal of different non-coding RNA sequences but still encode a TANK2 polypeptide, are referred to in the art as "splice variants," and are embraced by the invention. Splice Svariants comprehended by the invention, therefore, are encoded by the same DNA sequences but give rise to different amino acid sequences. Such splice variants can comprise regions in which the reading frame is shifted, wherein a downstream portion of the RNA sequence is translated differently, to yield different amino acid sequences in the resulting polypeptides. Allelic variants are known in the art to be modified forms of the wild-type (predominant) gene sequence. Such modifications result from recombination during chromosomal segregation or exposure to conditions that give rise to genetic mutation. Allelic variants, like wild-type genes, are naturally occurring Ssequences, as opposed to non-naturally occurring variants, which arise from in vitro manipulation.

The invention also comprehends cDNA, which is obtained through reverse transcription of an RNA polynucleotide encoding TANK2 followed by second strand synthesis of a complementary strand to provide a double stranded DNA. For example, the invention provides a cDNA sequence that encodes a polypeptide having an amino acid sequence selected from among the sequences defined by SEQ ID NO:133 and SEQ ID NO:135. In a preferred embodiment, the invention provides polynucleotides comprising the coding region of a nucleotide sequence selected from among the sequences defined by SEQ ID NO: 132 and SEQ ID NO:134.

As noted, highly preferred nucleic acid sequences according to the invention are defined by SEQ ID NO:132 or SEQ ID NO:134. However, because the genetic code is redundant or "degenerate" in its information-encoding properties, different nucleotide sequences may encode the same polypeptide sequence. Accordingly, the invention comprises the alternative (degenerate) nucleotide sequences that encode TANK2 polypeptides of the invention and functional equivalents thereof. For example, the invention includes polynucleotides comprising nucleotide sequences that are substantially homologous to the TANK2-encoding regions of the nucleotide sequences set forth in SEQ ID NO:132 or SEQ ID NO:134. More particularly, the invention includes polynucleotides whose corresponding nucleotide sequences have at least 90%, preferably at least 95%, more preferably at least 98%, and still more preferably at least 99% identity with a nucleotide sequence defined in SEQ ID NO:132 or SEQ ID NO:134.

-11 Variant polynucleotides of the invention further include fragments of the tank2 Snucleotide sequences defined in SEQ ID NO:132 and SEQ ID NO:134, and homologs thereof. The disclosure of full-length polynucleotides encoding TANK2 polypeptides Smakes readily available to the person having ordinary skill in the art every possible fragment of the full-length polynucleotides. Preferably, fragment polynucleotides of the invention comprise sequences unique to the TANK2-coding nucleotide sequence, and therefore hybridize under highly stringent or moderately stringent conditions only specifically) to polynucleotides encoding TANK2 or fragments thereof Scontaining the unique sequence. Polynucleotide fragments of genomic sequences of IN 10 the invention comprise not only sequences unique to the coding region, but also include fragments of the full-length sequence derived from introns, regulatory regions, and/or other untranslated sequences. Sequences unique to polynucleotides of the invention are recognizable through sequence comparison to other known polynucleotides, and can be identified through use of computer software routinely used in the art, alignment programs available in public sequence databases.

The invention also provides fragment polynucleotides that are conserved in one or more polynucleotides encoding members of the TANK2 family of polypeptides. Such fragments include sequences characteristic of the family of TANK2 polypeptides, referred to as "signature" sequences. The conserved signature sequences are readily discernable following simple sequence comparison of polynucleotides encoding members of the TANK2 family. Polynucleotide fragments of the invention can be labeled in a manner that permits their detection, including radioactive and non-radioactive labeling.

Hybridization can be defined to include the process of forming partially or completely double-stranded nucleic acid molecules through sequence-specific association of complementary single-stranded nucleic molecules. The invention, therefore, further encompasses the use of nucleic acid species that hybridize to the coding or non-coding strands of a polyhucleotide that encodes a TANK2 protein.

Preferred hybridizing species hybridize to the coding or non-coding strand of the nucleotide sequence defined by SEQ ID NO:132 or SEQ ID NO:134. Also encompassed are species that would hybridize to a TANK2-encoding polynucleotide 12- O but for the redundancy of the genetic code, polynucleotides that encode the same amino acid sequence but rely on different codon usage.

Hybridizing species include, for example, nucleic acid hybridization or Samplification probes (oligonucleotides) that are capable of detecting nucleotide sequences genomic sequences) encoding TANK2 or closely related molecules, such as alleles. The specificity of the probe, whether it is derived from a highly I conserved, conserved, or non-conserved region or domain, and the stringency of the hybridization or amplification conditions (high, intermediate, or low) will determine whether the probe identifies only naturally occurring tank2, or related sequences.

I 10 Probes for the detection of related nucleotide sequences are selected from conserved or highly conserved regions of tank2 family members and such probes may be used in a pool of degenerate probes. For the detection of identical nucleotide sequences, or where maximum specificity is desired, oligonucleotide probes are selected from the non-conserved nucleotide regions or unique regions of tank2 polynucleotides. As used herein, the term "non-conserved nucleotide region" refers to a nucleotide region that is unique to tank2 disclosed herein and does not occur in related tank2 family members.

Specificity of hybridization is typically characterized in terms of the degree of stringency of the conditions under which the hybridization is performed. The degree of stringency of hybridization conditions can refer to the melting temperature (Tm) of the nucleic acid binding complex [see, Berger and Kimmel, "Guide to Molecular Cloning Techniques," Methods in Enzymology, Vol. 152, Academic Press, San Diego, CA (1987)]. "Maximal stringency" typically occurs at about T, 5°C (5 0 C below the Tm of the probe); "high stringency" at about 5 0 C to 10°C below Tm; "intermediate stringency" at about 10 0 C to 20 0 C below Tm; and "low stringency" at about 20 0 C to 0 C below Tm.

Alternatively, the stringency of hybridization can refer to the physicochemical conditions employed in the procedure. To illustrate, exemplary moderately stringent hybridization conditions are: hybridization in 3X saline sodium citrate (SSC), 0.1% sarkosyl, and 20 mM sodium phosphate, pH 6.8, at 65 0 C; and washing in 2X SSC with 0.1% sodium dodecyl sulfate (SDS), at 65 0 C. Exemplary highly stringent 13- Shybridization conditions are: hybridization in 50% formamide, 5X SSC, at 42°C N overnight, and washing in 0.5X SSC and 0.1% SDS, at 50 0 C. It is understood in the art that conditions of equivalent stringency can be achieved through variation of O temperature and buffer, or salt concentration as described Ausubel et al. (Eds.), Current Protocols in Molecular Biology, John Wiley Sons (1994), at pp.

6.0.3-6.4.10. Modifications in hybridization conditions can be determined empirically or calculated precisely based on the length of the oligonucleotide probe and the i percentage of guanosine/cytosine (GC) base pairing of the probe. The hybridization conditions can be calculated as described in Sambrook et al., Molecular CN 10 Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York (1989), pp. 9.47-9.51.

The artisan will appreciate that hybridization under more stringent conditions enables the identification of species having a higher degree of homology or sequence identity with the target sequence. By contrast, hybridization under less stringent conditions enables identification of species having a lesser but still significant degree of.homology or sequence identity with the target sequence. Therefore, also included within the scope of the present invention are nucleic acid species that are capable of hybridizing to the nucleotide sequence of SEQ ID NO:132 or SEQ ID NO:134 under conditions of intermediate (moderate) to maximal stringency. Preferably, the hybridizing species hybridize to the coding or non-coding strands of a polynucleotide defined by SEQ ID NO:132 or SEQ ID NO:134 under highly stringent conditions.

The polynucleotides of the invention encompass oligonucleotides nucleic acid oligomers typically about 10 to 60 nucleotides in length) that hybridize to either the coding or the non-coding strands of a nucleic acid encoding a TANK2 amino acid sequence. In particular, the invention comprises oligonucleotides that hybridize to the coding or non-coding strand of a polynucleotide defined by SEQ ID NO:132 or SEQ ID NO:134. The length of the oligonucleotide is not critical, as long as it is capable of hybridizing to the target nucleic acid molecule. However, longer nucleic acid molecules are more difficult to prepare and require longer hybridization times.

Therefore, the oligonucleotide should not be longer than necessary. Accordingly, the oligonucleotide should contain at least 10 nucleotides, preferably at least -14nucleotides, and more preferably at least 20 nucleotides. Normally, the oligonucleotide will not contain more than 60 nucleotides, preferably not more than 30 nucleotides, and more preferably not more than 25 nucleotides. Such Soligonucleotides may be used as described herein as primers for DNA synthesis as primers in PCR; "amplimers"), as probes for detecting the presence of target DNA in a sample northern or Southern blots and in situ hybridization), as therapeutic agents in antisense therapy), or for other purposes. Oligonucleotides may be i single- or double-stranded, with the double-stranded forms having one or both ends O blunt or stepped.

c 10 The oligonucleotides may be obtained or derived by known methods from natural sources. Alternatively, the oligonucleotides may be produced synthetically according to methods known in the art. Such methods include, for example, cloning and restriction of appropriate sequences or direct chemical synthesis by any suitable method. Various chemical methods for making oligonucleotides are known in the art, including the phosphotriester method, the phosphodiester method; the diethylphosphoramidite method; the solid support method, and the H-phosphonate method [for reviews, see Caruthers, Science 230:281-5 (1985); Caruthers et al., Methods Enzymol 211:3-20 (1992)]. Typically, preparation of oligonucleotides is carried out by automated phosphoramidite synthesis on polymer support. Nucleic !0 acid molecules consisting of 100 or more nucleotides may also be produced by such methods.

The tank2 polynucleotides of the invention include variants, which are polynucleotides that encode hAPRP2 or a functional equivalent thereof, and which can include deletions, insertions, or substitutions of nucleotide residues. As used herein a "deletion" is a change in a nucleotide or amino acid sequence in which one or more nucleotides or amino acid residues, respectively, are absent. As used herein an "insertion" or "addition" is a change in a nucleotide or amino acid sequence that results in the addition of one or more nucleotides or amino acid residues, respectively.

As used herein a "substitution" is a change in a nucleotide or amino acid sequence in D which one or more nucleotides or amino acids are replaced by different nucleotides or amino acids, respectively.

0 Polynucleotide variants also included within the scope of the present invention are alleles or alternative naturally occurring forms of tank2. Alleles result from naturally occurring mutations, deletions, insertions or substitutions, in the O genomic nucleotide sequence, which may or may not alter the structure or function or the expressed polypeptides. Each of these types of mutational changes may occur alone, or in combination with the others, one or more times in a given allelic sequence. Single nucleotide polymorphisms (SNPs) may occur, in which a single Sbase mutation may define an altered polypeptide, which in turn may be associated Swith an overt phenotypic difference. Of course, SNPs may be silent, as they may not N 10 change the encoded polypeptide, or any change they do encode may have no effect on phenotype.

The invention further embraces natural homologs of the human tankyrase2 DNA that occur in other animal species, such as other mammal species. Mammalian homologs include, for example, homologs in mouse, rat, guinea pig, and the like, and more preferably homologs in other primate species. Such species homologs, in general, share significant homology at the nucleotide level within the protein-coding.

regions. Thus, the invention encompasses polynucleotides that share at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% nucleotide identity with the protein-coding region of a polynucleotide encoding a human TANK2 polypeptide, a polynucleotide defined by SEQ ID NO: 132 or SEQ ID NO: 134. Percent sequence "homology" with respect to polynucleotides of the invention can be defined as the percentage of nucleotide bases in a candidate sequence that are identical to nucleotides in the TANK2-encoding sequence after aligning the sequences and introducing gaps, if necessary, to achieve maximum percent sequence identity. Computer software is available (from commercial and public domain sources) for calculating percent identity in an automated fashion

FASTA).

The invention includes polynucleotides that have been engineered to selectively modify the cloning, processing, and/or expression of the TANK2 gene product. Mutations may be introduced using techniques well known in the art, e.g., site-directed mutagenesis to insert new restriction sites, to alter glycosylation patterns, -16or to change codon preferences inherent in the use of certain expression systems, while simultaneously maintaining control of the amino acid sequence of the expressed polypeptide product. For example, codons preferred by a particular prokaryotic or O eukaryotic host cell can be selected ("codon optimization") to increase the rate of TANK2 expression or to produce recombinant RNA transcripts having desirable properties, such as longer half-lives.

SThe tank2 polynucleotides can be synthesized, wholly or partly, using i chemical methods well known in the art. "Chemically synthesized," as used herein and is understood in the art, refers to purely chemical, as opposed to enzymatic, Ci 10 methods for producing polynucleotides. "Wholly" chemically synthesized

DNA

sequences are therefore produced entirely by chemical means; "partly" chemically synthesized DNAs embrace those wherein only portions of the resulting DNA were produced by chemical means.

DNA molecules may be modified to increase intracellular stability and halflife. Possible modifications include, but are not limited to, the addition of flanking sequences of the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiester linkages within the backbone of the molecule.

The invention also provides TANK2 peptide nucleic acid (PNA) molecules.

These TANK2 PNAs are informational molecules that have a neutral "peptide-like" backbone with nucleobases that allow the molecules to hybridize to complementary TANK2-encoding DNA or RNA with higher affinity and specificity than corresponding oligonucleotides (PerSeptive Biosystems).

Polvpeptide Expression Systems Knowledge of TANK2-encoding DNA sequences enables the artisan to modify cells to permit or increase expression of TANK2. Accordingly, host cells are provided, including prokaryotic or eukaryotic cells, either stably or transiently modified by introduction of a polynucleotide of the invention to permit expression of the encoded TANK2 polypeptide. Autonomously replicating recombinant expression constructs such as plasmid and viral DNA vectors incorporating TANK2-encoding sequences are also provided.

-17- O Expression constructs are also provided comprising TANK2-encoding polynucleotides operatively linked to an endogenous or exogenous expression control DNA sequence and a transcription terminator. Expression control DNA sequences Sinclude promoters, enhancers, and operators, and are generally selected based on the expression systems in which the expression construct is to be used. Preferred promoter and enhancer sequences are generally selected for the ability to increase Sgene expression, while operator sequences are generally selected for the ability to regulate gene expression. Preferred constructs of the invention also include sequences Snecessary for replication in a host cell. Expression constructs are preferably used for N 10 production of an encoded TANK2 polypeptide, but may also be used to amplify the construct itself.

Polynucleotides of the invention may be introduced into the host cell as part of a circular plasmid, or as linear DNA comprising an isolated protein coding region or a viral vector. Methods for introducing DNA in to a host cell include transformation, transfection, electroporation, nuclear injection, or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts. Expression systems of the invention include, for example, bacteria, yeast, fungal, plant, insect, invertebrate, amphibian, and mammalian cell systems. Some suitable prokaryotic host cells include, for example, E. coli strains SG-936, HB 101, W3110, X1776, X2282, DHI, and MRC1, Pseudomonas sp., Bacillus sp. such as B. subtilis, and Streptomyces sp. Suitable eukaryotic host cells include yeasts, such as Saccharomyces cerevisiae, S. pombe, Pichiapastoris and other fungi, insect cells such as sf9 or sf21 cells (Spodoptera frugiperda), animal cells such as Chinese hamster ovary (CHO) cells, human cells such as JY, 293, and NIH3T3 cells, and plant cells such as Arabidopsis thaliana cells.

The tank2 nucleotide sequence, or any portion of it, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of labeled nucleotides and an appropriate RNA polymerase such as T7, T3, or SP6.

0 The type of host cell, the form of the expressed TANK2 product, the conditions of growth, etc., can be selected by the skilled artisan according to known -18criteria. Use of mammalian host cells is expected to provide for such post- Stranslational modifications glycosylation, truncation, lipidation, and phosphorylation) as may be needed to confer optimal biological activity on O recombinant expression products of the invention. Glycosylated and non-glycosylated forms of TANK2 polypeptides are embraced. The protein produced by a recombinant cell may be secreted or may be contained intracellularly, depending on the sequence i and/or the vector used. As will be understood by those of skill in the art, expression vectors containing tank2 can be designed with signal sequences that direct secretion of TANK2 through a particular prokaryotic or eukaryotic cell membrane.

N

I 10 Expression constructs may include sequences that facilitate, and preferably promote, homologous recombination in a host cell. This can be accomplished by replacing all or part of the naturally occurring tank2 promoter with all or part of a heterologous promoter so that the cells express TANK2 at higher levels. The heterologous promoter should be inserted so that it is operatively linked to TANK2encoding sequences. See, for example, PCT International Publication Nos. WO 94/12650, WO 92/20808, and WO 91/09955.

Host cells of the invention are useful in methods for large-scale production of TANK2 polypeptide products. For example, host cells of the invention are a valuable source of immunogen for development of antibodies that are immunoreactive with TANK2 polypeptides. As another example, recombinant TANK2 can be produced and isolate from host cells for use in in vitro binding assays such as drug screening assays. In such methods, the host cells are grown in a suitable culture medium and the desired polypeptide product is isolated from the cells or from the medium in which the cells are grown.

The polypeptide product can be isolated by purification methods known in the art, such as conventional chromatographic methods including immunoaffinity chromatography, receptor affinity chromatography, hydrophobic interaction chromatography, lectin affinity chromatography, size exclusion filtration, cation or anion exchange chromatography, high performance liquid chromatography

(HPLC),

reverse phase HPLC, and the like.

-19- 0 Still other methods of purification include those in which the desired protein is expressed and purified as a fusion protein in which the TANK2 polypeptide is ligated to a heterologous amino acid sequence. Suitable heterologous sequences can include O a specific tag, label, or chelating moiety that is recognized by a specific binding partner or agent. For example, for screening of peptide libraries for modulators of TANK2 activity, it is possible to express a TANK2 protein fused to a selected heterologous protein selected to be specifically identifiable using a probe antibody.

A

fusion protein may also be engineered to contain a cleavage site a factor XA or Senterokinase sensitive sequence) located between the TANK2 sequence and the C 10 heterologous protein sequence, to permit the TANK2 protein to be cleaved from the heterologous protein and subsequently purified. Cleavage of the fusion component may produce a form of the desired protein having additional amino acid residues resulting from the cleavage process.

Exemplary heterologous peptide domains include metal-chelating peptides such as histidine-tryptophan modules that allow purification on immobilized metals [Porath, Protein Expr Purif3:263-81 (1992)], and protein A domains that allow purification on immobilized immunoglobulin. Another useful system is the divalent cation-binding domain and antibodies specific thereto used in the peptide extension/immunoaffinity purification system described in US Patents Nos.

4,703,004; 4,782,137; 4,851,431; and 5,011,912. This system is commercially available as the FLAG® system from Immunex Corp. (Seattle WA). Another suitable heterologous fusion partner is glutathione S-transferase (GST), which can be affinity purified using immobilized glutathione. Other useful fusion partners include immunoglobulins and fragments thereof, Fc fragments.

Identification of host cells expressing recombinant TANK2 may be crucial to identifying appropriate expression systems. Accordingly, expression constructs of the invention may also include sequences encoding one or more selectable markers that permit identification of host cells bearing the construct in operative condition. It is also contemplated that, in addition to the insertion of heterologous promoter

DNA,

amplifiable marker DNA ada, dhfr, and the multifunctional CAD gene that encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the TANK2-encoding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the STANK2-encoding sequences in the cells. Detection of expression of the marker gene in response to induction or selection usually indicates expression of TANK2 as well.

Alternatively, if the tank2 polynucleotide is inserted within a marker gene sequence, Srecombinant cells containing tank2 can be identified by the absence of marker gene C function.

SHost cells that contain the coding sequence for TANK2 and express TANK2 N 10 may also be identified by a variety of other procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridization and protein bioassay or immunoassay techniques that include membrane-based, solution-based, or chip-based technologies for the detection and/or quantification of the nucleic acid or protein.

The presence of the tank2 polynucleotide sequence can be detected by DNA- DNA or DNA-RNA hybridization or amplification using fragments of a tank2 polynucleotide, fragments of the sequences set forth in SEQ ID NO: 132 or SEQ ID NO:134, as probes. Nucleic acid amplification based assays involve the use of oligonucleotides based on the tank2 sequence to detect transformants containing tank2 DNA or RNA. Labeled hybridization or PCR probes for detecting tank2 polynucleotide sequences can be made by various methods, including oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.

In an embodiment of the present invention, TANK2 or a variant thereof and/or a host cell line that expresses the TANK2 or variant thereof may be used to screen for antibodies, peptides, or other molecules, such as organic or inorganic molecules, that act as modulators of a biological or immunological activity of TANK2. For example, anti-TANK2 antibodies capable of neutralizing the polymerase or DNA-binding activity of TANK2 may be used to inhibit TANK2-mediated cell death. Alternatively, screening of peptide libraries or organic libraries made by combinatorial chemistry with recombinantly expressed TANK2 or variants thereof or cell lines expressing TANK2 or variants thereof may be useful for identification of therapeutic molecules -21 Sthat function by modulating a biological or immunological activity of TANK2.

Synthetic compounds, natural products, and other sources of potentially biologically active materials can be screened in a number of ways deemed routine by those of skill O in the art. For example, nucleotide sequences encoding the DNA-binding domain of TANK2 may be expressed in a host cell, which can be used for screening of allosteric modulators, either agonists or antagonists, of TANK2 activity. Alternatively, Snucleotide sequences encoding the conserved catalytic domain of TANK2 can be Sexpressed in host cells and used to screen for inhibitors of ADP-ribose Spolymerization.

CI TANK2 Polvpeptides The invention also provides purified and isolated mammalian TANK2 polypeptides. Exemplary TANK2 polypeptides have amino acid sequences defined in SEQ ID NO:133 or SEQ ID NO:135. TANK2 polypeptides of the invention may be isolated from natural cell sources or may be chemically synthesized, but are preferably produced by recombinant procedures involving host cells of the invention. TANK2 products of the invention may be full-length polypeptides, or variant polypeptide products such as fragments, truncates, deletion mutants, and other variants thereof that retain specific TANK2 biological activity. As used herein, "biologically active" refers to a TANK2 polypeptide having structural, regulatory or biochemical functions of the naturally occurring TANK2 protein. Specifically, a TANK2 protein of the present invention has the ability to bind DNA and to polymerize ADP-ribose subunits in response to DNA damage in a cell.

The protein and fragments of the present invention may be prepared by methods known in the art. Such methods include isolating the protein directly from cells, isolating or synthesizing DNA encoding the protein and using the DNA to produce recombinant protein, and synthesizing the protein chemically from individual amino acids.

The TANK2 polypeptides can be isolated from a biological sample, such as a W0 solubilized cell fraction, by standard methods. Some suitable methods include precipitation and liquid chromatographic protocols such as ion exchange, hydrophobic -22interaction, and gel filtration [see, Deutscher Methods Enzymol (Guide to Protein Chemistry, Section VII) 182:309 (1990) and Scopes, Protein Purification, Springer-Verlag, New York (1987)]. Alternatively, purified material is obtained by O separating the protein on preparative SDS-PAGE gels, slicing out the band of interest and electroeluting the protein from the polyacrylamide matrix by methods known in the art. The detergent SDS is removed from the protein by known methods, such as N by dialysis or the use of a suitable column, such as the Extracti-Gel® column from CN Pierce Chemical Co. (Rockford, IL).

SThe TANK2 polypeptide of the invention may also be chemically synthesized, 10 wholly or partly, by methods known in the art [see, Stuart and Young, Solid Phase Peptide Synthesis, 2d ed., Pierce Chemical Co. (1984)]. For example, peptides can be synthesized by solid phase techniques, cleaved from the resin, and purified by preparative HPLC [see, Roberge et al.,.Science 269:202-4 (1995)]. Automated synthesis may be accomplished, for example, using the ABI 431 A Peptide Synthesizer (Perkin Elmer, Norwalk, CT) in accordance with the instructions provided by the manufacturer. The composition of the synthetic peptides may be confirmed by amino acid analysis or sequencing the Edman degradation procedure).

Recombinant TANK2 protein may be produced in and isolated from a host cell transformed with an expression vector containing a tank2 nucleotide sequence and grown in cell culture. As described herein, the host cells, either prokaryotic or eukaryotic, are either stably or transiently transfected (eukaryotic) or transformed (prokaryotic) with a TANK2-encoding polynucleotide of the invention in manner that permits directed expression of a TANK2 polypeptide. In such methods, the host cells are grown in a suitable culture medium and the desired polypeptide products are isolated from the cells or from the medium in which the cells are grown. Isolation of the polypeptides can be accomplished by, for example, immunoaffinity purification.

The use of transformed host cells is preferred for large-scale production of TANK2 polypeptides.

The invention includes polypeptides comprising amino acid sequences that are substantially homologous to the sequences of TANK2 polypeptides described herein.

For example, the invention includes polypeptides whose corresponding amino acid -23- O sequences have at least 90%, preferably at least 95%, more preferably at least 98%, and still more preferably at least 99% identity with the polypeptide sequence defined c' in SEQ ID NO:133 or SEQ ID NO:135.

O Percent sequence "identity" with respect to a preferred polypeptide of the invention can be defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference TANK2 sequence ci after aligning the sequences and introducing gaps, if necessary, to achieve maximum I percent sequence identity, and not considering any conservative substitutions as part Sof the sequence identity.

CI 10 Percent sequence "homology" with respect to a preferred polypeptide of the invention can be defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference TANK2 sequence after aligning the sequences and introducing gaps, if necessary, to achieve maximum percent sequence identity, and also considering any conservative substitutions as part of the sequence identity.

Determinations of whether two amino acid sequences are substantially homologous can also be based on FASTA searches [Pearson et al., Proc Natl Acad Sci USA 85:2444-8 (1988)]. Alternatively, percent homology is calculated as the percentage of amino acid residues in the smaller of the two sequences that align with identical amino acid residues in the sequence being compared, when four gaps in a length of 100 amino acids may be introduced to maximize alignment [see Dayhoff, in Atlas ofProtein Sequence and Structure, Vol. 5, National Biochemical Research Foundation, Washington, D.C. (1972), at p. 124].

A polypeptide may be considered homologous to a TANK2 polypeptide of the invention ifpolynucleotides encoding the two polypeptides hybridize with one another. A higher degree of homology is shown if the hybridization occurs under hybridization conditions of greater stringency. Control of hybridization conditions and the relationships between hybridization conditions and degree of homology are understood by those skilled in the art [see, Sambrook et al., supra]. Thus, a -24homologous polypeptide may be a polypeptide that is encoded by a polynucleotide Sthat hybridizes with a polynucleotide encoding a polypeptide of the invention under hybridization conditions having a specified degree of stringency.

O It may be desirable that such structurally homologous polypeptides will also exhibit functional homology, insofar as the homologous polypeptide has substantially the same function as the polypeptide of the invention. For example, structurally homologous polypeptides may be considered functionally homologous if they exhibit similar binding of a ligand, or similar immune reactivity, etc.

However, it is known that two polypeptides or two polynucleotides may be N 10 considered to be substantially homologous in structure, and yet differ substantially in function. For example, single nucleotide polymorphisms (SNPs) among alleles may be expressed as polypeptides having substantial differences in function along one or more measurable parameters such as antibody- or ligand-binding affinity or enzymatic substrate specificity, and the like. Other structural differences, such as substitutions, deletions, splicing variants, and the like, may affect the function of otherwise structurally identical or homologous polypeptides.

The TANK2 polypeptides of the invention include functional derivatives of a TANK2 polypeptides defined in SEQ ID NO:133 or SEQ ID NO:135. Such functional derivatives include polypeptide products that possesses a structural feature or a biological activity that is substantially similar to a structural feature or a biological activity of the TANK2 protein. Accordingly, functional derivatives include variants, fragments, and chemical derivatives of the parent TANK2 protein.

As used herein "variant" refers to a molecule substantially similar in structure and function to either the entire TANK2 molecule, or to a fragment thereof. A molecule is said to be "substantially similar" to another, if both molecules have substantially similar structures or if both molecules possess a similar biological activity. Thus, provided that two molecules possess a similar activity, they are considered variants, as that term is used herein, even if one of the molecules possesses a structure not found in the other molecule, or if the sequence of amino acid residues is not identical.

Among the variant polypeptides provided under the invention are variants that Scomprise one or more changes in the amino acid sequence of the TANK2 polypeptide.

Such sequence-based changes include deletions, substitutions, or insertions in the TANK2 sequence, as well as combinations thereof.

SDeletion variants of the TANK2 polypeptides are polypeptides in which at least one amino acid residue of the sequence is removed. Deletions can be effected at one or both termini of the protein, or with removal of one or more residues within the c- TANK2 amino acid sequence. Deletion variants include, for example, all incomplete N fragments of the TANK2 polypeptides of the invention. As used herein "fragment" refers to any polypeptide subset of the TANK2 protein.

"N 10 Fragments of TANK2 that exhibit a biological activity characteristic of TANK2 and that are soluble not membrane bound) are desirable. A soluble fragment is preferably generated by deleting any membrane-spanning region(s) of the parent molecule or by deleting or substituting hydrophilic amino acid residues for hydrophobic residues. Identification of such residues is well known in the art.

Substitution variants are provided, including polypeptides in which at least one amino acid residue of a TANK2 polypeptide is replaced by an alternative residue.

Any substitution can be made, with conservative substitutions being preferred.

Directed amino acid substitutions may be made based on well defined physicochemical parameters of the canonical and other amino acids the size, shape, polarity, charge, hydrogen-bonding capacity, solubility, chemical reactivity, hydrophobicity, hydrophilicity, or the amphipathic character of the residues.) as well as their contribution to secondary and tertiary protein structure. Substitution variants can include polypeptides comprising one or more conservative amino acid substitutions, a substitution of one amino acid by another having similar physicochemical character as desired. To illustrate, the canonical amino acids can be grouped according to the following categories: Aliphatic Side Chains Gly, Ala; Val, Leu, lie Aromatic Side Chains Phe, Tyr, Trp Aliphatic Hydroxyl Side Chains Ser, Thr Basic Side Chains Lys, Arg, His Acidic Side Chains Asp, Glu Amide Side Chains Asn, Gin Sulfur-Containing Side Chains Cys, Met Secondary Amino Group Pro -26- Substitutions are preferably made in accordance with the following Table I when it is Sdesired to controllably define the characteristics of the TANK2 molecule.

TABLE 1 O Exemplary Conservative Original Residue Substitutions Ala gly; ser Arg lys S 1 Asn gin; his l 0 Asp glu Cys ser SGin asn C Glu asp Gly ala; pro His asn; gin Ile leu; val Leu ile; val Lys arg; gin; glu Met leu; tyr; ile Phe met; leu; tyr Ser thr Thr ser Trp tyr Tyr trp; phe Val ile; leu Substantial changes in functional or immunological identity are made by selecting substitutions that are more progressive than those in Table 1, selecting residues that differ more significantly in their effect on maintaining the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. The substitutions that are in general more progressive are those in which: glycine and/or proline is substituted by another amino acid or is deleted or inserted; a hydrophilic residue is substituted for a hydrophobic residue; a cysteine residue is substituted for (or by) any other residue; a residue having an electropositive side chain is substituted for (or by) a residue having an electronegative charge; or a residue having a bulky side chain is substituted for (or -27by) one not having such a side chain. Most preferred are amino acid substitutions that affect the solubility of TANK2. These are most preferably generated by substituting hydrophilic for hydrophobic amino acids.

O Substitution variants, however, can include non-canonical or non-naturally occurring amino acid residues substituted for amino acid residues in the principal sequence. Substitution variants include those polypeptides in which amino acid Ssubstitutions have been introduced by modification ofpolynucleotides encoding a cN TANK2 polypeptide.

Insertion variants are provided, in which at least one amino acid residue is N 10 present in addition to a TANK2 amino acid sequence. Insertions may be located at either or both termini of the polypeptide, or may be positioned within the TANK2 amino acid sequence. Insertional variants also include fusion proteins in which the amino or carboxy terminus of the TANK2 polypeptide is fused to another polypeptide.

Examples of such fusion proteins include immunogenic polypeptides, proteins with long circulating half-life immunoglobulin constant regions), marker proteins green fluorescent protein) and proteins or polypeptides that facilitate purification of the desired TANK2 polypeptide FLAG® tags or polyhistidine sequences).

Another example of a terminal insertion is a fusion of a signal sequence, whether heterologous or homologous to the host cell, to the N-terminus of the molecule to facilitate the secretion of the derivative from recombinant hosts. Intrasequence insertions insertions within a TANK2 molecule sequence) may range generally from about 1 to 10 residues, more preferably 1 to Polypeptide variants of the invention also include mature TANK2 products, TANK2 products wherein leader or signal sequences are removed, as well as products having additional amino terminal residues. TANK2 products having an additional methionine residue at position -1 (Met-'-TANK2) are contemplated, as are TANK2 products having additional methionine and lysine residues at positions -2 and respectively (Met-'-Lys-'-TANK2). Other such variants are particularly useful for recombinant protein production in bacterial host cells.

-28- SThe invention also encompasses TANK2 variants having additional amino acid residues resulting from use of specific expression systems. For example, use of commercially available vectors that express a desired polypeptide as a glutathione-S- 0 transferase (GST) fusion product yields the desired polypeptide having an additional glycine residue at position -1 (Gly'-TANK2) upon cleavage of the GST component from the desired polypeptide. Variants that result from expression in other vector CN systems are also contemplated.

SThe invention further provides TANK2 polypeptide products that are chemical derivatives of a TANK2 polypeptide defined in SEQ ID NO:133 or SEQ ID NO:135.

N 10 As used herein, the term "chemical derivative" refers to molecules that contain additional chemical moieties that are not normally a part of the naturally occurring molecule. Such moieties may impart desirable properties to the derivative molecule, such as increased solubility, absorption, biological half-life, etc. The moieties may alternatively decrease the toxicity of the derivative molecule, or eliminate or attenuate any undesirable side effect of the derivative molecule. Thus, chemical derivatives of TANK2 polypeptides include polypeptides bearing modifications other than (or in addition to) insertion, deletion or substitution of amino acid residues. Preferably, the modifications are covalent in nature, and include, for example, chemical bonding with polymers, lipids, non-naturally occurring amino acids, and other organic and inorganic moieties. Derivatives of the invention may be prepared to increase circulating halflife of a TANK2 polypeptide, or may be designed to improve targeting capacity for the polypeptide to desired cells, tissues, or organs.

For example, methods are known in the art for modifying a polypeptide to include one or more water-soluble polymer attachments such as polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. Particularly preferred are TANK2 products that have been covalently modified with polyethylene glycol (PEG) subunits.

Water-soluble polymers may be bonded at specific positions, for example at the amino terminus of the TANK2 products, or randomly attached to one or more side chains of the polypeptide. Additional derivatives include TANK2 species -29- O immobilized on a solid support, pin microparticle, or chromatographic resin, as well as TANK2 species modified to include one or more detectable labels, tags, chelating agents, and the like. l-- SDerivatization with bifunctional agents can be used to cross-link TANK2 to a water-insoluble support matrix. Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and reactive substrates may be Semployed for protein immobilization [see, US Patent Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440.] SExpression of TANK2 variants can be expected to have utility in investigating a biological activity characteristic of a wild-type TANK2 polypeptide. TANK2 variants can be designed to retain all biological or immunological properties characteristic for TANK2, or to specifically disable one or more particular biological or immunological properties of TANK2. For example, fragments and truncates may be designed to delete a domain associated with a particular property, or substitutions and deletions may be designed to inactivate a property associated with a particular domain. Forced expression (overexpression) of such variants ("dominant negative" mutants) can be employed to study the function of the protein in vivo by observing the phenotype associated with the mutant.

Functional derivatives of TANK2 having up to about 100 residues may be conveniently prepared by in vitro synthesis. If desired, such fragments may be modified using methods known in the art by reacting targeted amino acid residues of the purified or crude protein with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues. The resulting covalent derivatives may be used to identify residues important for biological activity.

Functional derivatives of TANK2 having altered amino acid sequences can also be prepared by mutating the DNA encoding TANK2. Any combination of amino acid deletion, insertion, and substitution may be employed to generate the final O construct, provided that the final construct possesses the desired activity. Obviously, the mutations that will be made in the DNA encoding the functional derivative must not place the sequence out of reading frame and preferably will not create O complementary regions that could produce secondary mRNA structure [see EP Patent Publication No. 75,444].

While the site for introducing a variation in the amino acid sequence is predetermined, the mutation per se need not be predetermined. For example, to optimize the performance of a mutation at a given site, random mutagenesis, such as Slinker scanning mutagenesis, may be conducted at a target codon or target region to I 10 create a large number of derivative which could then be expressed and screened for the optimal combination of desired activity. Alternatively, site-directed mutagenesis or other well-known technique may be employed to make mutations at predetermined sites in a DNA known sequence.

The technique of site-directed mutagenesis is well known in the art [see, e.g., Sambrook et al., supra, and McPherson Directed Mutagenesis: A Practical Approach, IRL Press, Oxford (1991)]. Site-directed mutagenesis allows the production of TANK2 functional derivatives through use of specific oligonucleotide sequences that encode the DNA sequence of the desired mutation. Site-directed mutagenesis methods and materials are commercially available, the QuikChangeT kit available from Stratagene (La Jolla, CA). One can selectively generate precise amino acid deletions, insertions, or substitutions using this method.

Amino acid sequence deletions generally range from about 1 to 30 residues, more preferably 1 to 10 residues, and typically are contiguous. The most preferred deletions are those that are performed to generate catalytic fragments or DNA-binding fragments.

Mutations designed to increase the affinity of TANK2 may be guided by the introduction of the amino acid residues that are present at homologous positions in other poly(ADP-ribose) polymerase proteins. Similarly, such mutant TANK2 molecules may be prepared that lack residues of a functional domain, the catalytic domain, to create a dominant negative protein.

-31 0 It is difficult to predict a priori the exact effect any particular modification, substitution, deletion, insertion, etc., will have on the biological activity of TANK2. However, one skilled in the art will appreciate that the effect will be O evaluated by routine screening assays. For example, a derivative typically is made by linker scanning site-directed mutagenesis of the DNA encoding the native TANK2 molecule. The derivative is then expressed in a recombinant host, and, optionally, ,i purified from the cell culture, for example, by immunoaffinity chromatography. The I activity of the cell lysate or the purified derivative is then screened in a suitable screening assay for the desired characteristic. For example, a change in the tIN 10 immunological character of the functional derivative, such as affinity for a given antibody, is measured by a competitive type immunoassay. Changes in other parameters of the expressed product may be measured by the appropriate assay.

Antibodies The present invention provides antibodies that bind with specificity to a TANK2 polypeptide. An "antibody" as used herein is defined broadly as a protein that characteristically immunoreacts with an epitope (antigenic determinant) that is characteristic of the TANK2 polypeptide. As used herein, an antibody is said to "immunoreact" with an antigen such as a polypeptide if the antibody specifically recognizes and binds an epitope that is characteristic of the antigen by way of one or more variable regions or one or more of the complementarity determining regions (CDRs) of the antibody.

An antibody that is immunoreactive with a given polypeptide may exhibit cross-reactivity to another polypeptide if the two polypeptides each comprise a common structural feature that defines the same characteristic epitope. In the case of related polypeptides, cross-reactivity can correlate to common structural features such as sequence identity, homology, or similarity found among the related polypeptides.

Accordingly, families of polypeptides can often be identified by a cross-reactive antibody, an antibody that immunoreacts with some or all of the members of the polypeptide family sharing the common epitope. Thus, the invention encompasses antibodies that immunoreact with a particular member of the TANK2 family of -32polypeptides, a polypeptide comprising the amino acid sequence defined by SEQ ID NO:133 or SEQ ID NO:135. The invention further encompasses antibodies that immunoreact with some or all members of the TANK2 family of polypeptides.

O Screening assays to determine the binding specificity of an antibody are well known and routinely practiced in the art [see, Harlow et al. Antibodies:

A

Laboratory Manual, Ch. 6, Cold Spring Harbor Laboratory, Cold Spring Harbor NY (1988)]. The immunoreactive specificity with which an antibody binds to a given polypeptide antigen is to be distinguished from interactions with other proteins, e.g., SStaphylococcus aureus protein A or other antibodies in ELISA techniques, that are N 10 mediated through parts of the antibody other than the variable regions, in particular the constant regions of the antibody.

Antibodies include, for example, monoclonal antibodies, polyclonal antibodies, single chain antibodies (scFv antibodies), chimeric antibodies, multifunctional/multispecific bifunctional or bispecific) antibodies, humanized antibodies, human antibodies, and CDR-grafted antibodies (including moieties that include CDR sequences that specifically immunoreact with a polypeptide of the invention). Antibodies according to the invention also include antibody fragments, so long as they exhibit the desired biological activity. "Antibody fragments" comprise a portion of a full-length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab') 2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

Antibodies of the invention can be produced by any method known in the art.

For example, polyclonal antibodies are isolated from mammals that have been immunized against the protein or a functional analog in accordance with methods known in the art. Briefly, polyclonal antibodies may be produced by injecting an immunogenic TANK2 polypeptide (immunogen) into a host mammal rabbit, mouse, rat, or goat). Adjuvants may be employed to increase the immune response.

Sera from the host mammal are extracted and screened to obtain polyclonal antibodies that are specific for (immunoreact with) the TANK2 polypeptide.

-33- Monoclonal antibodies (also referred to herein as "mAbs") are preferred. As used herein "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, the individual antibodies comprising the O population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific ("monospecific"), being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

C

N 10 The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

Monoclonal antibodies may be prepared using any suitable technique capable of yielding a continuous cell line producing a homogeneous antibody. Such methods include the immunological method [K6hler and Milstein, Nature 256:495-7 (1975); Campbell, "Monoclonal antibody technology, the production and characterization of rodent and human hybridomas" in Burdon et al. Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 13, Elsevier Science Publishers, Amsterdam (1985)] or any similar method. Monoclonal antibodies may also be isolated from phage antibody libraries [Clackson et al., Nature 352:624-8 (1991); Marks et al., JMol Biol 222:581-97 (1991)].

To illustrate, to produce monoclonal antibodies a host mammal is immunized by injection of an immunogenic TANK2 polypeptide, and then boosted. Spleens are collected from immunized mammals a few days after the final boost. Cell suspensions from the spleens are fused with a tumor cell line to create immortalized hybrid cell lines or "hybridomas." Individual clones can be isolated by limiting dilution and then tested for the specificity of the antibodies they produce. Selected cells can then be grown, by the ascites method, to provide a continuous source of the desired homogeneous antibody.

34o Antibodies can be engineered using genetic techniques to produce chimeric antibodies including protein components from two or more species. For use in in vivo applications with a human subject, the antibody can be "humanized," modified to O contain an antigen binding region from one species, a rodent, with the bulk of the antibody replaced with sequences derived from human immunoglobulin. In one method, the non-human CDRs of one species a mouse or rabbit, are inserted into a framework sequence of another species, a human, or into a consensus framework sequence. Further changes can then be introduced into the antibody Sframework to modulate affinity or immunogenicity of the engineered antibody.

CI 10 Methods are also known for inducing expression of engineered antibodies in various cell types, such as mammalian and microbial cell types. Numerous techniques for preparing engineered antibodies are described in the art Owens and Young, J Immunol Meth 168:149-65 (1994)].

Antibodies further include recombinant polyclonal or monoclonal Fab fragments Huse et al., Science 246:1275-81 (1989)]. Alternatively, techniques described for the production of single chain antibodies US Patent No.

4,946,778] can be adapted to produce TANK2-specific single chain antibodies single chain Fv fragments; abbreviated "scFv"). Rapid, large-scale recombinant methods for generating antibodies may be employed, such as phage display or ribosome display methods, optionally followed by affinity maturation [see, e.g., Ouwehand et al., Vox Sang 74 (Suppl 2):223-32 (1998); Rader et al., Proc Natl Acad Sci USA 95:8910-5 (1998); Dall'Acqua et al., Curr Opin Struct Biol 8:443-50 (1998)].

Fully human antibodies are especially preferred for therapeutic use in humans, but.they are typically difficult to produce. For example, when the immunogen is a human self-antigen, a human will typically not produce any immune response to the antigen. Methods for making fully human antibodies have been developed and are known in the art. Accordingly, fully human antibodies can be produced by using an immunogenic TANK2 polypeptide to immunize an animal mouse) that has been transgenically modified to express at least a significant fraction of the human repertoire of immunoglobulin genes [see, Bruggemann et al., Immunol Today 17:391-7 (1996)].

O As noted herein, host cells of the invention are a valuable source of immunogen for development of antibodies specifically immunoreactive with TANK2.

STo be useful as an immunogen for the preparation of polyclonal or monoclonal Santibodies, a TANK2 peptide fragment must contain sufficient amino acid residues to define an immunogenic epitope. If the fragment is too short to be immunogenic per se, it may be conjugated to a carrier molecule. Suitable carrier molecules include, for ,I example, keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA).

I Conjugation may be carried out by methods known in the art. One such method is to combine a cysteine residue of the fragment with a cysteine residue on the carrier I 10 molecule.

Antibodies of the invention are useful for therapeutic methods (by modulating activity of TANK2), diagnostic methods (by detecting TANK2 in a sample), as well as purification of TANK2. The antibodies are particularly useful for detecting and/or quantitating TANK2 expression in cells, tissues, organs, and lysates and extracts thereof, as well as in fluids such as serum, plasma, cerebrospinal fluid, urine, sputum, peritoneal fluid, pleural fluid, or bronchoalveolar lavage fluid. Kits comprising an antibody of the invention for any of the purposes described herein are also contemplated. In general, a kit of the invention also includes a control antigen with which the antibody immunoreacts, and may further include other reagents, containers, and package inserts.

Further, the invention includes neutralizing antibodies, antibodies that significantly inhibit or impair a biological activity of the proteins or functional analogs of the invention. In particular, neutralizing antibodies inhibit or impair the poly(ADP-ribose) polymerase activity of TANK2. Neutralizing antibodies may be especially desirable for therapeutic and diagnostic applications.

Functional equivalents further include fragments of antibodies that have the same binding characteristics as, or that have binding characteristics comparable to, those of the whole antibody. Such fragments may contain one or both Fab fragments or the fragment. Preferably, the antibody fragments contain all six complement determining regions ("CDRs") of the whole antibody, although fragments containing fewer than all of such regions, such as three, four, or five CDRs, -36may also be functional. Fragments may be prepared by methods described in the art Lamoyi et al., JImmunol Meth 56:235-43 (1983); Parham, Jlmmunol 131:2895-902 (1983)].

O Moreover, specific binding proteins can be developed using isolated or recombinant TANK2 products, TANK2 variants, or cells expressing such products.

Binding proteins are useful for purifying TANK2 products and detection or quantification of TANK2 products in fluid and tissue samples using known immunological procedures. Binding proteins are also manifestly useful in modulating blocking, inhibiting, or stimulating) biological activities of TANK2 CI 10 polypeptides, especially those activities involved in signal transduction. Thus, neutralizing antibodies that inhibit the activity of TANK2 polypeptides are provided.

Anti-idiotypic antibodies specific for anti-TANK2 antibodies are also contemplated.

Detectable Polvnucleotide and Polvpeptide Probes The present invention further provides a method of detecting the presence of a TANK2-encoding polynucleotide or a TANK2 polypeptide in a sample. The method involves use of a labeled probe that recognizes the presence of a defined target in the sample. The probe may be an antibody that recognizes a TANK2 polypeptide, or an oligonucleotide that recognizes a polynucleotide encoding TANK2 polypeptide.

The probes of the invention can be detectably labeled in accordance with methods known in the art. In general, the probe can be modified by attachment of a detectable label (reporter) moiety to the probe, or a detectable probe can be manufactured with a detectable label moiety incorporated therein. The detectable label moiety can be any detectable moiety, many of which are known in the art, including radioactive atoms, electron dense atoms, enzymes, chromogens and colored compounds, fluorogens and fluorescent compounds, members of specific binding pairs, and the like.

Methods for labeling oligonucleotide probes have been described in the art [see, Leary et al., Proc NatlAcadSci USA 80:4045-49 (1983); Renz and Kurz, ;0 Nucleic Acids Res 12:3435-44 (1984); Richardson and Gumport, Nucleic Acids Res 11:6167-84 (1983); Smith et al., Nucleic Acids Res 13:2399-412 (1985); Meinkoth -37and Wahl, Anal Biochem 138:267-84 (1984); and US Patent Nos. 4,711,955; 4,687,732; 5,241,060; 5,244,787; 5,328,824; 5,580,990; and 5,714,327].

Methods for labeling antibodies have been also been described [see, e.g., O Hunter et al., Nature 144:495-6 (1962); David et al., Biochemistry 13:1014-21 (1974); and US Patent Nos. 3,940,475 and 3,645,090].

The label moiety may be radioactive. Some examples of useful radioactive labels include P, 125, 1311, and 3 H. Use of radioactive labels has been described SUK patent document 2,034,323 and US Patent Nos. 4,358,535 and 4,302,204].

Some examples of non-radioactive labels include enzymes, chromogens, I 10 atoms and molecules detectable by electron microscopy, and metal ions detectable by their magnetic properties.

Some useful enzymatic labels include enzymes that cause a detectable change in a substrate. Some useful enzymes (and their substrates) include, for example, horseradish peroxidase (pyrogallol and o-phenylenediamine), beta-galactosidase (fluorescein beta-D-galactopyranoside), and alkaline phosphatase (5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium). The use of enzymatic labels has been described in the art [see, UK patent document 2,019,404, European patent document EP 63,879, and Rotman, Proc Natl Acad Sci USA 47:1981-91 (1961)].

Useful reporter moieties include, for example, fluorescent, phosphorescent, chemiluminescent, and bioluminescent molecules, as well as dyes. Some specific colored or fluorescent compounds useful in the present invention include, for example, fluoresceins, coumarins, rhodamines, Texas red, phycoerythrins, umbelliferones, Luminol®, and the like. Chromogens or fluorogens, molecules that can be modified oxidized) to become colored or fluorescent or to change their color or emission spectra, are also capable of being incorporated into probes to act as reporter moieties under particular conditions.

The label moieties may be conjugated to the probe by methods that are well known in the art. The label moieties may be directly attached through a functional group on the probe. The probe either contains or can be caused to contain such a -38functional group. Some examples of suitable functional groups include, for example, amino, carboxyl, sulfhydryl, maleimide, isocyanate, isothiocyanate.

Alternatively, label moieties such as enzymes and chromogens may be O conjugated to antibodies or nucleotides by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like.

The label moiety may also be conjugated to the probe by means of a ligand attached to the probe by a method described above and a receptor for that ligand attached to the label moiety. Any of the known ligand-receptor binding pair Scombinations is suitable. Some suitable ligand-receptor pairs include, for example, NI 10 biotin-avidin or -streptavidin, and antibody-antigen. The biotin-streptavidin combination may be preferred.

Methods of Using Tankvrase2 Polvnucleotides and Polypeptides The scientific value of the information contributed through the disclosures of DNA and amino acid sequences of the present invention is manifest. As one series of examples, knowledge of the sequence of a cDNA for tank2 makes possible through use of Southern hybridization or polymerase chain reaction (PCR) the identification of genomic DNA sequences encoding TANK2 and TANK2 expression control regulatory sequences. DNA/DNA hybridization procedures carried out with DNA sequences of the invention under moderately to highly stringent conditions are also expected to allow the isolation of DNAs encoding allelic variants of TANK2.

Similarly, non-human species genes encoding proteins homologous to TANK2 can also be identified by Southern and/or PCR analysis. As an alternative, complementation studies can be useful for identifying other human TANK2 products as well as non-human proteins, and DNAs encoding the proteins, sharing one or more biological properties of TANK2. Oligonucleotides of the invention are also useful in hybridization assays to detect the capacity of cells to express TANK2.

Polynucleotides of the invention may also be the basis for diagnostic methods useful for identifying a genetic alteration in the tank2 locus that underlies a disease state.

W0 For example, the differential expression or activity of TANK2-LONG and TANK2- SHORT may be capable of correlation with particular disease state(s), rendering one -39- Sor both forms of TANK2 suitable as diagnostic markers or as therapeutic targets as described herein. Therefore, selective reagents, oligonucleotides that selectively Shybridize to one form of tank2 or antibodies that selectively immunoreact with one Sform of TANK2, may be especially useful.

Oligonucleotides of the invention, as described herein, may be used in methods to amplify DNA for various purposes. "Amplification" according to the I method of the invention refers to any molecular biology technique for detection of trace levels of a specific nucleic acid sequence by exponentially amplifying a template Snucleic acid sequence. In particular, suitable amplification techniques include such I 10 techniques as the polymerase chain reaction (PCR), the ligase chain reaction (LCR) and variants thereof. PCR is known to be a highly sensitive technique, and is in wide use [see, Innis et al., PCR Protocols: A Guide to Methods and Applications, Academic Press, Inc., San Diego (1990); Dieffenbach and Dveksler, PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Plainview NY (1995); and US Patents Nos. 4,683,195; 4,800,195; and 4,965,188]. The more recently developed LCR technique is known to be highly specific, and is capable of detecting point mutations [see, Landegren et al., Science 241:1077-80 (1988) and Barany et al., PCR Methods and Applications 1:5-16 (1991)]. An LCR kit is available from Stratagene. In certain circumstances, it is desirable to couple the PCR and LCR techniques to improve precision of detection. Other amplification techniques may be employed in accordance to the invention.

Oligonucleotide amplification primers are often provided as matched pairs of single-stranded oligonucleotides; one with sense orientation and one with antisense orientation. Such specific primer pairs can be employed under optimized conditions for identification of a specific gene or condition. Alternatively, the same primer pair, nested sets of oligomers, or even a degenerate pool of oligomers, may be employed under less stringent conditions for detection and/or quantitation of closely related DNA or RNA sequences.

Such oligonucleotides can be used in various methods known in the art to extend the specified nucleotide sequences. These methods permit use of a known 0 sequence to determine unknown adjacent sequence, thereby enabling detection and determination of upstream sequences such as promoters and regulatory elements.

For example, restriction-site polymerase chain reaction is a direct method that 0 uses universal primers to retrieve unknown sequence adjacent to a known locus [see, Gobinda et al., PCR Methods Applic 2:318-22 (1993)]. In this method, genomic DNA is first amplified in the presence of primer to a linker sequence and a primer c, specific to the known region. The amplified sequences are subjected to a second Sround of PCR with the same linker primer and another specific primer internal to the first one. Products of each round of PCR are transcribed with an appropriate RNA Cl 10 polymerase and sequenced using reverse transcriptase.

Inverse PCR can be used to amplify or extend sequences using divergent primers based on a known region [Triglia et al., Nucleic Acids Res 16:8186 (1988)].

The primers may be designed using Oligo 4.0 (National Biosciences, Inc., Plymouth, MN), or another appropriate program, to be 22-30 nucleotides in length, to have a GC content of 50% or more, and to anneal to the target sequence at temperatures about 68 0 -72 0 C. This method uses several restriction enzymes to generate a suitable fragment in the known region of a gene. The fragment is then circularized by intermolecular ligation and used as a PCR template.

Capture PCR is a method for PCR amplification of DNA fragments adjacent to a known sequence in human and yeast artificial chromosome (YAC) DNA [Lagerstrom et al., PCR Methods Applic 1:111-9 (1991)]. Capture PCR also requires multiple restriction enzyme digestions and ligations to place an engineered doublestranded sequence into an unknown portion of the DNA molecule before PCR.

Walking PCR is a method for targeted gene walking that permits retrieval of unknown sequence [Parker et al., Nucleic Acids Res 19:3055-60 (1991)]. The PromoterFinderTM kit (Clontech, Palo Alto, CA) uses PCR, nested primers, and special libraries to "walk in" genomic DNA. This process avoids the need to screen libraries and is useful in finding intron/exon junctions.

Such methods can be used to explore genomic libraries to extend 5' sequence and to obtain endogenous tank2 genomic sequence, including elements such as promoters, introns, operators, enhancers, repressors, and the like. Preferred libraries -41 0 for screening for full-length cDNAs are ones that have been size-selected to include larger cDNAs. In addition, randomly primed libraries are preferred in that they will contain more sequences that contain the 5' and upstream regions of genes.

O The oligonucleotide probes may also be used for mapping the endogenous genomic sequence. The sequence may be mapped to a particular chromosome or to a Sspecific region of the chromosome using well known techniques. These include in c, situ hybridization to chromosomal spreads [Venna et al., Human Chromosomes:

A

N, Manual ofBasic Technique, Pergamon Press, New York NY (1988)], flow-sorted Schromosomal preparations, or artificial chromosome constructions such as YACs, C 10 bacterial artificial chromosomes (BACs), bacterial PI constructions, or single chromosome cDNA libraries.

Hybridization of chromosomal preparations and physical mapping techniques such as linkage analysis using established chromosomal markers are invaluable in extending genetic maps. Examples of genetic maps can be found in the art Hodgkin et al., Science 270:410-4 (1995) and Murray et al., Science 265:2049-54 (1994)]. Often the placement of a gene on the chromosome of another mammalian species may reveal associated markers even if the number or arm of a particular human chromosome is not known. Such sequences can be assigned to particular structural features of chromosomes by physical mapping. This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once a disease or syndrome has been crudely localized by genetic linkage to a particular genomic region, any sequences mapping to that area may represent associated or regulatory genes for further investigation. See, Gatti et al., Nature 336:577-80 (1988). The polynucleotides of the invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., between normal, carrier, or affected individuals. Other types of genetic maps can also be developed, physical maps of the genome based on sequence-tagged sites (STS) [see, Hudson et al., Science 270:1945-54 (1995)].

The DNA sequence information provided by the present invention also makes possible the development, through homologous recombination or "knock-out" strategies [Capecchi, Science 244:1288-92 (1989)], of animals that fail to express -42- Sfunctional TANK2 or that express a variant of TANK2. Such animals are useful as models for studying the in vivo activities of TANK2 and modulators thereof.

As described herein, the invention provides antisense nucleic acid sequences O that recognize and hybridize to polynucleotides encoding TANK2. Modifications of gene expression can be obtained by designing antisense sequences to the control regions of the tank2 gene, such as the promoters, enhancers, and introns.

Co Oligonucleotides derived from the transcription initiation site, between -10 and +10 regions of the leader sequence, are preferred. Antisense RNA and DNA Smolecules may also be designed to block translation of mRNA by preventing the CN 10 transcript from binding to ribosomes. The worker of ordinary skill will appreciate that antisense molecules of the invention include those that specifically recognize and hybridize to tank2 DNA (as determined by sequence comparison of tank2 DNA to DNA encoding other known molecules). The antisense molecules of the invention also include those that recognize and hybridize to DNA encoding other members of the TANK2 family of proteins. Antisense polynucleotides that hybridize to multiple DNAs encoding other members of the TANK2 family of proteins are also identifiable through sequence comparison to identify characteristic or signature sequences for the family of TANK2 proteins. Accordingly, such antisense molecules preferably have at least 95%, more preferably at least 98%, and still more preferably at least 99% :0 identity to the target tank2 sequence.

Antisense polynucleotides are particularly relevant to regulating expression of TANK2 by those cells expressing tank2 mRNA. Antisense polynucleotides (preferably 10 to 20 bp oligonucleotides) capable of specifically binding to tank2 expression control sequences or tank2 RNA are introduced into cells, by a viral vector or a colloidal dispersion system such as a liposome. The antisense oligonucleotide binds to the tank2 target nucleotide sequence in the cell and prevents transcription or translation of the target sequence. Phosphorothioate and methylphosphonate antisense oligonucleotides are specifically contemplated for therapeutic use under the invention. The antisense oligonucleotides may be further -43- Smodified by poly-L-lysine, transferrin polylysine, or cholesterol moieties at their ends [for a recent review of antisense technology, see Delihas et al., Nat Biotechnol 15:751-3 (1997)].

o The invention further comprises methods to modulate TANK2 expression by means of ribozyme technology [for a review, see Gibson and Shillitoe, Mol Biotechnol 7:125-37 (1997)]. Ribozyme technology can be used to inhibit translation of tank2 mRNA in a sequence specific manner through the hybridization of a complementary RNA to a target mRNA and (ii) cleavage of the hybridized mRNA Sthrough endonuclease activity inherent to the complementary RNA. Ribozymes can C 10 be identified by empirical methods such as using complementary oligonucleotides in ribonuclease protection assays, but more preferably are specifically designed based on scanning the target molecule for accessible ribozyme cleavage sites [Bramlage et al., Trends Biotechnol 16:434-8 (1998)]. Delivery of ribozymes to target cells can be accomplished using either exogenous or endogenous delivery techniques well known and practiced in the art. Exogenous can include use of targeting liposomes or direct local injection. Endogenous methods include use of viral vectors and non-viral plasmids.

Ribozymes can specifically modulate expression of TANK2 when designed to be complementary to regions unique to a polynucleotide encoding TANK2.

"Specifically modulate," therefore is intended to mean that ribozymes of the invention recognize only a polynucleotide encoding TANK2. Similarly, ribozymes can be designed to modulate expression of all or some of the TANK2 family of proteins.

Ribozymes of this type are designed to recognize nucleotide sequences conserved all or some of the polynucleotides encoding the TANK2 family members.

The invention further embraces methods to modulate transcription of tank2 through use of oligonucleotide-directed triple helix formation (also known as Hogeboom base-pairing methodology) [for a review, see Lavrovsky et al., Biochem Mol Med 62:11-22 (1997)]. Triple helix formation is accomplished using sequencespecific oligonucleotides that hybridize to double stranded DNA in the major groove ;0 as defined in the Watson-Crick model. This triple helix hybridization compromises the ability of the original double helix to open sufficiently for the binding of -44polymerases, transcription factors, or regulatory molecules. Preferred target sequences for hybridization include promoter and enhancer regions to permit transcriptional regulation of TANK2 expression. Oligonucleotides that are capable of triple helix formation can alternatively be coupled to DNA damaging agents, which can then be used for site-specific covalent modification of target DNA sequences [see Lavrovsky et al., supra].

Both antisense RNA and DNA molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of RNA molecules.

These include techniques for chemically synthesizing oligonucleotides such as solidphase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro or in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly can be introduced into cell lines, cells, or tissues.

Mutations in a gene that result in loss of normal function of the gene product may underlie TANK2-related disease states. The invention comprehends gene therapy to restore TANK2 activity as indicated in treating those disease states characterized by a deficiency or absence ofpoly(ADP-ribose) polymerase activity associated with the TANK2 enzyme. Delivery of functional tank2 gene to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors adenovirus, adeno-associated virus, or retrovirus), or ex vivo by use of physical DNA transfer methods liposomes or chemical treatments) [see, e.g., Anderson, Nature 392(6679 Suppl):25-30 (1998)]. Alternatively, it is contemplated that in other disease states, preventing the expression or inhibiting the activity of TANK2 will be useful in treating those disease states. Antisense therapy or gene therapy can be applied to negatively regulate the expression of TANK2.

The DNA and amino acid sequence information provided by the present invention also makes possible the systematic analysis of the structure and function of TANK2 proteins. DNA and amino acid sequence information for TANK2 also permits identification of molecules with which a TANK2 polypeptide will interact.

O Agents that modulate increase, decrease, or block) TANK2 activity may be identified by incubating a putative modulator with TANK2 and determining the effect of the putative modulator on TANK2 activity. The selectivity of a compound that 0 modulates the activity of the TANK2 polypeptide can be evaluated by comparing its activity on the TANK2 to its activity on other proteins.

Numerous methods are amenable to modification by including TANK2 CN polypeptides or tank2 polynucleotides of the invention, including cell based methods N such as dihybrid and trihybrid screens to detect binding partners and split hybrid screens to detect compounds that disrupt complexing of binding partners. Other I 10 methods include in vitro methods, such as assays in which a TANK2 polypeptide, tank2 polynucleotide, or a binding partner thereof is immobilized, as well as solution assays, are contemplated under the invention. These methods are exemplified by a general approach that includes the steps of contacting a TANK2 polypeptide with a putative binding partner compound, detecting or measuring binding of the TANK2 polypeptide with the compound, and optionally isolating and/or identifying the binding partner compound.

Cell-based assays include methods of screening genomic DNA or cDNA libraries to identify binding partners of TANK2 polypeptides. Exemplary methods include the dihybrid or two-hybrid screen [Fields and Song, Nature 340:245-6 (1989); Fields, Methods: A Companion to Methods in Enzymology 5:116-24 (1993)] which can be used identify DNAs encoding binding partners. Modifications and variations of the dihybrid assay are described [Colas and Brent, Trends Biotechnol 16:355-63 (1998)]. Trihybrid screens can also be employed [Fuller et al., Biotechniques 25:85-8, 90-2 (1998)].

Cell-based methods of the invention may be used to identify components in biological pathways that are mediated by TANK2 biological activity. In one aspect, the method is carried out in a host cell containing a soluble TANK2 polypeptide and a soluble form of its binding partner and wherein decreased of increased binding is quantitated through measurement of a binding-dependent phenotypic change in the host cell that is associated with a change in expression of a reporter gene product.

-46- O Alternatively, cell-based assays to identify inhibitors of TANK2 polypeptide interaction with a known binding partner may be based on methods such as the split hybrid assay [PCT patent publication WO 98/13502] and variations thereof [PCT O patent publication WO 95/20652].

In vitro methods can comprise the steps of contacting an immobilized TANK2 polypeptide with a candidate binding partner compound, and detecting binding of the candidate compound to the TANK2 polypeptide. In an alternative I embodiment, the candidate binding partner compound is immobilized and binding of Sthe TANK2 polypeptide is detected. Immobilization may be accomplished using any CN 10 of the methods well known in the art, including bonding to a support, beads, or a chromatographic resin, as well as high affinity interactions such as antibody binding or use of an avidin:biotin type system. Detection of binding of the ligands can be accomplished, for example, by using a detectable radioactive or fluorescent) label on the ligand that is not immobilized, (ii) using an antibody immunospecific for the non-immobilized ligand, (iii) using a label on the non-immobilized ligand that promotes excitation of a fluorescent support to which the immobilized ligand is bound, as well as other techniques routinely practiced in the art.

In solution assays, methods of the invention comprise the steps of(a) contacting a TANK2 polypeptide with one or more candidate binding partner compounds, and identifying the compounds that bind to the TANK2 polypeptide.

Identification of the compounds that bind TANK2 can be achieved by isolating the TANK2:binding partner complex, and separating the TANK2 polypeptide from the binding partner compound. An additional step of characterizing the physical, biological, or biochemical properties of the binding partner compound is also comprehended under the invention. In one approach the TANK2:binding partner complex is isolated using a second binding partner compound an antibody or other protein) that interacts with either of the principal ligands in the complex.

Selective modulators may include, for example, antibodies and other proteins or peptides that selectively or specifically bind to a TANK2 polypeptide or a TANK2encoding polynucleotide, oligonucleotides that selectively or specifically bind to TANK2 polypeptides or TANK2-encoding polynucleotides, and other non-peptide -47compounds isolated or synthetic organic molecules) that selectively or Sspecifically react with TANK2 polypeptides or TANK2-encoding polynucleotides.

Modulators also include compounds as described above but which interact with a O specific binding partner of TANK2 polypeptides. Mutant forms of TANK2, such as those that affect the biological activity or cellular location of the wild-type TANK2, are also contemplated under the invention. Presently preferred targets for the C, development of selective modulators include, for example: I cytoplasmic or transmembrane regions of TANK2 polypeptides that contact other proteins and/or localize TANK2 within a cell, to telomeres;

C

N 10 extracellular regions of TANK2 polypeptides that bind specific binding partners; regions of the TANK2 polypeptides that bind substrate, ADP-ribose; allosteric regulatory sites of the TANK2 polypeptides; regions of the TANK2 polypeptides that mediate multimerization; regions of TANK2 or other proteins TRFI or TRF2) that act as acceptors ADP-ribosylation.

Still other selective modulators include those that recognize particular regulatory or TANK2-encoding nucleotide sequences. Selective and specific modulators of TANK2 activity may be therapeutically useful in treatment of a wide range of diseases and physiological conditions in which aberrant TANK2 activity is involved.

A TANK2-encoding polynucleotide sequence may be used for the diagnosis of diseases resulting from or associated with TANK2 expression or activity. For example, polynucleotide sequences encoding a TANK2 polypeptide TANK2- LONG or TANK2-SHORT) may be used in hybridization or PCR assays of biological samples, samples or extracts of fluids or tissues from biopsies or autopsies, to detect abnormalities in TANK2 expression. Such qualitative or quantitative methods may include Southern or northern analysis, dot blot, or other membrane-based technologies; PCR technologies; dipstick, pin or chip technologies; and ELISA or other multiple-sample format technologies. These types of techniques are well known W0 in the art and have been employed in commercially available diagnostic kits.

-48- Q Such assays may be tailored to evaluate the efficacy ofa particular therapeutic treatment regimen and may be used in animal studies, in clinical trials, or in monitoring the treatment of an individual patient. To provide a basis for the diagnosis Sof disease, a normal or standard profile for TANK2 expression must be established.

This is accomplished by combining a biological sample taken from a normal subject with a tank2 polynucleotide, under conditions suitable for hybridization or Ni amplification. Standard hybridization may be quantified by comparing the values obtained for normal subjects with a dilution series of positive controls run in the same Sexperiment where a known amount of a purified tank2 polynucleotide is used.

Standard values obtained from normal samples may be compared with values obtained from samples from subjects potentially affected by a disorder or disease related to TANK2 expression. Deviation between standard and subject values establishes the presence of the disease state. If disease is established, an existing therapeutic agent is administered, and treatment profile or values may be generated.

The assay may be repeated on a regular basis to evaluate whether the values progress toward or return to the normal or standard pattern. Successive treatment profiles may be used to show the efficacy of treatment over a period of several days or several months.

Anti-TANK2 antibodies are useful for the diagnosis of conditions, disorders, or diseases characterized by or associated with abnormal expression of a TANK2 polypeptide. Diagnostic assays for TANK2 polypeptides include methods that employ a labeled antibody to detect a TANK2 polypeptide in a biological sample such as a body fluid, cells, tissues, sections, or extracts of such materials. The polypeptides and antibodies of the present invention may be used with or without modification.

Preferably, the polypeptide or the antibody will be labeled by linking them, either covalently or non-covalently, with a detectable label moiety as described herein.

Antibody-based methods for detecting the presence of TANK2 polypeptides in biological samples are enabled by virtue of the present invention, including assays for differential detection of TANK2-LONG versus TANK2-SHORT. Assays for detecting the presence of proteins with antibodies have been previously described, and follow known formats, such as enzyme-linked immunosorbent assay (ELISA), -49- O radioimmunoassay (RIA), and fluorescence activated cell sorting (FACS) and flow cytometry, western blots, sandwich assays, and the like. These formats are normally based on incubating an antibody with a sample suspected of containing the TANK2 Sprotein and detecting the presence of a complex between the antibody and the protein.

The antibody is labeled either before, during, or after the incubation step. The specific concentrations of antibodies, the temperature and time of incubation, as well as other Ssuch assay conditions, can be varied, depending upon various factors including the Sconcentration of antigen in the sample, the nature of the sample, etc. Those skilled in Sthe art will be able to determine operative and optimal assay conditions for each I 10 determination by employing routine experimentation [see, Hampton et al., Serological Methods: A Laboratory Manual, APS Press, St Paul, MN (1990)].

To provide a basis for the quantitation of TANK2 protein in a sample or for the diagnosis of disease, normal or standard values of TANK2 polypeptide expression must be established. This is accomplished by combining body fluids or cell extracts taken from a normal sample or from normal subjects, either animal or human, with antibody to a TANK2 polypeptide. The amount of standard complex formation may be quantified by comparing it with a dilution series of positive controls where a known amount of antibody is combined with known concentrations of a purified TANK2 polypeptide. Then, standard values obtained from normal samples may be compared with values obtained from samples from test sample, subjects potentially affected by a disorder or disease related to a TANK2 expression.

Deviation between standard and test values establishes the presence of the disease state.

Methods for Identifyin Modulators of Tankvrase2 Activity The TANK2 protein, as well as fragments thereof possessing biological activity can be used for screening putative modulator compounds in any of a variety of drug screening techniques. The term "modulator" as used herein refers to a compound that acts as an agonist or as an antagonist of TANK2 activity. Modulators 0 according to the invention include allosteric modulators of activity as well as inhibitors of activity. An "agonist" of TANK2 is a compound that enhances or O increases the ability of TANK2 to carry out any of its biological functions. An example of such an agonist is an agent that increases the ability of TANK2 to bind to damaged DNA or to polymerize ADP-ribose. An "antagonist" of TANK2 is a Scompound that diminishes or abolishes the ability of TANK2 to carry out any of its biological functions. An example of such antagonists is an anti-TANK2 antibody.

Accordingly, the invention provides a method for screening a plurality of test compounds for specific binding affinity with a TANK2 polypeptide, comprising providing a plurality of test compounds; combining a TANK2 polypeptide with each Sof the plurality of test compounds for a time sufficient to allow binding under suitable conditions; and detecting binding of the TANK2 polypeptide to each of the plurality of test compounds, thereby identifying those test compounds that specifically bind the TANK2 polypeptide.

The present invention also provides a method of identifying a modulator of a biological activity of a TANK2 polypeptide, comprising the steps of a) contacting the compound with a TANK2 polypeptide, b) incubating the mixture of step a) with a substrate under conditions suitable for the biological activity, c) measuring the amount of the biological activity; and d) comparing the amount of biological activity of step c) with the amount of biological activity obtained with the TANK2 polypeptide, incubated without the compound, thereby determining whether the compound stimulates or inhibits the biological activity. In one embodiment of the method, the TANK2 polypeptide is a fragment from the non-catalytic region of the TANK2 and provides a method to identify allosteric modulators of TANK2. In another embodiment, the TANK2 polypeptide is a fragment from the catalytic region of TANK2 and provides a method to identify inhibitors of the biological activity.

TANK2-LONG and TANK2-SHORT polypeptides or specific fragments thereof may be employed.

Accordingly, the polypeptide employed in such methods may be free in solution, affixed to a solid support, displayed on a cell surface, or located intracellularly. The modulation of activity or the formation of binding complexes between the TANK2 polypeptide and the agent being tested may be measured.

TANK2 polypeptides are amenable to biochemical or cell-based high throughput -51 O screening (HTS) assays according to methods known and practiced in the art, including melanophore assay systems to investigate receptor-ligand interactions, yeast-based assay systems, and mammalian cell expression systems [for a review, see 0 Jayawickreme and Kost, Curr Opin Biotechnol 8:629-34 (1997)]. Automated and miniaturized HTS assays are also comprehended Houston and Banks, Curr Opin r Biotechnol 8:734-40 (1997)].

,I Such HTS assays are used to screen libraries of compounds to identify ,I particular compounds that exhibit a desired property. Any library of compounds may 0 be used, including chemical libraries, natural product libraries, combinatorial libraries CI 10 comprising random or designed oligopeptides, oligonucleotides, or other organic compounds.

Chemical libraries may contain known compounds, proprietary structural analogs of known compounds, or compounds that are identified from natural product screening.

Natural product libraries are collections of materials isolated from naturals sources, typically, microorganisms, animals, plants, or marine organisms. Natural products are isolated from their sources by fermentation of microorganisms followed by isolation and extraction of the fermentation broths or by direct extraction from the microorganisms or tissues (plants or animal) themselves. Natural product libraries include polyketides, non-ribosomal peptides, and variants (including non-naturally occurring variants) thereof [for a review, see Cane et al., Science 282:63-8 (1998)].

Combinatorial libraries are composed of large numbers of related compounds, such as peptides, oligonucleotides, or other organic compounds as a mixture. Such compounds are relatively straightforward to design and prepare by traditional automated synthesis protocols, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries.

Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries [for a review of combinatorial chemistry and libraries created thereby, see Myers, Curr Opin Biotechnol 8:701-7 (1997)].

-52- O Once compounds have been identified that show activity as modulators of TANK2 function, a program of optimization can be undertaken in an effort to improve the potency and or selectivity of the activity. This analysis of structure- O activity relationships (SAR) typically involves of iterative series of selective modifications of compound structures and their correlation to biochemical or biological activity. Families of related compounds can be designed that all exhibit the N desired activity, with certain members of the family potentially qualifying as Stherapeutic candidates.

SThe invention also encompasses the use of competitive drug screening assays 1 10 in which neutralizing antibodies capable of binding a TANK2 polypeptide specifically compete with a test compound for binding to the TANK2 polypeptide. In this manner, the antibodies can be used to detect the presence of any compound, e.g., another peptide that shares one or more antigenic determinants with the TANK2 polypeptide.

Therapeutic Uses of TANK2-Encoding Polvnucleotides and TANK2 Polvpeptides The invention provides a method for inhibiting the expression or activity of TANK2 therapeutically or prophylactically in a human or other animal. The method comprises administering a TANK2 antagonist in an amount effective for inhibiting TANK2 expression or activity. The invention thus provides a method for treating tissue damage resulting from cell damage or death due to necrosis or apoptosis, comprising administering to the animal an effective amount of a compound that inhibits TANK2 activity. This method may be employed in treating animals that are or may be subject to any disorder whose symptoms or pathology is mediated by TANK2 expression or activity. Antagonists having specificity for TANK2-LONG or TANK2-SHORT may have particular utility in diseases whose pathology or symptoms are mediated by a specific form of TANK2.

The method may further involve administering an antagonist of another poly(ADP-ribose) polymerase activity, such as activity associated with the enzymes PARP, tankyrase 1, and the like. Exemplary PARP antagonists suitable for use in this embodiment include, for example, the compounds described by Banasik et al. [JBiol -53- (Chem 267:1569-75 (1992)]. Other exemplary compounds include those described in PCT patent publications WO 99/11623 and WO 99/11649. Alternatively, the TANK2 r- inhibitory method may entail use of a compound that antagonizes both TANK2 and another enzyme having poly(ADP-ribose) polymerase activity.

"Treating" as used herein refers to preventing a disorder from occurring in an animal that may be predisposed to the disorder, but has not yet been diagnosed as Shaving it; inhibiting the disorder, arresting its development; relieving the disorder, causing its regression, or ameliorating the disorder, reducing the severity of Ssymptoms associated with the disorder. "Disorder" is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.

The methods of the invention embrace various modes of treating an animal in which TANK2 is expressed, and in which TANK2-mediated disorders may be treated.

Animals treatable according to the invention include mammals (including humans) and non-mammalian animals, birds, fish, reptiles, and amphibians. Among the non-human mammals that may be treated are companion animals (pets) including dogs and cats; farm animals including cattle, horses, sheep, pigs, and goats; laboratory animals including rats, mice, rabbits, guinea pigs, and primates. The method is most preferably employed in the treatment of TANK2-mediated disorders in humans.

In particular, the method of the invention may be employed to treat animals therapeutically or prophylactically who are or may subject to a disorder associated with excessive or undesirable telomerase activity. One aspect of the present invention derives from the ability of TANK2 and its functional derivatives to interact with damaged DNA and to modulate the activity of telomere repeat binding factors TRF1 and TRF2).

Excessive telomerase activity in cells has been shown to correlate with induction of apparently unlimited capacity of the cells to replicate. In addition, evidence exists that telomerase activity is higher in tumor tissue than most normal tissues suggesting that increased telomerase activity may be essential for tumor growth. Accordingly, the invention also provides to a method of inhibiting oncogenic transformation or inhibiting neoplastic tissue growth, cancer, in an animal, comprising administering to the animal an effective amount of a compound that -54inhibits TANK2 activity. In this embodiment, the method may further comprise adjuvant administration of a chemotherapeutic or anti-cancer drug and/or radiation therapy.

Tumors or neoplasms include new growths of tissue in which the multiplication of cells is uncontrolled and progressive. Some such growths are benign, but others are termed "malignant," leading to death of the organism.

Malignant neoplasms or "cancers" are distinguished from benign growths in that, in Saddition to exhibiting aggressive cellular proliferation, cancers invade surrounding tissues and metastasize. Moreover, malignant neoplasms are characterized in that they show a greater loss of differentiation (greater "dedifferentiation"), and of their organization relative to one another and their surrounding tissues. This property is also called "anaplasia." Neoplasms treatable by the present invention include solid tumors, i.e., carcinomas and sarcomas. Carcinomas include those malignant neoplasms derived from epithelial cells which tend to infiltrate (invade) the surrounding tissues and give rise to metastases. Adenocarcinomas are carcinomas derived from glandular tissue or in which the tumor cells form recognizable glandular structures. Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue. The invention also enables treatment of cancers of the myeloid or lymphoid systems, including leukemias, lymphomas and other cancers that typically do not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems.

The type of cancer or tumor cells amenable to treatment according to the invention include, for example, ACTH-producing tumor, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver ;0 cancer, lung cancer (small and non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, Q neuroblastoma, glioma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, (N ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, and Wilm's tumor.

As noted above, regulation oftelomere structure appears to be associated with Saging. Drugs that modulate the regulation oftelomere structure can be expected to N have utility in treatment of age-related syndromes or in cases of genetically Sdetermined premature aging and premature senility syndromes progeria (Hutchinson-Gilford progeria syndrome), Werner's syndrome, and other such disorders. Accordingly, the invention provides a method of enhancing the activity of TANK2 in animals suffering from such syndromes. The method may be expected to decrease TRF binding to the telomeres, which in turn promotes increased telomerase activity.

Shortening of telomeres beyond a critical length results in the induction of senescence in many cell types. As telomerase activity is frequently required for maintenance oftelomere length, and since TANK2 inhibition may diminish telomerase function, the invention provides for treatment of non-neoplastic proliferative disorders in which TANK2 antagonists may be useful to induce shortened telomeres and cellular senescence. Proliferative disorders include, but are not limited to, andrestenosis, diabetic retinopathy, mesangial proliferative disorder, proliferative glomerulonephritis, polycythemia, myelofibrosis, post-transplantation lymphoproliferative disorder, endometriosis, craniosynostosis, immunoproliferative small intestinal disease, thymic lymphoproliferative disease, myelodysplastic disorders, myeloproliferative disorders, von Willebrand's disease, and proliferative nephritis.

In addition, TANK2 inhibitors may be useful in any inflammatory disorder, including autoimmune disorders, in which proliferation oflymphocytes plays a role.

"Inflammatory disorder" as used herein can refer to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function.

-56- S"Inflammatory disorders" can also refer to pathological states mediated by influx of leukocytes and or neutrophil chemotaxis.

'"Inflammation" as used herein refers to a localized, protective response Selicited by injury or destruction of tissues, which serves to destroy, dilute or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes and or neutrophil chemotaxis. Inflammation may N result from infection with pathogenic organisms and viruses and from noninfectious N means such as trauma or reperfusion following myocardial infarction or stroke, O immune response to foreign antigen, and autoimmune responses. Inflammatory disorders amenable to the invention encompass disorders associated with reactions of the specific defense system as well as with reactions of the non-specific defense system.

Accordingly, the present invention enables methods of treating such inflammatory disorders as arthritic diseases, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis; Behcet disease; sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma; pulmonary or respiratory disorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic pulmonary inflammatory disease chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis, and pulmonary oxygen toxicity; reperfusion injury of the myocardium, brain, or extremities; fibrosis such as cystic fibrosis; keloid formation or scar tissue formation; atherosclerosis; autoimmune diseases such as systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, some forms of diabetes, and Reynaud's syndrome; and transplant rejection disorders such as GVHD and allograft rejection; chronic glomerulonephritis; inflammatory bowel diseases such as Crohn's disease, ulcerative colitis and necrotizing enterocolitis;.

inflammatory dermatoses such as contact dermatitis, atopic dermatitis, psoriasis, or urticaria; fever and myalgias due to infection; central or peripheral nervous system -57- Sinflammatory disorders such as meningitis, encephalitis, and brain or spinal cord injury due to minor trauma; Sjbgren's syndrome; diseases involving leukocyte diapedesis; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex O mediated diseases; hypovolemic shock; Type I diabetes mellitus; acute and delayed hypersensitivity; disease states due to leukocyte dyscrasia and metastasis; thermal injury; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.

SThe tank2 polynucleotides provided by the invention also enable therapeutic applications of these polynucleotides in treating the diseases and disorders described Sherein whose etiology involves TANK2 expression or activity. For example, a tank2 antisense molecule may provide the basis for treatment of various abnormal conditions related to excessive or undesirable levels ofpoly(ADP-ribose) polymerase activity. Alternatively, polynucleotide sequences encoding TANK2 may provide the basis for the treatment of various abnormal conditions related to deficiency of poly(ADP-ribose) polymerase activity. Polynucleotides having specificity for one or both of tank2-long and tank2-short may have particular utility in certain diseases.

Expression vectors derived from retroviruses, adenovirus, herpes, or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of recombinant tank2 sense or antisense molecules to the targeted cell population. Methods that are well known to those skilled in the art can be used to construct recombinant vectors containing tank2. See, for example, the techniques described in Sambrook et al., supra, and Ausubel et al., supra. Alternatively, recombinant tank2 can be delivered to target cells in liposomes.

The cDNA sequence, and/or its regulatory elements, enables researchers to use a tank2 polynucleotide as a tool in sense [Youssoufian and Lodish, Mol Cell Biol 13:98-104 (1993)] or antisense [Eguchi et al., Annu Rev Biochem 60:631-52 (1991)] investigations of gene function. Oligonucleotides, designed from the cDNA or control sequences obtained from the genomic DNA, can be used in vitro or in vivo to inhibit expression. Such technology is now well known in the art, and sense or antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions. Again, tank2-long- or tank2-short-specific sequences may have distinct utilities depending on which form of tank2 is of interest.

-58- O Additionally, TANK2 expression can be modulated by transfecting a cell or tissue with expression vectors that express high levels of a tank2 polynucleotide fragment in conditions where it would be preferable to block a biological activity of STANK2. Such constructs can flood cells with untranslatable sense or antisense sequences. Even in the absence of integration into the DNA, such vectors may continue to transcribe RNA molecules until all copies of the vector are disabled by Sendogenous nucleases. Such transient expression may be accomplished using a nonreplicating vector or a vector incorporating appropriate replication elements.

Methods for introducing vectors into cells or tissue include those methods l 10 discussed herein. In addition, several of these transformation or transfection methods are equally suitable for ex vivo therapy. Furthermore, the tank2 polynucleotide sequences disclosed herein may be used in molecular biology techniques that have not yet been developed, provided the new techniques rely on properties ofnucleotide sequences that are currently known, including but not limited to such properties as the triplet genetic code and specific base pair interactions.

Pharmaceutical Compositions The present invention further relates to pharmaceutical compositions that comprise a chemical or biological compound ("agent") that is active as a modulator of TANK2 expression or activity and a biocompatible pharmaceutical carrier, adjuvant, or vehicle. The active agent in the pharmaceutical compositions may be selected from among all or portions of tank2 polynucleotide sequences, tank2 antisense molecules, TANK2 polypeptides, protein, peptide, or organic modulators of TANK2 bioactivity, such as inhibitors, antagonists (including antibodies) or agonists. Preferably, the agent is active in treating a medical condition that is mediated by or characterized by TANK2 expression or activity. The composition can include the agent as the only active moiety or in combination with other nucleotide sequences, polypeptides, drugs, or hormones mixed with excipient(s) or other pharmaceutically acceptable carriers.

Techniques for formulation and administration of pharmaceutical compositions may be found in Remington 's Pharmaceutical Sciences, 18 1 h Ed., Mack Publishing Co., Easton, PA (1990). The pharmaceutical compositions of the present -59invention may be manufactured using any conventional method, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. However, the optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo N clearance of the administered agent. Depending on the condition being treated, these i pharmaceutical compositions may be formulated and administered systemically or locally.

The pharmaceutical compositions may be administered to the subject by any conventional method, including parenteral and enteral techniques. Parenteral administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enteral administration modalities include, for example, oral (including buccal and sublingual) and rectal administration.

Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enteral administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and rectal administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Surgical techniques include implantation of depot (reservoir) compositions, osmotic pumps, and the like. A preferred route of administration for treatment of inflammation would be local or topical delivery for localized inflammation such as arthritis, and intravenous delivery for reperfusion injury or for systemic conditions such as septicemia.

The pharmaceutical compositions are formulated to contain suitable pharmaceutically acceptable carriers, and may optionally comprise excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The administration modality will generally determine the O nature of the carrier. For example, formulations for parenteral administration may comprise aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parenteral administration can be selected from among saline, buffered Ssaline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parenteral administration are physiologically compatible buffers such as Hank's solution, Ringer's solutions, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated N are used in the formulation. Such penetrants are generally known in the art. For Spreparations comprising proteins, the formulation may include stabilizing materials, CI 10 such as polyols sucrose) and/or surfactants nonionic surfactants), and the like.

Alternatively, formulations for parenteral use may comprise suspensions of the active compounds prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Emulsions, oil-in-water and water-in-oil dispersions, can also be used, optionally stabilized by an emulsifying agent or dispersant (surface-active materials; surfactants).

Liposomes containing the active agent may also be employed for parenteral administration. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent may also be used as coatings or matrix structures, methacrylic polymers such as the Eudragit® series available from Rbhm America Inc. (Piscataway,

NJ).

Alternatively, the pharmaceutical compositions comprising the agent in dosages suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art. The preparations formulated for oral administration may be in the form of tablets, pills, capsules, cachets, drag6es, lozenges, liquids, gels, syrups, slurries, suspensions, or powders. To illustrate, -61 pharmaceutical preparations for oral use can be obtained by combining the active r compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Note that oral formulations may employ liquid carriers similar in type to those described for parenteral use, buffered aqueous solutions, suspensions, and the like.

Preferred oral formulations include tablets, drag6es, and gelatin capsules.

These preparations may contain one or excipients, which include, without limitation: a) diluents such as sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol; b) binders such as magnesium aluminum silicate, starch from corn, wheat, rice, potato, etc.; c) cellulose materials such as methyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose, polyvinyl pyrrolidone, gums such as gum arabic and gum tragacanth, and proteins such as gelatin and collagen; d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a salt thereof such as sodium alginate, or effervescent compositions; e) lubricants such as silica, talc, stearic acid or its magnesium or calcium salt, and polyethylene glycol; f) flavorants, and sweeteners; g) colorants or pigments, to identify the product or to characterize the quantity (dosage) of active compound; and h) other ingredients such as preservatives, stabilizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.

Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds may be dissolved or -62suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

.The pharmaceutical composition may be provided as a salt of the active agent, which can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.

To be effective therapeutically in modulating central nervous system targets, the agents used in the methods of the invention should readily penetrate the blood brain barrier when peripherally administered. Compounds that cannot penetrate the blood brain barrier, however, can still be effectively administered by an intravenous route.

As noted above, the characteristics of the agent itself and the formulation of the agent can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Such pharmacokinetic and pharmacodynamic information can be collected through pre-clinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for any compound used in the method of the invention, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range that modulates TANK2 expression or activity. As human studies are conducted, further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for determining the LD, 0 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the "therapeutic index," which is typically expressed as the ratio 63- QLDo/ED 0 Compounds that exhibit large therapeutic indices are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies O preferably within a range of circulating concentrations that include the ED, 0 with little or no toxicity.

For the method of the invention, any effective administration regimen regulating the timing and sequence of doses may be used. Doses of the agent Cpreferably include pharmaceutical dosage units comprising an effective amount of the agent. As used herein, "effective amount" refers to an amount sufficient to modulate TANK2 expression or activity and/or derive a measurable change in a physiological parameter of the subject through administration of one or more of the pharmaceutical dosage units.

Exemplary dosage levels for a human subject are of the order of from about 0.001 milligram of active agent per kilogram body weight (mglkg) to about 100 mg/kg. Typically, dosage units of the active agent comprise from about 0.01 mg to about 10,000 mg, preferably from about 0.1 mg to about 1,000 mg, depending upon the indication, route of administration, etc. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface area, or organ size. The final dosage regimen will be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, the agent's specific activity, the severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, the severity of any infection, etc. Additional factors that may be taken into account include time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages may be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.

-64- The frequency of dosing will depend on the pharmacokinetic parameters of the Sagent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect.

Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent.

Short-acting pharmaceutical compositions short half-life) can be administered tI once a day or more than once a day two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks. Pumps, such as subcutaneous, intraperitoneal, or subdural pumps, may be preferred for continuous infusion.

Compositions comprising a compound of the invention formulated in a pharmaceutical acceptable carrier may be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Conditions indicated on the label may include treatment of inflammatory disorders, cancer, nervous tissue injury, etc.

Kits are also contemplated, wherein the kit comprises a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition.

The following Examples are provided to further aid in understanding the invention. The particular materials and conditions employed are intended to exemplify particular aspects of the invention and should not be construed to limit the reasonable scope thereof.

The Examples presuppose an understanding of conventional methods wellknown to those persons having ordinary skill in the art to which the examples pertain, the construction of vectors and plasmids, the insertion of genes encoding polypeptides into such vectors and plasmids, or the introduction of vectors and plasmids into host cells. Such methods are described in detail in numerous publications including, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989), Ausubel et al.

Current Protocols in Molecular Biology, John Wiley Sons, Inc. (1994); and O Ausubel et al. Short Protocols in Molecular Biology, 4 1h ed., John Wiley Sons, Inc. (1999).

EXAMPLE 1 Identification of an EST Related to Human Tankyrase 1 and Isolation of a Tankvrase2 Polvnucleotide g Using the nucleotide sequence of human tankyrasel (SEQ ID NO:3) [Smith et Sal. (1998), supra], a search of the National Center for Biotechnology Information 10 (NCBI) Expressed Sequence Tags (EST) database was performed to identify novel genes that are homologous to tankyrasel. The EST database provides 5' and/or 3' nucleotide sequences for cDNA clones from a variety of tissue sources. The NCBI BLASTn program [Altschul et al., Nucleic Acids Res 25:3389-402 (1997)] was used to compare the nucleotide query sequence of human tankyrasel against a nucleotide sequence database and to identify DNA sequences in the EST sequence database that have significant homology to human tankyrasel. This BLASTn search identified two EST sequences of interest: AA307492 (SEQ ID NO:5) cloned from a human colon carcinoma cell line designated HCC, and HI17748 (SEQ ID NO:7), cloned from human brain.

A comparison of the AA307492 and tankyrasel polynucleotides revealed that a region consisting ofnucleotides 307 to 432 (nt 307-432) of AA307492 (SEQ ID shared significant homology with a region consisting of nt 3313-3438 of tankyrasel (SEQ ID NO:3); 105 of 126 nucleotides were the same; 83% identity).

Nucleotides 307-432 of AA307492 were translated and the predicted protein (SEQ ID NO:6) was compared with tankyrasel protein (amino acids 1105 to 1146 of SEQ ID NO:4). The proteins were found to be the same at 36 of 42 amino acid positions (86% identity). A comparison of the H17748 and tankyrasel polynucleotides revealed that nt 3-356 ofH17748 (SEQ ID NO:7) shared significant homology with nt 3544-3897 of tankyrasel (SEQ ID NO:3; 280 of 354 nucleotides were identical; 79% identity).

When nt 3-356 of H 17748 was translated and the predicted protein (SEQ ID NO:8) was compared with the corresponding region of tankyrasel (aa 1182-1299 of SEQ ID NO:4), the proteins were found to be the same at 111 of 118 amino acid positions -66- (94% identity). The putative amino acid sequences of AA307492 and H 17748 are homologous to, but distinct from, tankyrasel protein, indicating that they represented protein products translated from a novel tankyrase gene or genes.

AA307492 and HI 7748 were used in a search of the GenBank® database using the NCBI UniGene® program in order to identify other EST sequences originating from the same gene(s). The UniGene® program assembles GenBank Ssequences into a non-redundant set of gene-oriented clusters, with each cluster Scontaining a group of sequences from the same gene. The UniGene® search of the 0 human GenBank® database with AA307492 did not identify any other human EST sequences clustering in the same gene region as AA307492. By contrast, the UniGene® search of the human GenBank database with HI7748 identified sixteen human EST sequences belonging in the same gene cluster as H1 7748, as follows: AA305587 (SEQ ID NO:9), AA371079 (SEQ ID NO:10), AA970617 (SEQ ID NO:11), AI247608 (SEQ ID NO:12), HI 1505 (SEQ ID NO:13), H11865 (SEQ ID NO:14), H17635 (SEQ ID NO:15), N29528 (SEQ ID NO:16), N57467 (SEQ ID NO:17), R06902 (SEQ ID NO:18), R06946 (SEQ ID NO:19), R14158 (SEQ ID R33944 (SEQ ID NO:21), R63031 (SEQ ID NO:22), R63337 (SEQ ID NO:23), and T17118 (SEQ ID NO:24). EST H17748 and EST H17635 contained sequence from opposite ends of the same clone, designated 50806. EST H11505 and EST HI 1865 contained sequence from opposite ends of the same clone, designated 47912. EST R06902 and EST R06946 contained sequence from opposite ends of the same clone, designated 126654. E. coli strains harboring cDNA clones 50806, 47912, and 126654 were purchased from the American Type Culture Collection

(ATCC,

Rockville, MD), which maintains and makes publicly available deposits of ESTs identified and sequenced by I.M.A.G.E. (Lawrence Livermore National Laboratory, Livermore, CA). The three clones were sequenced as follows: -67- Clone 50806 was sequenced In its entirety on both strands using primers that hybridized to the vector DNA (SEQ ID NOs:25-26), and primers designed to hybridize to the human cDNA (SEQ ID NOs:27-34).

M13 Forward TGTAAAACGACGGCCAGT (SEQ ID M 13 Reverse GCAAACAGCTATGACCATG (SEQ ID NO:26) NT-7 TFJTGCCGGGTAACCTTGG (SEQ I1D NO:27) NT-8 CCAAGGTTACCCGGCAAA (SEQ ID NO:28) NT-9 GTAGGCCCAGTGTAAATG (SEQ ID NO:29) 0NT-10 CATTTACACTGGGCCTAC (SEQ ID C1 10 NT-1 1 GAGTAAGTTGCAGGGCATGT (SEQ ID NO:3 1) NT-12 ACATGCCCTGCAACTTACTC (SEQ ID NO:32) NT-13 GAATCACCGCAGTTACTA&A (SEQ ID NO:33) NT-14 TTTAGTAACTGCGGTGATTC (SEQ ID NQ:34) Clone 47912 was sequenced in its entirety on both strands using primers that hybridized to the vector DNA (SEQ ID N~s:25-26, supra), and primers designed to hybridize to the human cDNA (SEQ ID NOs:27-34, supra, and SEQ ID NOs:35-37).

GGCCTGAAGGTATGGTCGAT (SEQ ID NT-16 ATCGACCATACCTTCAGG~CC (SEQ ID NO:36) NT-18 TGAGGGCATTACAGTTTGTT (SEQ ID NO:37) Clone 126654 was sequenced in its entirety on both strands using primers that hybridized to the vector DNA: M 13 Forward (SEQ ID) NO:25, supra) and T7 Promoter (SEQ 11D NO:38), and primers designed to hybridize to the human cDNA (SEQ ID NOs:27-30, supra, and SEQ ID NOs:39-40).

T7 Promoter TAATACGAACTCACTATAGGG (SEQ ID NO:38) NT-5 ATACACTCACCGGAGA&A (SEQ ID NQ:39) NT-6 TTTCTCCGGTGAGTGTAT (SEQ ID Upon sequencing, 50806, 47912, and 126654 were found to be consistent with the sequences reported in the EST database. The polynucleotide sequences for 50806, 47912, and 126654 are set out in SEQ ID NOs:41, 43, and 45, respectively. The deduced amino acid sequences for 50806, 47912, and 126654 are set out in SEQ ID NOs:42, 44, and 46, respectively. The sequences of 50806 and 47912 indicated that -68- Sthe clones were identical, and only 50806 was considered further. 50806 and 126654 contain overlapping nucleotide sequence, but 126654 was 63 base pairs longer at the end, while 50806 was approximately 400 base pairs longer at the 3' end.

50806 was determined to have an open reading (ORF) beginning at nucleotide position 1, a potential intron sequence at nt 358-1138, a stop codon beginning at nt 1999, and a potential poly A tail 474 base pairs 3' to the stop codon. When nt 1-357 N of 50806 were compared with nt 3538-3897 of tankyrasel, 283 of 357 nucleotides were the same (79% identical). When 50806 was translated from nt 1-357 and the Sresultant protein was compared with tankyrasel (aa 1181-1299), the proteins were the same at 116 of 120 amino acid positions (97% identity).

A putative intron was identified in 50806, consisting ofnt 358-1138, which may have been an artifact of cDNA cloning. DNA sequences preceding the putative intron (AG) and at the 3' end of the putative intron (CAG) showed high resemblance to the consensus sequence for exon/intron/exon junctions [Lewin, GENESIV, Oxford University Press: New York (1997), at p. 88]. The most common sequence at the 3' end of an exon is AG, and at the 3' end of an intron is CAG. To determine if an intron is included in the 50806 sequence, PCR analysis of genomic DNA is used to verify this prediction.

A comparison of 50806 with tankyrasel showed that a small region consisting ofnt 1139-1198 of 50806 was significantly homologous with nt 3896-3957 of tankyrasel (40 of 60 nucleotides were the same; 67% identity). When 50806 was translated from nt 1139-1198 and the resultant protein was compared with tankyrasel (aa 1300 to 1319), the proteins were the same at 14 of 20 amino acid positions identity).

126654 was determined to have an ORF beginning at nucleotide position 1, a stop codon beginning at position 481, and a potential poly A tail 81 base pairs 3' of the stop codon. Comparison of 126654 with tankyrasel showed that a region consisting ofnt 1-480 of 126654 shared significant homology with nt 3478-3957 of tankyrasel (367 of 481 nucleotides identical; 76% identity). When this region of 126654 was translated and the resultant protein compared with the corresponding region of the tankyrasel protein aa 1160-1319), the proteins were the same at -69- S149 of 160 amino acid positions (97% identity). It is possible that either of the putative poly A tails of 50806 and 126654 were artifacts of cDNA cloning or that S50806 and 126654 represented a population of mRNA that use different Spolyadenylation sites. 50806 had a stretch of 8 A residues 81 base pairs 3' to the stop codon, indicating that the putative poly A tail of 126654 was most likely a cloning artifact.

c- Alignment of AA307492 and 126654 with human tankyrasel using the SSequencherTM program (Gene Codes Corporation, Ann Arbor, MI) suggested that AA307492 was upstream of 126654, and that 11 nucleotides separated AA307492 C 10 and 126654. To confirm that AA307492 and 126654 represented polynucleotide sequence from the same gene, a primer (SEQ ID NO:47) corresponding to the sense strand of AA307492 and a primer (SEQ ID NO:48) corresponding to the antisense strand of 126654 were synthesized for use in a polymerase chain reaction (PCR) with human Marathon®-Ready spleen and testis cDNA (Clontech) as the template.

AA307492 sense CTCCGGACAACAAGGTCTTAACC (SEQ ID NO:47) 126654 antisense CCACCTATGTACGCATGCC (SEQ ID NO:48) The PCR reaction contained 2.5 pL human spleen Marathon®-Ready cDNA, 2.5 uL human testis Marathon-Ready cDNA, 250 nM each primer, 0.25 mM dNTPs, IX PCR buffer, 1.8 mM MgCl, and 5 Units of Taq polymerase (Perkin Elmer). The reaction was performed in a GeneAmp® PCR System 9700 machine (hereinafter "GeneAmp® PCR System 9700"; PE Applied Biosystems, Norwalk CT) and first heated at 94 0

C

for 2 min, followed by 35 cycles of 94 0 C for 30 sec, 55°C for 30 sec, and 72 0 C for sec, and ended with 7 min at 72 0 C. The PCR fragment was isolated using gel electrophoresis and a QIAquick® Gel Extraction Kit (hereinafter "QIAquick® kit"; Qiagen, Valencia, CA), according to the manufacturer's instructions. The PCR fragment was directly cloned into pCR®2.1 -TOPO® vector (Invitrogen, Carlsbad, CA), according to the manufacturer's instructions. The PCR fragment was sequenced with primers that hybridized to the vector DNA (SEQ ID NOs:25 and 26, supra), and the sequence of the AA307492/126654 PCR fragment is set out in SEQ ID NO:49.

The sequence confirmed that AA307492 was upstream of 126654 and that these two ESTs were separated by 11 nucleotides, and that AA307492 and 126654 were sequences from a novel gene, designated tankyrase2.

To identify the full-length tankyrase2 gene, a probe was generated from S126654 and used to screen a cDNA library using procedures routinely practiced in the art. 126654 was digested with XhoI and BgilI, and an approximately 260 nucleotide fragment designated NT-5' was isolated using gel electrophoresis and the QIAquick® kit. NT-5' was labeled with "P with a Random Primed DNA Labeling Kit ,I (Boehringer Mannheim/Roche Molecular Biochemicals, Indianapolis, IN) according to the manufacturer's instructions and used to screen 106 cDNAs from a human fetal I 10 brain library (Stratagene). Hybridization with labeled probe was performed overnight at 65 0 C in buffer containing: 3X SSC, 0.1% sarkosyl, 20 mM sodium phosphate, pH 6.8, 10X Denhardt's solution, and 50 jg/mL salmon sperm DNA. The filters were washed at 65 0 C in buffer containing 2X SSC and 0.1% SDS prior to autoradiography.

Forty-six positives were obtained with the NT-5' probe, of which fifteen were first characterized with respect to strength of hybridization with NT-5'. Restriction digest mapping and partial sequencing led to the selection of two clones, designated FB2B.1 and FB2D. 1, for further characterization.

FB2B. 1 was sequenced in its entirety on both strands with primers that hybridized to the vector DNA, including T7 promoter (SEQ ID NO:38, supra) and T3 >0 promoter (SEQ ID NO:50), and primers designed to anneal to the cDNA sequence (SEQ ID NOs:51-69).

T3 promoter ATTTAACCCTCACTAAAGGG (SEQ ID 2B.1 Fl AAAGGCTCCCATCGGCAAAT (SEQ ID NO:51) 2B.1 F2 GTTGAGGGCATTACAGTTTG (SEQ ID NO:52) 2B.1 F3 AAAACGTAGAGGCCACTGCT (SEQ ID NO:53) 2B.1 F4 TGGTGTAGACTGACGCCCTT (SEQ ID NO:54) 2B.1 F5 TCCGGTGAGTGTATCTTTCC (SEQ ID 2B.1 F6 CTCCTTTGTCTTGGGCATTC (SEQ ID NO:56) 2B.1 F9 ATCTGCTCTGCCCTCTTGTT (SEQ ID NO:57) S 2B.1 F10 GGGTATCGCGGCAATTTACA (SEQ ID NO:58) 2B.1 Fl 1 AACAAGAGGGCAGAGCAGAT (SEQ ID NO:59) 71 2B.1 F12 2B.1 R2 2B.1 R3 2B.1 R4 2B.1 R5 2B.1 R6 2B.1 R7 2B.1 R8 2B.1 R9 2B.1&2D.1

TGCCCCATCTCAACTAATAC

GTAATGCCCTCAACAGAACT

GGCGTCAGTCTACACCACTT'

TAAATTGCCCGCGATACCCA

CACTCAGTCACTGGTAGGCC

ATCTGCTCTGCCCTCTG

TAGTTGAGATGGGGCACAAG

AAACGTAGAGGCCACTGCTG

CGGGTAACCTTGJGAALGTC

GGGCTTTACTGCTITACAGA

(SEQ ID (SEQ ID NO:61) (SEQ ID NO:62) (SEQ ID NO:63) (SEQ ID NO:64) (SEQ ID (SEQ ED NO:66) (SEQ ID NO:67) (SEQ ID NO:68) FB32D. 1 was sequenced in its entirety on both strands with primers that hybridized to the vector DNA (SEQ ID) NOs:38 and 50, supra) and primers designed to anneal to the cDNA sequence, including 2B.1&2D.1 (SEQ ID NO:69) and SEQ ID NOs:70-87.

2D.1 Fl 2D.1 F2 2D.1 F3 2D.1 F4 2D.1 F5 2D.1 F6 2D.1 F7 2D.1 F8 2D.1 F9 2D.1 FIO 2D.1 R2 2D.1 R3 2D.1 R4 2D.1 R5 2D.1 R6 2D.1 R7 2D.lI R8

GTAAGGGGTGCTGACAGTGA

TTACTCCAGCAGAGGGCACT

CTGACGCCCTTCAATGTCTC

GGTACTAAGGCCACAATTCA

GGGTATCGCGGCAATTTACA

GTI'GAcGGCATTACAGTTTG

TAACAAGAGGGCAGAGCAGA

AGTTCTGTTGAGGGCAUTAC

GGCCTACCAGTGACTGAGTG

GGGCTAGAGGACCTGAA~GAG

AGTGCCCTCTGCTGGAGTAA

GGCGTCAGTCTACACCACTT

TGAATTGTGGCCTTAGTACC

ATGCCCAAGACAAAGGAGGA

GTAATGCCCTCAACAGAACT

ATCTGCTCTGCCGTCTTGTT

CGGTAACCTGGGAAAGTC

(SEQ ID (SEQ ID NO:71) (SEQ ID NO:72) (SEQ ID NO: 73) (SEQ II) NO:74) (SEQ ID (SEQ ID NO:76) (SEQ ID NO:77) (SEQ ID NO:78) (SEQ ID NO:79) (SEQ ID (SEQ ID NO:81) (SEQ ID NO:82) (SEQ ID NO:83) (SEQ ID NO:84) (SEQ ID (SEQ ID NO:86) -72- S2D. 1 R9 CCGGACAACAAGGTCTTAAC (SEQ ID NO:87).

The polynucleotide sequences for FB2B.land FB2D.1 are set out in SEQ ID NOs:88 and 90, respectively, and the deduced amino acid sequences of FB2B.1 and FB2D. 1 Sare set out in SEQ ID NOs:89 and 91, respectively.

The nucleotide and amino acid sequences of FB2B.1 and tankyrasel were compared to determine the degree of relatedness between the sequences. A region g consisting of nt 4-279 of FB2B.1 (SEQ ID NO:88) was found to have significant 1 identity with nt 1624-1899 of tankyrasel (SEQ ID NO:3), wherein 203 of 276 Snucleotides were identical (73% identity). Nucleotides 402-1254 of FB2B.1 showed S 10 significant identity with nt 2022-2874 oftankyrasel, wherein 630 of 853 nucleotides were identical (73% identity). Furthermore, nt 1507-2338 of FB2B.1 showed homology to nt 3112-3943 of tankyrasel, wherein 634 of 832 nucleotides were identical (76% identity). FB2B.1 was determined to have an ORF beginning at nucleotide position 1, a stop codon beginning at position 2353, approximately I kb of 3' untranslated sequence, but no apparent poly A tail. A translation ofnt 1-2352 of FB2B.1 showed that a region consisting of the predicted amino acid sequence (SEQ ID NO:89) was homologous to a corresponding region of tankyrasel (aa 540-1327 of SEQ ID NO:4). In this region, the proteins were identical at 623 of 777 amino acid positions (80% identity).

A similar comparison of FB2D.1 was made with tankyrasel. In this case, a region consisting of nt 6-197 of FB2D. (SEQ ID NO:90) was significantly related to nt 1708-1899 oftankyrasel, wherein 137 of 192 nucleotides were identical (71% identity). Nucleotides 320-1172 of FB2D.1 were found to share significant homology with corresponding nt 2022-2874 of tankyrasel, wherein 630 of 853 nucleotides were identical (73% identity). Nucleotides 1425-2256 ofFB2D.I showed significant homology with nt 3112-3943 of tankyrasel, wherein 634 of 832 nucleotides were identical (76% identity). FB2D. was determined to have an ORF beginning at nucleotide position 3, a stop codon beginning at position 2271, approximately 1.5 kb of 3' untranslated sequence, but no apparent poly A tail. When FB2D.1 was translated (SEQ ID NO:91), a domain predicted by the nt 3-2270 showed homology to -73aa 569-1327 of tankyrasel (SEQ ID NO:4). Here, the proteins were the same at 602 of 749 amino acid positions (80% identity).

FB2B. 1 and FB2D. I were aligned using SequencherTM. FB2B. 1 and FB2D. 1 Scontained overlapping polynucleotide sequence, but FB2B. 1 was longer at the 5' end by 82 base pairs, and FB2D. 1 was longer at the 3' end by approximately 0.5 kb. The nucleotide sequences of FB2B.1 and FB2D.I were identical in the regions nt 83-2971 N of FB2B.1 and nt 1-2889 of FB2D.1. However, the remaining 382 nucleotides of c FB2B.I and 910 nucleotides of FB2D.1 did not align. It is possible that FB2B.1 and FB2D. were random primed from different positions in the 3' untranslated region 10 and/or that this misalignment was the result of the presence of a cloning artifact in one or both of the clones. Since FB2B.1 and FB2D.1 did not appear to have poly A tails, the poly A tails of ESTs 50806 and 126654 were most likely cloning artifacts, and the real poly A tail of tankyrase2 was most likely greater than 0.5 kb from the stop codon.

A consensus polynucleotide sequence, designated 2B.1/2D.1, was developed from the alignment of FB2B.1 and FB2D.1, and is set out in SEQ ID NO:92. 2B.1/2D.1 contained nt 1-2971 of FB2B.1 and nt 1-2889 of FB2D.1.

Alignment of FB2B.land FB2D.1 with tankyrasel using SequencherTM suggested that neither FB2B.1 nor FB2D.1 represented a full-length gene, and that nucleotide sequence was missing from the 5' end oftankyrase2. Thus, FB2B.1 was digested with EcoRI and Sphl, and an approximately 466 bp nucleotide fragment located at the immediate 5' end of FB2B.I (nt 49-515 of SEQ ID NO:88) was isolated using gel electrophoresis and the QIAquick® kit. This fragment was labeled with 32

P

with a Random Primed DNA Labeling Kit and used as a probe (designated NT-37/38) to screen 106 cDNA clones of the fetal brain library (Stratagene) using the conditions and procedures used in the first screening. Fourteen positives were obtained with the NT-37/38 probe, one of which (designated 30B.2A) also hybridized with the probe, but which had not been chosen for further characterization at that time.

Restriction mapping and partial sequencing led to the selection of 30B.2A for further characterization.

The region of 30B.2A upstream of clone FB2B.1 was sequenced with primers that hybridized to the vector DNA (SEQ ID NOs:38 and 50, supra) and primers -74- Q designed to anneal to the cDNA sequence, including 2B.1 F4 (SEQ ID NO:54, supra) and SEQ ID NOs:93-97).

30B.2A #1 GGGCGGAAAGACGTAGTTGA (SEQ ID NO:93) O 30B.2A #2 GCGGCTGTTCACCTTCTCAG (SEQ ID NO:94) 30B.2A #5 ACGCAAGTGATGGCAGAAAG (SEQ ID 30B.2A #6 TCACTTGCGTGGCAGTTGAC (SEQ ID NO:96) N 30B.2A #7 GCGGCAGGTTTGTAGATGAC (SEQ ID NO:97) The partial polynucleotide sequence of 30B.2A is set out in SEQ ID NO:98, and the Spartial deduced amino acid sequence is set out in SEQ ID NO:99. Comparison of 10 30B.2A with the nucleotide sequence oftankyrasel indicated that significant homology occurred in the region consisting of nt 167-1435 of 30B.2A which corresponded with nt 631-1899 oftankyrasel. In this region, 953 of the 1269 nucleotides were the same (75% identity). 30B.2A was determined to have an ORF beginning at nucleotide position 2. Significant amino acid sequence identity was observed between a 385 amino acid sequence predicted for 30B.2A (based on nt 2- 1156) and the corresponding region of tankyrasel (aa 160-539). In this region, the protein sequences were the same at 319 of 385 amino acid positions (83% identity).

2B.1/2D.1 and 30B.2A were aligned using Sequencher T M 30B.2A 2A contained 1.157 kb of novel sequence before it began overlapping with the 5' end of 2B.1/2D.1, and began overlapping with 2B.1/2D.1 at position 1158. A consensus polynucleotide sequence, designated 2B.1/2D.1/30B.2A, was developed from the alignment of 2B.1/2D.1 and 30B.2A, and is set out in SEQ ID NO:100.

2B.1/2D.1/30B.2A contained nt 1-1157 of 30B.2 and nt 1-2971 of 2B.1/2D.1. The predicted amino acid sequence encoded by nt 2-3508 of SEQ ID NO:100 is set forth as SEQ ID NO:101. The nucleotide sequence of the TANK2-encoding region is set forth as SEQ ID NO:1, and the corresponding TANK2 polypeptide sequence is set forth as SEQ ID NO:2.

EXAMPLE 2 Cloning of 5' End of Tankvrase2 o Alignment of 30B.2A with tankyrasel using the SequencherM program suggested that 5' sequence was still lacking from the tankyrase2 gene. To clone the end of human tankyrase2, 5' RACE analysis was performed using a Marathon®- Ready human spleen cDNA library (Clontech) as the template. A primer (NT- I Marathon; SEQ ID NO:102) corresponding to the antisense strand of 2B.1/2D.1/30B.2A polynucleotide sequence (nt 337-367 of SEQ ID NO:100) was I 10 synthesized for use in a polymerase chain reaction (PCR) with the API primer (Clontech; SEQ ID NO:103) that was designed to anneal to the Marathon® cDNA Adapters ligated to the ends of the cDNAs in the library.

NT-Marathon

GAGCATTGGGGTCTGCACCATGTCGCAAAAGG

(SEQ ID NO: 102) API CCATCCTAATACGACTCACTATAGGGC (SEQ ID NO:103) The PCR reaction contained 5 pL human spleen Marathon®-Ready cDNA, 0.20 pM each primer, 0.20 mM dNTPs, IX Clontech GC 2 PCR buffer, Clontech GC-Melt buffer 0.5, 1.0, or 1.5 and 1 pL of Clontech Advantage®-GC 2 polymerase mix. The reactions were performed in a GeneAmp® PCR System 9700 with the following four steps: 1) 1 cycle at 94°C for 1 min; 2) 5 cycles of 94°C for 30 sec and 72 0 C for 30 sec; 3) 5 cycles of 94°C for 30 sec and 70°C for 30 sec; and 4) 25 cycles of 94°C for 30 sec and 60°C for 30 sec. The reactions were then continued in the GeneAmp® PCR System 9700 under the following conditions: 1) 1 cycle at 94 0 C for 1 min; 2) 5 cycles of 94C for 30 sec, and 72 0 C for 3 min; 3) 5 cycles of 94°C for sec and 70°C for 3 min; and 4) 25 cycles of 94°C for 30 sec and 600C for 3 min. The PCR fragments were isolated using gel electrophoresis and a QIAquick® kit as directed. The PCR fragments were directly cloned into the pCR@2. I-TOPO® vector, as directed. Because Taq polymerase has an error rate of 8.0 x 10- 6 mutation/ base pair (Cline et al., Nucleic Acids Res 24:3546-51), four clones isolated from four separate PCR reactions were sequenced and compared to eliminate the possibility of Taq polymerase-induced errors in the 5' RACE sequences. The four 5' RACE clones -76- Q were sequenced with the Ml 3 forward and M13 reverse primers (SEQ ID NOs:25 and 26) that hybridize to the vector DNA. The four individual nucleotide sequences were compiled into a consensus nucleotide sequence designated 5'-RACE tank2 that is set O out in SEQ ID NO:104, and the deduced amino acid sequence is set out in SEQ ID NO:105. In the consensus nucleotide sequence of 5'-RACE tank2, every base pair was present at the corresponding position in at least three of the four unique clones used to compile the consensus sequence. 5'-RACE tank2 and tankyrase were aligned using the SequencherTM program. When nt 1-279 of 5'-RACE tank2 (SEQ ID SNO:104) were compared with tankyrase no significant similarity was found. RACE tank2 was determined to have an ORF beginning at nucleotide position 2.

When nt 2-277 of 5'-RACE tank2 was translated and the resultant protein was compared with tankyrase, no significant similarity was found.

tank2 and 2B.1/2D.1/30B.2A were aligned using the Sequencher T M program. 5'-RACE tank2 contained 279 bp of novel sequence before it began overlapping with the 5' end of FB2B.1/2D.1/30B.2A, and began overlapping with 2B.1/2D.1/30B.2A at position 280. A consensus polynucleotide sequence designated 2B.1/2D.1/30B.2A/5'-RACE, was developed from the alignment of 5'-RACE tank2 and 2B.1/2D.1/30B.2A and is set out in SEQ ID NO:106. 2B.1/2D.1/30B.2A/5'- RACE contained nt 1-279 of 5'-RACE tank2 and nt 1-4140 of 2B.1/2D.1/30B.2A.

The deduced putative amino acid sequence of 2B.1/2D.1/30B.2A/5'-RACE is set out in SEQ ID NO:107.

The presence of a continuous ORF in the 5'-RACE tank sequence suggested that 5' sequence was still lacking from the tankyrase2 gene. Further attempts to obtain additional 5' sequence of tankyrase2 using 5' RACE analysis were unsuccessful. The NCBI BLASTn program was used to compare the nucleotide query sequence of FB2B.1/2D.1/30B.2A against a nucleotide sequence tag database (a nonredundant database of GenBank®+EMBL+DDBJ STS Divisions). This BLASTn search identified a STS tag sequence designated stWI-16054 (GenBank® Accession No. G24639; SEQ ID NO:108). When nt 3608-3985 of 2B.1/2D.1/30B.2A was compared with the antisense complement nt 8-397 of stWI-16054, 361 of 378 nucleotides were the same (96% identical). The Sanger Centre (Cambridge,

UK)

-77- SHuman Genome Clone Search program (http://www.sanger.ac.uk/cgibin/humace/searcher.cgi) was used to identify BAC clones containing stWl-16054.

BAC clone bA329B8 was identified as containing the STS tag stWl-16054. BAC clone bA329B8 originates from the genomic RPCI-11.2 male white blood cell library (Pieter deJong, Roswell Park Cancer Institute, Buffalo, NY) and was purchased from r- Research Genetics, Inc. (Huntsville, AL). A Large Construct Kit (Qiagen) was used to isolate bA329B8 DNA, which was used as a template in inverse PCR amplification reactions [Ochman et al., "Amplification of Flanking Sequences by Inverse PCR," pp.

S219-27 in PCR Protocols: A Guide to Methods and Applications (Innis et al., eds.), Academic Press, San Diego, CA (1990)]. The inverse PCR technique allows for the amplification of unknown DNA sequence flanking a region of known sequence.

Briefly, template DNA is digested with a restriction enzyme (preferably, one that recognizes a four or five base pair consensus site), followed by circularization of the restriction fragments. Circularized fragments are used as a template in a PCR reaction with two primers designed to anneal to the known flanking sequence but pointed in opposite directions. One microgram (1 tg) of bA329B8 was digested in a 20 uL reaction containing IX appropriate reaction buffer and 10 units of one of the following restriction enzymes: RsaI (Promega, Madison, WI), Bfal (New England Biolabs, Beverly, MA), or Tru9I (Promega). The restriction digests were incubated for one hour at 37 0 C (Rsal and Bfal) or 65 0 C (Tru9). The Rsal and BfaI digests were heated at 68 0 C for 20 minutes to inactivate the restriction enzymes. A QIAquick® kit was used to inactivate the restriction enzyme in the Tru91 digest. Ligation reactions contained the following: 20 tL of the Tru91, Rsal, or Bfal reactions, 448 uL distilled water, 50 UL 10X reaction buffer, and 2 A.L T4 DNA ligase (5U/uL; Boehringer Mannheim, Indianapolis, IN). Ligations were incubated overnight at 15 0 C. The DNAs in the ligation reactions were then precipitated by adding 129.26 L 7 M ammonium acetate and 2.3 mL 95% ethanol. The DNAs were pelleted, washed with ethanol, resuspended in 15 AL distilled water, and used as templates in PCR amplification reactions. A primer (5-Inv-1; SEQ ID NO:109) corresponding to the sense strand of 5'-RACE tank2 (nt 423-443 of SEQ ID NO:104) and a primer (3-Inv- -78- 1; SEQ ID NO:110) corresponding to the antisense strand of 5'-RACE tank2 (nt 364- S383 of SEQ ID NO:104) were synthesized for use in PCR amplification reactions.

5-Inv-1 CGCCTGAGAAGGTGAACAGCC (SEQ ID NO: 109) 3-Inv-1 ACGCCTCGAACAGCTCTCGG (SEQ ID NO: 110) The PCR reactions (final reaction volume of 20 uL) contained 5 pL of the Tru91, Rsal, or BfaI DNA template, 0.20 pM each primer, 0.20 mM dNTPs, 1X Clontech GC 2 PCR buffer, 1.0 M Clontech GC-Melt buffer, and 0.4 pL of Clontech Advantage®- GC 2 polymerase. The reactions were performed in a GeneAmp® PCR System 9700 0 with the following four steps: 1) 1 cycle at 94 0 C for 1 minute; 2) 5 cycles of 94 0 C for 30 seconds and 65C for 3 minutes and 30 seconds; 3) 5 cycles of 94 0 C for seconds and 60°C for 3 minutes and 30 seconds; and 4) 25 cycles of 94°C for seconds and 58 C for 3 minutes and 30 seconds. The PCR fragments were isolated using gel electrophoresis and a QIAquick® kit as directed. The PCR fragments were directly cloned into the pCR®2.1-TOPO® vector, as directed. The Tru9I, RsaI, and BfaI clones were sequenced with the M13 primers that hybridize to the vector DNA (SEQ ID NOs:25 and 26) and primers designed to anneal to the cDNA sequence (SEQ ID NOs:109-112).

5-Inv-2 GCGTGGGCGCGGCCATGGGACTG (SEQ ID NO:111) 3-Inv-2 CAGCGCGAATCCGCCGTCCG (SEQ ID NO: 112) The Tru9I, Rsal, and Bfal polynucleotide sequences are set out in SEQ ID NOs: 113, 115, and 117, respectively. The deduced amino acid sequences of Tru91, Rsal, and Bfal are set out in SEQ ID NOs:114, 116, and 118, respectively.

Clones Tru91 and 5'-RACE tank2 were aligned using the Sequencher

T

M

program. Clone Tru91 (SEQ ID NO: 113) contained 235 bp of novel sequence before it began overlapping with the 5' end of 5'-RACE tank2 (SEQ ID NO: 104), and began overlapping with 5'-RACE tank2 at position 236. When nt 1-235 of clone Tru91 were compared with tankyrase no significant similarity was found. Clone Tru9I was determined to have an ORF beginning at nucleotide position 3. When clone Tru9I was translated from nt 3-236 and the resultant protein was compared with tankyrase no significant similarity was found.

-79- Clone Rsal and 5'-RACE tank2 were aligned using the SequencherM program. Clone Rsal (SEQ ID NO: 115) contained 654 bp of novel sequence before it began overlapping with the 5' end of 5'-RACE tank2 (SEQ ID NO:104), and began overlapping with 5'-RACE tank2 at position 655. When nt 1-654 of clone Rsal were compared with tankyrase no significant similarity was found. Clone RsaI was r determined to have an ORF beginning at nucleotide position 160, with a putative ATG start codon beginning at nucleotide 287. When clone RsaI was translated from nt 287-655 and the resultant protein was compared with tankyrase no significant Ssimilarity was found.

Clone BfaI (SEQ ID NO:117) and 5'-RACE tank2 were aligned using the Sequencher

T

program. Clone BfaI contained 88 bp of novel sequence before it began overlapping with the 5' end of 5'-RACE tank2 (SEQ ID NO:104), and began overlapping with 5'-RACE tank2 at position 89. When nt 1-88 of clone BfaI were compared with tankyrase no significant similarity was found. Clone Bfal was determined to have an ORF beginning at nucleotide position 3. When clone Bfal was translated from nt 3-89 and the resultant protein compared with tankyrase no significant similarity was found.

To confirm the new polynucleotide sequence obtained from the Tru9I, Rsal, and Bfal clones and to determine ifintrons are present in the new sequence, PCR amplification of cDNA was performed. A primer (5-RSA-1; SEQ ID NO: 119) corresponding to the sense strand of clone Rsal (nt 59-84 of SEQ ID NO: 115) and a primer (3-Inv-l; SEQ ID NO: 110) corresponding to the antisense strand of clone Rsal (nt 708-727 of SEQ ID NO: 115) were synthesized for use in PCR amplification reactions.

5-RSA-1 GTTCCTCTAATCAATCCTGAGC (SEQ ID NO:119) Six separate PCR reactions were performed (designated 18, 19, 20, 24, 25, and 26) to aid in the identification of Taq polymerase-induced errors as described above. Each pL reaction contained 5 pL of human spleen, placenta, or testis Clontech Marathon®-Ready cDNA DNA template, 0.20 ulM each primer, 0.20 mM dNTPs, IX Clontech GC 2 PCR buffer, 1.0 M Clontech GC-Melt buffer, and 0.4 pL of Clontech Advantage@-GC 2 polymerase. The reactions were performed in a GeneAmp®

PCR

Q System 9700 with the following four steps: 1) 1 cycle at 94 0 C for 1 min; 2) 5 cycles of 94 0 C for 30 sec and 65 0 C for 2.5 min; 3) 5 cycles of 94°C for 30 sec and 60 0 C for min; and 4) 25 cycles of 94 0 C for 30 sec and 58C for 2.5 min. The PCR fragments O were isolated using gel electrophoresis and a QIAquick® kit as directed. The PCR fragments were directly cloned into the pCR®2.1-TOPO® vector, as directed. Clones S18, 19,20, 24, 25, and 26 were sequenced with the M13 primers that hybridized to the N vector DNA (SEQ ID NOs:25 and 26) and primers designed to anneal to the cDNA sequence (SEQ ID NOs:112, 120, 121, and 122).

5-RSA-2 GGAAAGAGTAATTGATCAGAGCCATC (SEQ ID NO:120) 5-RSA-4 CGCCGAAGCCTCTCGCCTCACATTTCC (SEQ ID NO:121) 3-RSA-4 GGAAATGTGAGGCGAGAGGCTTCGGCG (SEQ ID NO:122) The polynucleotide sequences of clones 18, 19, 20, 24, 25, and 26 are set out in SEQ ID NOs:123-128, respectively.

Clones 18, 19, 20, 24, 25, 26 and clone RsaI were aligned using the Sequencher T M program. The polynucleotide sequence of the cDNA clones confirmed that there were no introns present in the RsaI clone sequence. Base pairs 1-596 of clones 18, 19, 20, 24, 25, and 26 were compiled into a consensus nucleotide sequence with bp 59-596 of clone Rsal that is designated 5'-RSA/cDNA and is set out in SEQ ID NO:129. The polynucleotide sequence of 5'-RSA/cDNA does not include nucleotide sequence 3' to base pair 597 of clones 18, 19, 20, 24, 25, 26, which is discussed below. The polynucleotide sequence of 5'-RSA/cDNA also does not include bp 1-58 of clone RsaI, as this nucleotide sequence was not confirmed in the cDNA clone sequence. In the consensus nucleotide sequence of 5'-RSA/cDNA, every base pair was present at the corresponding position in 6 of the 7 clones, except nucleotide position 47 in which the consensus base pair was present at the corresponding position in 4 of the 7 clones.

The alignment of clones 18, 19, 20, 24, 25, and 26 identified a difference in the nucleotide sequence 3' to base pair 597 (reference position in SEQ ID NOs:123- 128). All of the aligned clones contain one copy of a 10 base pair sequence (GAGCTGGCAG; SEQ ID NO:130) located at nt 588-597 (SEQ ID NOs:123-128).

Clones 19 and 26 have a second copy of the sequence GAGCTGGCAG repeated -81 Sdirectly adjacent to the first copy (nt 598-607) (SEQ ID NOs:124 and 128). Clone Rsal, clone Tru91, and clone BfaI also have two copies of the sequence GAGCTGGCAG directly adjacent to each other (nt 646-665 in clone Rsal, (SEQ ID NO: 115); nt 227-246 in clone Tru91 (SEQ ID NO:113); and nt 80-99 in clone Bfal (SEQ ID NO: 117)). Clones 18, 20, 24, and 25 do not have the second copy of the sequence GAGCTGGCAG. The presence or absence of the second copy of the sequence GAGCTGGCAG could result from an error in PCR amplification caused by C Taq polymerase. Direct sequencing of genomic DNA can be used to verify this 8 prediction. The presence or absence of the second copy of the sequence GAGCTGGCAG could also be caused by replication and/or repair proteins present in the bacteria used to propagate the cloned DNA. Direct sequencing of PCR products can be used to verify this prediction. The presence or absence of the second copy of the sequence GAGCTGGCAG could also result from alternative 3'-splice acceptor usage. This possibility seems unlikely since the sequences surrounding the GAGCTGGCAG sequence do not show high resemblance to the consensus sequence for exon/intron/exon borders [Lewin, supra]. In addition, clones generated from PCR amplification of genomic DNA have been isolated that contain only one copy of the GAGCTGGCAG sequence (Genomic 1X; SEQ ID NO:131) as well as clones containing two copies of the GAGCTGGCAG sequence (clones Rsal (SEQ ID NO:115) Tru9I (SEQ ID NO: 113) and BfaI (SEQ ID NO: 117)). The presence or absence of the second copy of the sequence GAGCTGGCAG may also be a polymorphism present in the human population. In this case, expression of a long and short form of the TANK2 protein would be possible, as discussed below.

The presence of two copies of the sequence GAGCTGGCAG produces a long form of the TANK2 protein. Clones 19, 26, Rsal, Tru9I, and BfaI were aligned with and 2B.1/2D.1/30B.2A/5'-RACE using the SequencherTM program. A consensus polynucleotide sequence designated tankyrase2-long was developed from the alignment and is set out in SEQ ID NO:132. The sequence of tankyrase2-long was determined to have an ORF from nt 103-4386, with the first methionine beginning at nt 229. An in-frame stop codon (beginning at nt 100) was present upstream of the putative initiating methionine. Assuming that this residue is the -82initiating methionine, the ORF of tankyrase2-long encodes a protein of 1385 amino acids (designated TANK2-LONG; SEQ ID NO: 133) with a predicted molecular weight of 149,892 Da.

The presence of one copy of the sequence GAGCTGGCAG produces a short form of the TANK2 protein. Clones 18, 20, 24, and 25 were aligned with RSA/cDNA and 2B.1/2D.1/30B.2A/5'-RACE using the Sequencher

T

M program. A Sconsensus polynucleotide sequence designated tankyrase2-short was developed from tI the alignment and is set out in SEQ ID NO:134. The sequence of tankyrase2-short 0was determined to have an ORF from nt 513-4376, with the first methionine beginning at nt 876. An in frame stop codon (beginning at nt 510) was present upstream of the putative initiating methionine. Assuming this residue to be the initiating methionine, the ORF of tankyrase2-short encoded a 1166 amino acid protein (designated TANK2-SHORT; SEQ ID NO:135) with a predicted molecular weight of 126,908 Da. TANK2-SHORT is 219 amino acids shorter at the amino terminal end than TANK2-LONG. The putative initiating methionine of TANK2-SHORT corresponds to a methionine at position 120 of TANK2-LONG. Excluding the first 219 amino acids of TANK2-LONG, TANK2-LONG and TANK2-SHORT are identical.

The tankyrasel gene (SEQ ID NO:3) encodes a protein TANK1 (SEQ ID NO:4) containing a carboxyl-terminal catalytic domain that has homology to the catalytic domain of human PARPI. The polynucleotide sequence ofparpl is set out in SEQ ID NO:136, and the amino acid sequence of PARPI is set out in SEQ ID NO:137. The catalytic domain of TANKI (aa 1176-1314 of SEQ ID NO:4) is homologous to the catalytic domain of PARP (aa 854-1014 of SEQ ID NO:137) and contains PARP catalytic activity (Smith et al., supra). Similarly, the putative catalytic domain of TANK2-LONG (aa 1242-1382 of SEQ ID NO:133) and TANK2-SHORT (aa 1023-1161 of SEQ ID NO:135) is highly homologous to the catalytic domain of TANKI (130 of 139 amino acids are the same; 94% identity).

The central domain of TANKI contains 24 ankyrin repeats, indicating that TANK1 might belong to the ankyrin family of proteins that bridge integral membrane proteins to the cytoskeleton [Bennett, JBiol Chem 267: 8703-6 (1992)]. The ankyrin -83- Srepeat domain of TANK 1 (aa 181-1110 of SEQ ID NO:4) is significantly homologous to a central domain of TANK2-LONG (aa 242-1078 of SEQ ID NO:133) and TANK2-SHORT (aa 23-859 of SEQ ID NO:135) (692 of 837 amino acids are the O same; 83% identity).

Within the ankyrin repeat domain of TANKI is a binding site for the telomeric repeat binding factor-1 (TRFI) (Smith et al., supra) that functions to regulate the Slength oftelomeres [van Steensel and de Lange, Nature 385:740-3 (1997)]. The TRF1 binding domain of TANKI (aa 436-797 of SEQ ID NO:4) is significantly 8 homologous to a region of TANK2-LONG (aa 497-858 of SEQ ID NO:133) and S 10 TANK2-SHORT (aa 278-639 of SEQ ID NO:135) (297 of 364 amino acids are the same; 82% identity).

TANKI also contains a sterile alpha module (SAM) domain [Smith et al., supra] that is thought to be involved in protein-protein interactions [Ponting, Protein Sci 4:1928-30 (1995); Schultz et al., Protein Sci 6: 249-53 (1997)]. A region of TANK2-LONG (aa 1089-1154 of SEQ ID NO:133) and TANK2-SHORT (aa 870-935 of SEQ ID NO:135) is homologous to the SAM domain of TANKI (aa 1023-1088 of SEQ ID NO:4) (50 of 66 amino acids are the same; 76% identity).

A comparison of several putative functional domains of TANK2 (catalytic domain, ankyrin repeats, TRF-I binding domain, and SAM domain) with TANK1 is discussed above. The additional amino terminal sequence contained in TANK2- LONG (all residues amino terminal to the ankyrin repeats, aa 1-241 of SEQ ID NO:133) allows for a comparison with the amino terminus of TANK1. The amino terminus of TANKI contains homopolymeric runs of histidines, prolines, and serines (HPS domain, aa 1-180 of SEQ ID NO:4) [Smith et al., supra]. The amino terminus of TANK2-LONG does not contain a HPS domain nor is it significantly homologous with the amino terminus of TANKI. The amino terminus of TANK2- LONG is also 61 amino acid residues longer than TANK1 and is composed of 48.1% non-polar residues, 32.4% polar residues, and 19.5% charged residues.

TANK2-SHORT is 219 amino acid residues shorter than TANK2-LONG and only contains 22 amino acid residues amino terminal to the ankyrin repeats.

Interestingly, the Drosophila melanogaster tankyrase gene (GenBank® Accession No.

-84- O AF132196; SEQ ID NO:138) encodes a putative protein designated dTANK (SEQ ID NO: 139) that only contains 21 amino acid residues amino terminal to its ankyrin repeats. The amino terminal ends of TANK2-SHORT and dTANK are not 0 significantly homologous, although the two proteins do share homology in the other putative functional domains discussed above. The catalytic domain of TANK2- SHORT (aa 1023-1161 of SEQ ID NO:135) is homologous to a region of dTANK (aa 1033-1171 ofSEQ ID NO:139) (113 of 139 amino acids are the same; 81% identity).

SThe putative ankyrin repeat domain of TANK2-SHORT (aa 23-859 of SEQ ID SNO: 135) is significantly homologous to a central domain of dTANK (aa 22-875 SEQ ID NO:139) (545 of 858 amino acids are the same; 64% identity). The putative TRFI binding domain of TANK2-SHORT (aa 278-639 of SEQ ID NO:135) is significantly homologous to a region of dTANK (aa 277-633 SEQ ID NO:139) (241 of 364 amino acids are the same; 66% identity). The putative SAM domain ofTANK2-SHORT (aa 870-935 of SEQ ID NO:135) is significantly homologous to a region of dTANK (aa 886-951 of SEQ ID NO:139) (31 of 66 amino acids are the same; 66% identity).

EXAMPLE 3 Preparation of Antibodies Immunoreactive with TANK2 Polypeptides The present invention provides for antibodies with specificity for TANK2 polypeptides. Antibodies to TANK2 may be produced by any method known in the art typically including, for example, the immunization of laboratory animals with preparations of purified native TANK2, purified recombinant TANK2, purified recombinant fragments of TANK2, or synthetic peptides derived from the TANK2 predicted amino acid sequence. To maximize the probability of obtaining antibodies with appropriate specificity for TANK2, regions of the polypeptide may be selected for use as an immunogen based upon differences in those regions between TANKI and TANK2. For example, alignment of TANKI and TANK2 demonstrates that a region consisting of aa 969-974 of TANK (SEQ ID NO:4) is substantially different from the corresponding region (aa 1030-1042) of TANK2-LONG (SEQ ID NO:133).

In addition, the amino terminal domains of TANK1 (aa 1-180 of SEQ ID NO:4) and TANK2-LONG (aa 1-241 of SEQ ID NO: 133) are substantially different, as discussed Q above. These regions can be expressed as truncated polypeptides in an appropriate Sexpression system for use as immunogen or to test polyclonal or monoclonal antibody preparations. Similar approaches can be applied to other regions of the TANK2 polypeptide. Likewise, synthetic peptides can be made to correspond to various regions of differences and such peptides can be utilized to generate specific polyclonal or monoclonal antibodies by methods known in the art. For examples, see discussions N in Harlow et al. (1988), supra.

Alignment of TANKI and TANK2 indicated that a region of TANK2-LONG Sconsisting of aa 1030-1042 (SEQ ID NO:133) was substantially different than the corresponding region of TANK1 (aa 969-974 of SEQ ID NO:4). A peptide, designated ICEC having this TANK2 sequence, was synthesized by AnaSpec Inc.

(San Jose, CA) for use as an immunogen in antibody development. Peptide ICEC #2 was conjugated to KLH using Imject® Maleimide Activated Carrier Proteins (Pierce, #77106) following the manufacturer's protocol.

Each of four 6 to 12 week old Balb/c mice were pre-bled on day 0 and immunized by subcutaneous injection of 50 pg per mouse of KLH-ICEC-2 peptide in Freund's complete adjuvant. Subsequent boosts were made on day 21 and 42 in Freund's incomplete adjuvant. Mice were test bled on day 52 and the bleeds were screened by ELISA, using standard methods, on plates coated with KLH-ICEC-2 peptide. Specific antibody was detected using goat anti-mouse IgG(fc) horseradish peroxidase (HRP) conjugate. Mouse #3616 was given pre-fusion boosts on day 118 and 119 with 50 pg KLH-ICEC-2 peptide in PBS. The spleen was removed and fused on day 122.

Splenocytes were fused to NS-1 cells in a ratio of 5:1 by standard methods using polyethylene glycol 1500 (Boehringer Mannheim/Roche Molecular Biochemicals) [Harlow et al. (1988), supra]. The fused cells were resuspended in 250 mL RPMI containing 15% FBS, 100 mM sodium hypoxanthine, 0.4 mM aminopterin, 16 mM thymidine (HAT) (Gibco BRL, Rockville, MD), 10 units/mL IL-6 (Boehringer Mannheim/Roche Molecular Biochemicals) and 1.5 X 106 murine thymocytes/mL.

The suspension was dispensed into twelve and a half96-well flat bottom tissue culture plates (Coming, United Kingdom) at 200 pL/well. Cells in plates were fed on -86- Sdays 4, 5, and 6 post fusion by aspirating approximately 100 L from each well and adding 100 UL/well plating medium described above except lacking thymocytes.

Supernatants from the fused cells were screened on day 7-12, initially by O ELISA on the immunogen, as described above. To ensure clonality, positive wells chosen from the fusion were subcloned 3 times by limiting dilution, using media lacking aminopterin. Cloning was completed for one fusion, 345C, which remained Sreactive to the immunizing protein. Isotyping of the antibody was performed by Sstandard ELISA methods, using goat anti-mouse IgGi, IgG2a, IgG2b, and IgG3 HRP conjugates as detecting antibodies. The clone 345C was IgGl.

Western analysis was also used to test immunoreactivity of 345C to TANK2.

1 X 107 non-proliferating human PBL cells were pelleted by centrifugation and lysed by addition of 0.5 mL Buffer D NP 40, 0.1% TX-100, 100 mM KC1, 20 mM HEPES, pH 7.9, 0.2 mM EDTA, 0.2 mM EGTA, 1.0 mM dithiothreitol (DTT), and protease inhibitor cocktail tablets, (Boehringer Mannheim/Roche Molecular Biochemicals)]. Lysates were sonicated (Sonifier® 250, Branson Ultrasonics Corp., Danbury, CT) at 20% output for 30 seconds and clarified in a 4°C microfuge for min and the pellets discarded. Mouse IgG (2.5 pg) or 0.5 mL 345C mAb culture supernatant was added to the lysates and they were incubated for 90 min at 4 0

C.

Immune complexes were collected by precipitation with 30 pL protein G-Agarose slurry (Pierce) with gentle rocking for 30 minutes at 4 0 C. Pellets were washed 4X in Buffer D, resuspended in 25 uL IX SDS Sample buffer [50 mM Tris-HCI, pH 6.8, 2% SDS, 0.1% bromophenol blue, 10% glycerol, and 100 mM DDT], and heated for min at 100 0

C.

Samples were electrophoresed on 8% Tris-Glycine polyacrylamide gels (Novex, San Diego, CA) at 60 mA for 30 min, as described by the manufacturer. Gels were transferred to Immobilon-P transfer membrane (Millipore, Bedford, MA) using a Bio-Rad (Hercules, CA) semi-dry blotting apparatus at 150 mA for 90 min as described by the manufacturer. Blots were then blocked in TBST buffer (Tris buffered saline, pH 7.5 and 0.5% Tween®) containing 5.0% nonfat dry milk for 20-30 min at room temperature. Primary mAb 345C culture supernatant was then added at a 1:2 dilution to TBST containing 1.0% nonfat dry milk and blots were incubated at -87room temperature for 90 min. Following 4 washes with TBST, secondary antibody (goat anti-mouse IgG HRP conjugate, Bio-Rad) was added at a 1/3,100 dilution in TBST containing 1.0% nonfat dry milk and blots were incubated for 30 min at room temperature. Blots were again washed 4X in TBST followed by incubation in ECL detection reagents (Amersham Life Sciences, Uppsala, Sweden) as described by the manufacturer, followed by exposure to X-ray film. Positive signals of approximately the expected size for TANK2-LONG and TANK2-SHORT were obtained. The entire I procedure is repeated to obtain more strongly immunoreactive monoclonal antibodies.

EXAMPLE 4 Analysis of Tank2 Expression by Northern Blot Hybridization In order to identify cell and tissue types that express tankyrase2 mRNA, Northern blot analysis was performed using commercially prepared multi-tissue Northern blots (Clontech). The DNA probe template was amplified by PCR using a primer (5-Tank2-15; SEQ ID NO:140) corresponding to the sense strand of FB2B.l polynucleotide sequence (nt 2330-2349 of SEQ ID NO:88) and a primer (3-Tank2-18; SEQ ID NO:141) corresponding to the antisense strand of FB2B.1 polynucleotide sequence (nt 2656-2675 of SEQ ID NO:88).

5-Tank2-15 GGCCTGAAGGTATGGTCGAT (SEQ ID NO:140) 3-Tank2-18 TGAGGGCATTACAGTTTGTT (SEQ ID NO:141) The PCR reaction contained 100 ng FB2B. cDNA, 0.25 pM each primer, 0.20 mM dNTPs, IX PCR buffer, and 1 UL of Clontech Advantage@ polymerase mix. The reactions were performed in a GeneAmp® PCR System 9700 with the following steps: 1) 1 cycle at 940C for I min; 2)'30 cycles of 94°C for 30 sec, 60°C for 30 sec, and 72°C for 30 sec; and 3) 1 cycle at 72°C for 7 min. The PCR fragment (designated Tank2-Nprobe; SEQ ID NO:142) was isolated using gel electrophoresis and a QIAquick® kit as directed. Tank2-Nprobe was labeled with 3 2 P with a Random Primed DNA Labeling Kit (Boehringer Mannheim/Roche Molecular Biochemicals) as directed and used to probe Clontech multi-tissue Northern blots. Prehybridization with Clontech's ExpressHybTM DNA Hybridization solution was performed at 680C for 30 min. Hybridization with labeled probe was performed for 1 hr at 68°C in -88- ExpressHybTM. The blots were washed three times at room temperature in buffer containing 2X SSC and 0.05% SDS and then washed two times at 50 0 C in buffer containing 0.1X SSC and 0.1% SDS prior to autoradiography.

The tissue Northern blot contained an approximately 6.3 kb band whose signal was strongest in placenta, PBL, ovary, and spleen and was present in pancreas, kidney, skeletal muscle, liver, lung, brain, heart, colon, small intestine, testis, prostate, Sand thymus.

EXAMPLE Analysis of Tank2 Expression by in situ Hybridization Expression of tankyrase2 was examined in tissue sections by in situ hybridization as described below.

Preparation of probes A probe for tankyrase2 in situ hybridization was generated using procedures routinely practiced in the art. A primer (5-Tank2-15p; SEQ ID NO:143) corresponding to the sense strand of FB2B.1 polynucleotide sequence (nt 2330-2349 of SEQ ID NO:88) and a primer (3-Tank2-18p; SEQ ID NO:144) corresponding to the antisense strand ofFB2B.1 polynucleotide sequence (nt 2656-2675 of SEQ ID NO:88) were synthesized for use in a PCR reaction using FB2B. 1 as the template.

5-Tank2-15p

GCCGAATTCGGCCTGAAGGTATGGTCGAT

(SEQ ID NO:143) 3-Tank2-18p

GCCGAATTCTAGATGAGGGCATTACAGTTTGTT

(SEQ ID NO:144) The PCR reaction contained 100 ng FB2B. 1 cDNA, 0.5 pM each primer, 0.25 mM dNTPs, IX PCR buffer, and 2.5 U ofPfuTurbo® polymerase mix (Stratagene). The reactions were performed in a GeneAmp® PCR System 9700 with the following steps: 1) 1 cycle at 94C for 1 min; 2) 25 cycles of 94°C for 30 sec, 55 0 C for 1 min, and 72 0 C for 1 min; and 3) 1 cycle at 72 0 C for 7 min. The PCR fragment was digested with EcoRI, isolated using gel electrophoresis and a QIAquick® kit, and subcloned into a Bluescript® vector (Stratagene). The clone, designated Tank2- -89- ISprobe, was sequenced with the M13 primers designed to anneal to the vector (SEQ ID NOs:25 and 26) and the sequence is set out in SEQ ID NO:145. Tank2-1Sprobe was digested with Xhol and transcribed (see below) with T3 polymerase to generate an antisense probe. A sense probe was generated by digesting Tank2-ISprobe with BamHI and transcribing with T7 polymerase.

To compare the tissue expression of tankyrase2 with tankyrasel, a tankyrase 1 probe was generated. The tankyrasel probe corresponds to a region in the 3' untranslated sequence of the tankyrasel gene. The 3' untranslated sequence of Stankyrasel, designated 3-TanklUT, is set out in SEQ ID NO:146. A primer Tankl-7p; SEQ ID NO:147) corresponding to the sense strand of 3-TanklUT polynucleotide sequence (nt 407-426 of SEQ ID NO:146) and a primer (3-Tankl-13p; SEQ ID NO:148) corresponding to the antisense strand of 3-TanklUT polynucleotide sequence (nt 742-767 of SEQ ID NO: 146) were synthesized for use in a PCR reaction using 3-TanklUT as the template.

5-Tankl-7p GCCGAATTCCTTGTTTTTGATTTGCCAGA (SEQ ID NO:147) 3-Tankl-13p

GCCGAATTCCGGCTTTGACTTCTCTGAATTTAGG

(SEQ ID NO:148) The PCR reaction contained 100 ng 3-TanklUT cDNA, 0.5 uM each primer, 0.25 mM dNTPs, IX PCR buffer, and 2.5 U ofPfuTurbo® polymerase mix (Stratagene).

The reactions were performed in a GeneAmp® PCR System 9700 with the following steps: 1) 1 cycle at 94 0 C for 1 min; 2) 30 cycles of 94°C for 30 sec, 55 0 C for 1 min, and 72°C for 1 min; and 3) 1 cycle at 72 0 C for 7 min. The PCR fragment was digested with EcoRI, isolated using gel electrophoresis and a QIAquick® kit, and subcloned into a Bluescript® vector (Stratagene). The clone, designated Tankl- ISprobe, was sequenced with the M 13 primers (SEQ ID NOs:25 and 26) and the sequence is set out in SEQ ID NO:149. Tankl-ISprobe was digested with BamHI and transcribed with T7 polymerase to generate an antisense probe. A sense probe was generated by digesting Tank -ISprobe with Xhol and transcribing with T3 polymerase.

The Tankl-IS probe and Tank2-ISprobe were transcribed using a RNA Transcription kit (Stratagene) in a reaction containing 5 tL of 5X transcription buffer, mM DTT, 0.8mM each ATP, CTP, GTP, 40 U RNase Block II, 12.5 U T3 or T7 polymerase, 300 ng linearized plasmid template, and 50 gCi 35 S-UTP (greater than 1000 Ci/mmol, Amersham, Arlington Heights, IL). The mixture was incubated at o 37 0 C for 1 hr, after which the template DNA was removed by addition of 1 AL of RNase-free DNase I (Stratagene) and incubated for 15 min at 37 0 C. A Quick Spin RNA column 3' Inc., Boulder, CO) was prepared according to the manufacturer's suggested protocol. Twenty-five microliters (25 L) of dHO was added to the probe and it was placed in the center of the column and the column centrifuged for 4 min at 1100 rpm in a desk top centrifuge. The column flow-through was mixed with 50 pL dH20, 2 pL of a 10mg/mL tRNA solution, 10 tL 3 M sodium acetate, and 200 uL 100% ethanol (VWR, So. Plainfield, NJ) and the resulting mixture was incubated at -20 0 C overnight. The probe solution was centrifuged for min at 4 0 C, the supernatant was removed, and the pellet was resuspended in 40 AL 1X TBE [90 mM Tris-Borate and 2 mM EDTA (pH containing 1 pL of 0.1 M DTT.

The probe was stored at -70C until the in situ hybridization was performed.

Preparation of tissue samples and in situ hybridization Tissues (National Disease Research Interchange, Philadelphia, PA and Cooperative Human Tissue Network, Philadelphia, PA) were sectioned at 6 pm and placed on Superfrost® Plus slides (VWR). Sections were fixed for 20 min at 4 0 C in 4% paraformaldehyde (Sigma, St. Louis, MO). The slides were rinsed in three changes of IX CMF-PBS, dehydrated with three successive washes with 70% ethanol, ethanol, and 100% ethanol, and dried for 30 min at room temperature. The slides were placed in 70% formamide Baker, Phillpsburg, NJ) in 2X SSC for 2 min at 70 0 C, rinsed in 2X SSC at 4 0 C, dehydrated through 70%, 95%, and 100% ethanol washes, and dried for 30 min at room temperature. Slides were placed in an airtight box containing a piece of filter paper saturated with box buffer containing formamide in 4X SSC. The probes, as described above, were individually prepared by mixing 4 X 10' cpm/ tissue section with 5 uL of a 10 mg/mL tRNA solution per section and heating the mixture at 95 0 C for 3 min. Ice-cold rHB2 buffer dextran sulfate (Sigma), 50% formamide, 100 mM DTT (Boehringer -91- Mannheim/Roche Molecular Biochemicals), 0.3 M NaCI (Sigma), 20 mM Tris, pH 5 mM EDTA (Sigma), and IX Denhardt's solution (Sigma)] was added to the 1' probe mixture to bring the final volume to 60 pUIsection. The probe solution was O then added to the tissue sections. The slides were incubated at 50 0 C for 12-16 hr.

Following hybridization, the slides were washed once in 4X SSC containing 10 mM DTT for 1 hr at room temperature, once in 50% deionized formamide, IX SSC, and 1 i mM DTT for 40 min at 60 0 C, once in 2X SSC for 30 min at room temperature, and ,I once in 0.1X SSC for 30 min at room temperature. The sections were dehydrated through 70%, 95%, and 100% ethanol washes and air dried for 30 min. The slides CI 10 were dipped in Kodak (Rochester, NY) NTB2 nuclear emulsion at 45 0 C for 3 hr at room temperature in the dark and stored in the dark at 4 0 C with desiccant until time of development.

The slides were rinsed in dH20 and stained with hematoxylin and eosin by transfer of the slides through a series of the following steps: 5 min in formaldehyde/alcohol (100 mL formaldehyde, 900 mL 80% ethanol); three rinses in water for a total of 2 min; 5 min in 0.75% Harris hematoxylin (Sigma); three rinses in water for a total of 2 min; one dip in 1% HCI/50% ethanol; one rinse in water; four dips in 1% lithium carbonate; 10 min in tap water; 2 min in 0.5% eosin (Sigma); three rinses in water for a total of 2 min; 2 min in 70% ethanol; three 1 min rinses in ethanol; two 1 min rinses in 100% ethanol; and two 2 min rinses in xylene. Slides were mounted with cytoseal 60 (Stephens Scientific, Riverdale, NJ).

The signals obtained with the antisense tankyrasel or antisense tankyrase2 probes were compared to the control signals obtained by the respective sense probes and any signal specific to the antisense tankyrasel or antisense tankyrase2 probe was assumed to represent tankyrasel or tankyrase2 expression, respectively. Both tankyrasel and tanyrase2 signal was detected in most areas of the human testis, including the spermatogonia and spermatocytes. Tankyrasel signal was detected in the red pulp of the human spleen while tankyrase2 signal was detected in the white pulp of the human spleen. The probes for tankyrasel and tankyrase2 are used to detect expression in other tissues in a similar manner. Tankyrasel signal was detected uniformly in mouse embryo, with the highest signal present in the skin. Tankyrase2 -92- O signal was also detected uniformly in mouse embryo, with the highest signal present in the mesenchymal areas and in the brain.

0 EXAMPLE 6 Identification of a Tankvrase2 Binding Partner As described above, TANK1 interacts with the telomere-specific DNA Sbinding protein TRFI [Smith et al., (1998), supra]. The polynucleotide sequence of TRFI is set out in SEQ ID NO:150, and the amino acid sequence of TRF1 is set out in SEQ ID NO: 151. The yeast two-hybrid system [Hollenburg et al., Mol Cell Biol 15:3813-22 (1995)] was used to detennine if TANK2 also interacts with TRF1. In this yeast two-hybrid system, the yeast strain L40 has been engineered to contain multiple LexA binding sites upstream of the HIS3 and beta-galactosidase genes.

Interaction of one protein fused to LexA (created in the BTM 16 vector) with a second protein fused to the VP16 activation domain (created in the VP16 vector) results in the expression of HIS3, allowing yeast growth in media lacking histidine.

Interaction of the two proteins also results in the expression of the beta-galactosidase gene, which can be measured in a colorometric assay [Breeden and Nasmyth, Cold Spring Harbor Symp Quant Biol 643-650 (1985)] The TANK1 binding domain of TRF1, here designated TRF1-TankBD, has been mapped to an amino terminal region ofTRF1. TRF1-TankBD was amplified by PCR using a primer (5-TRF1; SEQ ID NO:152) corresponding to the sense strand of TRF1 polynucleotide sequence (nt 1-24 of SEQ ID NO:150) and a primer (3-TRF1; SEQ ID NO:153) corresponding to the antisense strand of TRF1 polynucleotide sequence (nt 184-201 of SEQ ID NO:150).

5-TRF1 GCCCCGGGGATCCTCATGGCGGAGGATGTTTCCTCAGCG (SEQ ID NO:152) 3-TRF1 TCCCGGGGATCCTCACACCAGGCCCGCGTCCTC (SEQ ID NO: 153) The PCR reaction contained 5 uL Clontech human testis Marathon®-Ready cDNA, 0.20 AM each primer, 0.20 mM dNTPs, 1X PCR buffer, and 1 pL of Clontech Advantage® polymerase mix. The reactions were performed in a GeneAmp® PCR -93- Q) System 9700 with the following steps: 1) 1 cycle at 94 0 C for 1 min; 2) 30 cycles of S94°C for 30 sec, 60 0 C for 30 sec, and 72 0 C for 30 sec; and 3) 1 cycle at 72 0 C for 7 min. The PCR fragment was digested with BamHI, isolated using gel electrophoresis and a QIAquick® kit as directed, and subcloned into the BTM 116 vector. TRFI- TankBD was sequenced with the M13 reverse primer designed to anneal to the vector (SEQ ID NO:26) and a primer designed to anneal to the cDNA sequence (SEQ ID g NO:153). The polynucleotide sequence of TRFI-TankBD is set out in SEQ ID C NO:154 and the amino acid sequence is set out in SEQ ID NO:155.

SAs described above, the TRF1 binding domain of TANKI is very homologous to a region of TANK2 comprised of aa 497-858 of SEQ ID NO:133. The polynucleotide region corresponding to this domain of TANK2, designated Tank2- TRF1BD, was amplified in a PCR reaction with a primer (5-T2/TRFIBD; SEQ ID NO:156) corresponding to the sense strand of the tank2 polynucleotide sequence (nt 1717-1742 of SEQ ID NO:132) and a primer (3-T2/TRF1BD; SEQ ID NO:157) corresponding to the antisense strand of the tank2 polynucleotide sequence (nt 2765- 2805 of SEQ ID NO:132).

5-T2/TRFIBD

CGCAGGATCCCCTTCACTCCTCTTCATGAGGCAGCTTC

(SEQ ID NO:156) 3-T2/TRF1BD

GGATCCGCTAAATATCTGTATCTCCATCTTTAACAA

GATCCAAAGGAG (SEQ ID NO:157) The PCR reaction contained 5 pL Clontech human testis Marathon®-Ready cDNA, pM each primer, 0.25 mM dNTPs, IX PCR buffer, and 2.5 U of PfuTurbo® polymerase mix (Stratagene). The reactions were performed in a GeneAmp®

PCR

System 9700 with the following steps: 1) 1 cycle at 94°C for 1 min; 2) 30 cycles of 94C for 30 sec, 55 0 C for 2 min, and 72 0 C for 2 min; and 3) 1 cycle at 72 0 C for 7 min. The PCR fragment was isolated using gel electrophoresis and a QIAquick® kit as directed, and subcloned into the pCR-BluntIIM.-TOPO® vector (Invitrogen).

Tank2-TRFIBD was digested from the pCR-Bluntll

M

-TOPO® with BamHl, and subcloned into the VP16 vector. The Tank2-TRFlBD clone was sequenced with primers designed to adhere to the vector sequence: M13 forward (SEQ ID NO:25) and 009 (SEQ ID NO:158).

-94 009 GCCGACTTCGAGTTTGAGCAG (SEQ ID NO:158) The polynucleotide sequence is set out in SEQ ID NO:159 and the amino acid sequence is set out in SEQ ID NO: 160.

Co-transformation of L40 with the TRFI-TankBD and Tank2-TRF

BD

5 plasmids indicated that like TANKI, TANK2 binds to TRFI. r-_ 0\ EXAMPLE 7 Measurement of TANK2 Biological Activity Construction ofExpression Plasmids

N

The primary structure of the tankyrase2 polypeptide suggests that TANK2, like TANKI, will have poly(ADP-ribose) polymerase activity. The PARP activity of TANK2, or some substructure thereof, can be measured by the ability of that component to incorporate the ADP-ribose unit from NAD into polymers of ADPribose coupled to a protein substrate. For example, TANK1 adds polymers of ADPribose to the TRF-1 protein in molecular assays [Smith et al., supra]. TANK2 is expected to also perform this function and/or to ADP-ribosylate another substrate or substrates. The demonstration of such activity on a given substrate is readily accomplished by the skilled artisan [see, for example, Smith et al., supra].

Structural differences in TANK1 and TANK2 suggest the possibility that.

TANK2 may have different protein substrate specificity than does TANKI. As demonstrated by the observation that TANKI binds to TRF-1 and poly ADPribosylates TRF-1, it is anticipated that protein substrates of TANK2 can be identified by their ability to bind to TANK2. Additional substrates that bind TANK2 can be identified by a number of methods as described elsewhere in this application.

A fusion protein, designated PARPI A/TANK2B, containing aa 1-662 of PARPI (SEQ ID NO:137) fused upstream ofaa 996-1385 of TANK2 (SEQ ID NO: 133) was used in the measurement of TANK2 poly(ADP-ribose) polymerase activity. PARPIA/TANK2B contained the DNA binding domain (aa 1-373 of SEQ ID NO:137) and automodification domain (aa 373-525 of SEQ ID NO:137) of PARPI and the putative catalytic domain of TANK2 (aa 1242-1382 of SEQ ID NO:133).

95 The PARMPA piece of the fusion protein was amplified by PCR using a primer (Sal-PARPI; SEQ ID NO:161) corresponding to the sense strand of parpl polynucleotide sequence (nt 1-30 of SEQ ID NO: 136) and a primer (revMlu-PARP 1; SEQ ID NO: 162) corresponding to the antisense strand of parplI polynuc leotide sequence (nt 1957-1985 of SEQ ID NO: 136).

Sal-PARPI

CGCACAGCGGCTGAAGTTTG

CI (SEQ ID NO:] 61) revMlu-PARPI

GGAAACGCGTTGGTGCCAGGAACTGTCACT

(SEQ ID NO: 162) The PCR reaction contained 0.5 IiL of human thymus and testis QUlCK-Clone'*1 cDNA (Clontech), 0.25 pM each primer, 0.20 mM dNTPs, IX PCR buffer, and I IL of Clontech Advantage@ polymerase mix. The reactions were performed in a GeneAmnp@ (PE Applied Biosystemns) with the following steps: 1) 1 cycle at 94*C for 1 min; 2) 30 cycles of 94 0 C for 30 sec, 60'C for 2 min, and 72*C for 2 min; and 3) 1 c ycle at 72*C for 7 min. The PCR fragment (designated parp I A) was isolated using gel electrophoresis and a QiAquick@ kit as directed. ParplIA was subeloned into the pTrcHis2Tm-TOPQ®& vector (Invitrogen) as directed. Parp IA was digested from pTrcHis2Tm-TOPO®l with Sall and Miul, the fragment isolated using gel electrophoresis and a QlAquick® kit, and saved for further subcloning described below.

The TANX2B piece of the fusion protein was amplified by PCR using a primer (forMlu-TANK2; SEQ ID NO: 163) corresponding to the sense strand of tank2 polynucleotide sequence (nt 3214-3240 of SEQ ED NO: 132) and a primer (TANK2- Strep-Not; SEQ ID NO: 164) corresponding to the antisense strand of tank2 polynucleotide sequence (nt 4350-4383 of SEQ ID NO: 132).

ForMlu-TANK2 CTTAAACGCGTGAAGGACACACCTTnAGATTTAGTT (SEQ ID NO: 163) -96- TANK2-Strep-Not

GTCGAAAGCGGCCGGTTAGCCTCCGAACTGTGGATGCC

TCCACGCTCCATCGACCATACGTTCAGGCCTCATAATCTGG

(SEQ ID NO: 164) The PCR reaction contained 100 ng 2B. I cDNA, 0.25 jiM each primer, 0.20 m.M r- dNTPs, IX PCR buffer, and 1 jiL of Clontech Advantage® polymerase mix. The reactions were performed in a GeneAnip® PCR System 9700 with the following steps: 1) 1 cycle at 9400 for I min; 2) 30 cycles of 9400 for 30 sec, 6000 for 2 min, and 7200 for 2 min; and 3) 1 cycle at 7200 for 7 min. The PCR fragment (designated tank2B) was isolated using gel electrophoresis and a QiAquicks kit as directed.

Tank2B was subcloned into the pCDNA3. 1/NT-GFP-TOPO® vector (Invitrogen) as directed. Tank2B was digested from pCDNA3.l/NT-GFP-TOPOV with M4ul and Nod and subcloned with SallMuI digested parplIA (see above) into a pFASTBAC vector (Gibco BRL), which had previously been digested with Sall and NotI. The resultant plasmid was designated pFB-PARP1AJTANK2B.

pFB-PARPlIATANK2B3 was sequenced with primers designed to anneal to the vector sequence (SEQ ID NOs: 165-166) and primers designed to anneal to the cDNA sequence (SEQ ID NOs:55, 60, and 66, supra, and SEQ DD NOs: 167-176).

Vector Primers FastBac for TTTGTTCGCCCAGACTC (SEQ ID NO: 165) FastBac rev TATGITTCAGGTTCAGGGGGAG (SEQ ID NO: 166) cDNA Primr P1I GCGGAAGCTGGAGGAGTGAC (SEQ ID NO: 167) P2 GTCACTCCTCCAGCTCCC (SEQ ID NO: 168) P3 AAGCCCTGAAGAAGCAGCTC (SEQ ID NO: 169) P4 GAGCTGCTTCTTCAGGGCTT (SEQ ID NO: 170) CAGACACCCAACCGGAAGGA (SEQ ID NO: 17 1) P6 TCCTTCCGGTTGGGTGTCTG (SEQ ID NO: 172) P7 TCCGCCTCCACCAAGAGCCT (SEQ ID NO: 173) P8 AGGCTCTTGGTGGAGyy2GGA (SEQ ED NO: 174) P9 TGGCCTGGTGGACATCGTTA (SEQ ID NO: 175) TAACGATGTCCACCAGGCCA (SEQ ED NO: 176) 97- The nucleotide sequence of PARPIA/TANK2B is set out in SEQ ID NO:177 and the 3 amino acid sequence ofPARPIA/TANK2B is set out in SEQ ID NO:178.

t" PARP1A/TANK2B consists of the following regions: a HIS tag leader region at aa 1- 36; a PARP1 region at aa 37-698; a spacer region at aa 699-700; a TANK2 region at aa 701-1090; and a Strep-tag region at aa 1091-1099.

SProduction ofRecombinant Viral Stocks and Protein Purification I PARPIA/TANK2B recombinant viral stock was produced using the FastBac 0 system (Gibco BRL) according to the manufacturer's suggested protocol and protein expression was carried out as follows. Sf9 cells were grown at 27 0 C in CCM3 medium (Hyclone, Logan, UT) containing 50 U/mL penicillin and 50 ug/mL streptomycin sulfate (Gibco BRL). Exponentially growing cells were infected at a multiplicity of infection of approximately 0.5 virus per cell and incubated for 48 hr.

Cells were collected by centrifugation at 1000 X g for 15 min, and the pellets were frozen and stored at -80 0 C until use.

For protein purification, reagents were obtained from Sigma unless otherwise indicated. Cells were lysed in Lysis buffer [25 mM Tris-HCl, pH 9.0, 50 mM glucose, 10 mM EDTA, 1 mM 2-mercaptoethanol, 1 mM PMSF, 100 pM antipain, and 2 pg/mL aprotinin] by sonication. Igepal CA-630 (final concentration of Tween®-20 (final concentration of and NaCl (final concentration of 0.5 M) were added to the Lysis buffer and the samples were agitated for 30 min at 4 0 C. The supernatants were collected after centrifugation at 20,000 X g for 20 min at 4 0 C, at which time they were treated with 1 mg/mL protamine sulfate and allowed to stir for I hr at 4°C. The supernatants were collected after centrifugation at 4,000 X g for min at 4 0 C at which time the protein was precipitated with 70% ammonium sulfate.

Protein pellets were collected by centrifugation at 20,000 X g for 15 min at 4°C and resuspended in Re-suspension buffer [100 mM Tris-HC1, pH 7.4, 0.5 mM EDTA, glycerol, 1 mM PMSF, and 12 mM 2-mercaptoethanol].

Proteins were first purified via the HIS tag using Talon@ Superflow metal affinity resin (Clontech) and eluted with 200 mM imidazole (Clontech) as directed.

The protein elutions were next purified using a 3-aminobenzamide Affi-Gel® matrix -98- O (Bio-Rad Laboratories) prepared as described elsewhere [D'Amours et al., Anal Biochem 249:106-8 (1997)]. Proteins were eluted with 10 mM 3 -methoxybenzamide in Elution buffer [50 mM Tris-HC1, pH 7.5, 0.3 M NaCI, 10 mM 2 -mercaptoethanol, O 1 mM PMSF, 100 IM antipain, and 2 pg/mL aprotinin]. The proteins were dialyzed 4 X in 1 L Dialysis buffer [50 mM Tris-HC1, pH 8.0, 1 mM DTT, 4 mM MgCI 2 mM EDTA, 1 mM PMSF, and 2 pg/mL aprotinin). Glycerol was added to a final I concentration of 10% and the proteins were stored at -80 0

C.

Polv(ADP-ribose polvmerase activity For poly(ADP-ribose) polymerase activity assays, reagents were obtained from Sigma unless otherwise indicated. PARP1A/TANK2B (250 ng) protein was incubated for 10 min at room temperature in Assay buffer (total volume of 20 L) [100 mM Tris-HC1, pH 8.0, 10 mM MgCI,, 10% glycerol, 1.5 mM DTT (Boehringer Mannheim/Roche Molecular Biochemicals), 2.5 uM unlabeled NAD, 16.7 pg/mL E.

coli Strain B DNA, and 0.33 pCi y-[ 32 P]-NAD (NEN, Boston, MA). Reactions were stopped by boiling in SDS running buffer and separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Autoradiography was used to visualize labeled protein.

Addition ofpoly(ADP-ribose) polymers to protein substrate results in an increase in molecular weight of the protein, and consequently causes the protein to run higher on SDS PAGE. Also, the level ofpoly(ADP-ribose) polymers added to the protein substrate can vary with each single protein molecule, resulting in labeled proteins with different molecular weights, which appears on the autoradiography film as a ladder or smear [for example, see Smith et al. Science 282:2484-7 (1998)]. PARPIA/TANK2B possessed intrinsic poly(ADP-ribose) polymerase activity as shown by its ability produce poly(ADP-ribose) polymers. The PARPIA/TANK2B poly(ADP-ribose) polymerase reaction produced a ladder of labeled protein from approximately 136 kDa to 250 kDa.

All publications and patent documents cited in this specification are incorporated herein by reference for all that they disclose.

-99- While the present invention has been described with specific reference to certain preferred embodiments for purposes of clarity and understanding, it will be apparent to the skilled artisan that further changes and modifications may be practiced within the scope of the invention as it is defined in the claims set forth below.

Accordingly, no limitations should be placed on the invention other than those specifically recited in the claims.

Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Claims (5)

100- WHAT IS CLAIMED IS: r-i 1. A purified and isolated tankyrase2 polypeptide. 2. The polypeptide according to Claim 1, comprising the amino acid sequence defined in SEQ ID NO:133. 3. The polypeptide according to Claim 1, comprising the amino acid Ssequence defined in SEQ ID NO: 135. 4. A polynucleotide encoding the polypeptide according to Claim 1. The polynucleotide according to Claim 4, comprising the coding region of the nucleotide sequence defined in SEQ ID NO: 132. 6. The polynucleotide according to Claim 4, comprising the coding region of the nucleotide sequence defined in SEQ ID NO:134. 7. A polynucleotide selected from the group consisting of: the polynucleotide according to Claim 4, a polynucleotide complementary to the polynucleotide of(a), and a polynucleotide that hybridizes under moderately stringent hybridization conditions to the polynucleotide of or 8. The polynucleotide according to Claim 7, wherein the polynucleotide is a DNA molecule or an RNA molecule. 9. The polynucleotide according to Claim 8, further comprising a detectable label moiety. 101 An expression construct, comprising the polynucleotide according to SClaim 4. 11. A host cell transformed or transfected with the expression construct according to Claim t"- S12. The polynucleotide according to Claim 4, wherein the polynucleotide 0 is operatively linked to a heterologous promoter. 13. A host cell, comprising the polynucleotide according to Claim 12. 14. A method for producing a tankyrase2 polypeptide, comprising the steps of: a) growing the host cell according to Claim 11 or 13 under conditions appropriate for expression of the polypeptide; and b) isolating the polypeptide from the host cell or the medium in which the host cell is grown. An antibody that is specifically immunoreactive with the polypeptide according to Claim 1. 16. The antibody according to Claim 15, wherein the antibody is selected from the group consisting of monoclonal antibodies, polyclonal antibodies, single chain antibodies (scFv antibodies), chimeric antibodies, bifunctional/bispecific antibodies, humanized antibodies, human antibodies, CDR-grafted antibodies, Fab fragments, Fab' fragments, F(ab') 2 fragments, and Fv fragments. 17. A cell line that produces an antibody according to Claim 18. An anti-idiotype antibody that is specifically immunoreactive with an antibody according to Claim -102- 19. A method for identifying a binding partner of a tankyrase2 polypeptide, comprising: a) contacting the tankyrase2 polypeptide with a test compound under conditions that permit binding of the tankyrase2 polypeptide and the test compound; b) detecting binding of the test compound and the tankyrase2 polypeptide; and c) identifying the test compound as a binding partner of the tankyrase2 polypeptide. The method according to Claim 19, wherein said specific binding partner selectively or specifically modulates a biological activity of the tankyrase2 polypeptide. 21. A method for identifying a specific binding partner of a tankyrase2 polynucleotide, comprising: a) contacting the tankyrase2 polynucleotide with a test compound under conditions that permit binding of the tankyrase2 polynucleotide and the test compound; b) detecting binding of the test compound and the tankyrase2 polynucleotide; and c) identifying the test compound as a specific binding partner of the tankyrase2 polynucleotide. 22. The method according to Claim 21, wherein said binding partner selectively or specifically modulates activity of the tankyrase2 polynucleotide. 23. 'A method of treating an animal having a medical condition mediated by poly(ADP-ribose) polymerase activity, comprising administering to said animal a tankyrase2 inhibitory compound in an amount effective for inhibiting tankyrase2 activity in said animal.

103- 24. The method according to Claim 23, wherein said medical condition is associated with growth of neoplastic tissue. The method according to Claim 24, wherein said neoplastic tissue is a Scancer selected from the group consisting of carcinomas, sarcomas, leukemias, and lymphomas. 26. The method according to Claim 25, wherein said cancer is selected Sfrom the group consisting of ACTH-producing tumor, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, and Wilm's tumor. Dated this SEVENTH day of JULY

2005. ICOS Corporation Applicant Wray Associates Perth, Western Australia Patent Attorneys for the Applicant SEQUENCE LISTING <110> Christenson, Erik DeMaggio, Anthony J Goldman, Phyllis S McEiligott, David L <120> Tankyrase2 Materials and Methods <130> 36559 <140> <141> <150> 60/141,582 <151> 1999-06-29 <160> 178 <170> Patentln Ver. 2.1 <210> 1 <211> 3507 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (3508) <400> 1 9 9CC agg atc atg tcg ggt cgc cgc tgc 9CC ggc ggg gga gcg 9CC tgc 49 Ala Arg Ile Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys 1 5 10 gcg agc 9CC gcg 9CC gag gcc gtg gag ccg gec gcc cga gag ctg ttc 97 Ala Ser Ala Ala Ala Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe 25 gag gcg tgc cgc aac ggg gac gtg gaa cga gtc aag agg ctg gtg acg 145 Giu Ala Cys Arg Asn Gly Asp Val Glu Arg Val Lys Arg Leu Val Thr 40 45 cct gag aag gtg aae agc cgc gac acg gcg ggc agg aaa tcc acc ccg 193 Pro Glu Lys Val Asn Ser Arg Asp Thr Ala Gly Arg Lys Ser Thr Pro s0 55 ctg cac ttc gcc gca ggt ttt ggg cgg aaa gac gta gtt gaa tat ttg 241 Leu His Phe Ala Ala Gly Phe Gly Arg Lys Asp Val Val Glu Tyr Leu 70 75 ctt cag aat ggt gca aat gtc caa gca cgt gat gat 999 ggc ctt att 289 Leu Gin Asn Gly Ala Asn Val Gin Ala Arg Asp Asp Gly Gly Leu Ile 90 cct ctt cat aat gca tgc tct ttt ggt cat gct gaa gta gtc aat ctc 337 Pro Leu His Asn Ala Cys Ser Phe Gly His Ala Glu Val Val Asn Leu 100 105 110 ctt ttg cga cat ggt gca gac CCC aat gct cga gat aat tgg aat tat 385 Leu Leu Arg His Gly Ala Asp Pro Asn Ala Arg Asp Asn Tx-p Asn Tyr 115 120 125 act cct ctc cat gaa gct gca att aaa gga aag att gat gtt tgc att 433 Thr Pro Leu His Giu Ala Ala Ile Lys Gly Lys Ile Asp Val Cys Ile 130 135 140 -2- gtg ctg Val Leu 14S agg aca Arg, Thr ggt gaa Gly Glu gaa gaa Glu Giu gca agt Ala Ser 210 aac aga Asn Arg 225 cat gct His Ala tat ggt Tyr Gly gta aat Val Asn t ta Leu 9ca Al a tat Tyr aaa Lys 195 gat Asp gta Val aaa Lys cat H~is gca cac GlI tE Let. aac Lys 180 atg Met ggc Gly aag Lys gat Asp tat Tyr 260 atg Met 3 cat 9gi -i His G13 15C gat tta aAsp Let 165 aaa gat Lys Asp atg gct Met Ala aga aag Arg Lys att gta Ile Val 230 aaa ggt Lys Gly 245 gaa gta Giu Val gac ttg Asp Leu k gct gag rAla Glu igca gat i Ala Asp gaa ctc Glu Leu cta ctc Leu Leu 200 tca act Ser Thr 215 cag ctg Gin Leu gat ctg Asp Leu act gaa c Thr GiuI tgg caa t Trp Gin P cca Pr cc~ PrC t ta Leu 185 aca Thr cca Pro t ta Lieu ?ta 7al: :tt .,Ou !65 :tc aacc atc cga aat Thr Ile Arg Asn 155 tct gcc aaa gca Ser Ala Lys Ala 170 gaa agt gcc agg Giu Ser Ala Arg cca tta aat gtc Pro Leu Asn Val 205 tta cat ttg gca Leu His Leu Ala 220 ctg caa cat gga Leu Gin His Gly 235 cca tta cac aat Pro Leu His Asn 250 ttg gtc aag cat Leu Val Lys His act cct ctt cat Thr Pro Leu HisC 285 aci Thi gtg Val agt Ser 190 aac Asn gca Ala gct. Ala 9cc Ala 3gt fly ;ag ;iu Igat Asp ctt *Leu 175 ggc *Gly tgc Cys gga Gly gat Asp tgt Cys 255 gcc Ala gca 5 Ala JI 99a Gi y 160 act Thr aa t Asn cac His tat Tyr gtc Val 240 tct Ser tgt -ys ;ct 481 529 577 625 673 721 769 817 865 913 961 1009 1057 1105 1153 1201 1249 275 280 tct Ser gac Asp 305 ccc Pro tcg Ser cat His aca Thr ata Ile 385 aag aac agg gtt Lys 290 cca Pro aca Thr ttg Leu ctc Leu gca Ala 370 tgt Cys Asn Arg aca ctg Thr Leu cca cag Pro Gin ctg caa Leu Gin 340 tct ctg Ser Leu 355 ttg cat Leu His gaa ctg Giu Leu Val ctc Leu tta Leu 325 gct Ala gaa Glu tgt Cys t tg Leu gaa Glu aat Asn 310 aaa Lys qca Ala atg Met gct Ala cta Leu gta IVal 295 tgt Cys gaa Glu cga Arg gtg Val gct Ala 375 aga Arg tqt Cys cac His aga Arg gaa Glu aat Asn 360 gca Ala aaa Lys tct Ser aat Asn t ta Leu gct Al a 345 ttc Phe tct Scr gga ct t Leu aaa Lys gca Ala 330 gat Asp aag Lys cca Pro gca ctc Leu agt Scr 315 tat Tyr gt t Val1 cat His tat Tyr aac Asn 395 tta Leu 300 gct Ala gaa Giu act Thr cct Pro ccc Pro 380 atc Ile agt Ser a ta Ile ttt Phe cga Arg caa Gin 365 aaa Lys aat Asn tat Tyr gac Asp aaa Lys atc Ile 350 aca Thr aga Arg gaa flu g9t Gl) t tg Leu ggc Gly 335 aaa Lys cat His aag Lys aag Lys q ca Ala gct Ala 320 cac His aaa Lys gaa Glu caa Gin act Thr 390 aaa gaa ttc ttg Lys Giu Phe Leu act cct ctg cac gtg Thr Pro Leu His Val 405 gca tct Ala Ser 410 gag aaa gct Giu Lys Ala cat aat His Asn 415 gat qtt gtt gaa gta gtg gtg aaa cat gaa gca aag gtt aat gct ctg 1297 Asp Val Val Glu Val Val Val Lys His Glu Ala Lys Val Asn Ala Leu C1420 42543 gat aat ctt ggt cag act tct cta cac aga gct gca tat tgt ggt cat 1345 Asp Asn Leu Gly Gin Thr Ser Leu His Arg Ala Ala Tyr Cys Giy His 435 440 445 cta caa acc tgc cgc cta ctc ctg agc tat ggg tgt gat cct aac att 1393 Leu Gin Thr Cys Arg Leu Leu Leu Ser Tyr Gly Cys Asp Pro Asn Ile 450 455 460 ata tcc ctt cag ggc ttt act gct tta cag atg gga aat gaa aat gta 1441 Ile Ser Leu Gin Gly Phe Thr Ala Leu Gin Met Gly Asn Glu Asn Val (Nl465 470 475 480 (]cag caa cto ctc caa gag ggt atc tca tta ggt aat tca gag gca gac 1489 Gin Gin Leu Leu Gin Glu Giy Ile Ser Leu Gly Asn Ser Glu Ala Asp 485 490 4 aga caa ttg cig gaa got gca aag gct gga gat gto gaa act gta aaa 1537 Arg Gin Leu Leu Giu Ala Ala Lys Ala Gly Asp Val Giu Thr Val Lys 500 505 510 aaa ctg tgt act gtt cag agt gto aac tgc aga gac att gaa ggg. ogt 1585 Lys Leu Cys Thr Vai Gin 5cr Val Asn Cys Arg Asp Ile Glu Gly Arg 515 520 525 cag tct aca cca ott cat ttt gca gct ggg tat aac aga gtg tcc gtg 1633 Gin 5cr Thr Pro Leu His Phe Ala Ala Gly Tyr Asn Arg Val Ser Val 530 535 540 gtq gaa tat ctg cta cag cat gga gct gat gtg cat got aaa gat aaa 1681 Val Giu Tyr Leu Leu Gin His Gly Ala Asp Val His Ala Lys Asp Lys 545 550 S55 560 gga ggc ctt gta cot ttg cac aat gca tgt tot tat gga cat tat gaa 1729 Gly Gly Leu Val Pro Leu His Asn Ala Cys Ser Tyr Gly His Tyr Glu 565 570 575 git gca gaa ott ctt gtt aaa cat gga gca gta gtt aat gta got gat 1777 Val Ala Giu Leu Leu Val Lys His Gly Ala Val Val Asn Val Ala Asp 580 585 590 tta tgg aaa ttt aca cct tta cat gaa gca gca gca aaa gga aaa tat 1825 Leu Trp, Lys Phe Thr Pro Leu His Glu Ala Ala Ala Lys Gly Lys Tyr 595 600 605 gaa att tgo aaa Ott ctg etc cag cat ggt goa gac cct aca aaa aaa 1873 Giu Ile Cys Lys Leu Leu Leu Gin His Gly Ala Asp Pro Thr Lys Lys 610 615 620 aac agg gat gga aat act oct ttg gat ott gtt aaa gat gga gat aca 1921 Asn Arg Asp Gly Asn Thr Pro Leu Asp Leu Val Lys Asp Gly Asp Thr 625 630 635 640 gat att caa gat ctg Ott agg gga gat gca got ttg cta gat got gcc 1969 Asp Ile Gin Asp Leu Leu Arg Gly Asp Ala Ala Leu Leu Asp Ala Ala 645 650 655 aag aag ggt tgt tta 9CC aga gtg aag aag ttg tct tct cct gat aat 2017 Lys Lys Gly Cys Leu Ala Arg Val Lys Lys Leu Ser Ser Pro Asp Asn 660 665 670 gta aat tgo ogc gat ace caa ggc aga cat tea aca oct tta cat tta 2065 Val Asn Cys Arg, Asp Thr Gin Gly Arg His Ser Thr Pro Leu His Leu 675 680 685 gca gc Ala Al 69 gga gc Gly Al, 705 aat gc Asn Al tat aal Tyr Asi cac gaz His Gil 9CC cat Ala His 770 tta gat Leu Asp 785 atg ccc Met Pro ggt gtg Gly Val tCt egc Ser Ser 999 agt Gly Ser 850 ggt gct Gly Ala 865 ata act Ile Thr ttt gag Phe Glu aag gag Lys Glu cta att Leu Ile 930 cce tat Pro Tyr 945 t ggt tat aat eat a Gly Tyr Asn Asn 0 t gat gtg aet gcc a Asp Val Asn Ala 710 gca tct tac ggg Ala Ser Tyr Gly 725 t gca tgt gtc aat a Ala Cys Val Asn 740 gca 9CC cae aag Ala Ala Gin Lys 755 *gga gct gac ccg Gly Ala Asp Pro tta gtt tca gca *Leu Val Ser Ala 790 cce tct gct ctg Pro Ser Ala Leu 805 aga agc cca gga, E Arg Ser Pro Gly; 820 cca tca agc ctt t Pro Ser Ser Leu s 835 ttt tca gaa ctg t Phe Ser Glu Leu S 8 tcc agt ttg gag a Ser Ser Leu GiuL 870 caa ttc gte egg a Gin Phe Val Arg A 885 aga gaa cag atc a Arg Giu Gin Ile TI 900 ctg eag gag ett g~ Leu Lys Glu Ile G 915 aaa gga gtc gag as Lys Gly Val. Glu A~ 93 tte act ttg aac ac Leu Thr Leu Asn T1' 950 tt Le 65 ca G1 ca Hi gc Al 99 GI ac Th: 77' ga ksI :cc rc ;cc ct er Ct er 55 aa YB at Sn Li' hr '5 -C -4- :a gaa gtt gca gag u Giu Val Ala Glu *a gac eaa gga gga Asp Lys Gly Gly 715 .t gte get gte gca s Val Asp Val Ala 730 c ecg gac aaa tgg a Thr Asp Lys Trp 745 a cga ace cag ctt y Arg Thr Gin Leu 760 t ctt aaa aat cag r LeU Lys Asn Gin tget gtc agc gCt Asp Vai Scr Ala 795 tCt tgt tac aeg Ser Ci's Tyr Ly's 810 act gca gat gct C Thr Ala Asp Ala 1 825 gca 9CC agc agt c Ala Ala 5cr Ser 1 840 tCa gta gtt egt t Ser Val Val Ser S 8 eag gag gtt Cca g Lys Giu Val Pro G 875 ctt gga ctt gag c Leu Gly Leu Giu H 890 ttg get gta tta g Leu Asp Val Leu V~ 905 atc aat gct tat g Ile Asn Ala Tyr G; 920 ctt etc tcc gga c~ Leu Ile Ser Gly G1 94 tct ggt agt gga ac Ser Gly Ser Guy T' 955 tat tt Tyr Le 700 Ctt at Leu Ii gct Ct Ala Le gCt ttl Ala Ph, tgt gci Ci's Ali 76! gaa ggj Glu G13 780 ctt ctc Leu Let cct caa ?ro Gin :tc tct ~eu Ser ~tt gac ~eu Asp 845 ca agt :er 5cr ga gte ii' Val ac eta is Leu tt gag al Glu ge cat Ly His 925 ia ca In Gin I0 *a att *r Ile :9 tte caa cec !u Leu Gin His t Cct tta cat e Pro Leu His 720 a cta ata aeg Leu Ile Ly's 735 c aca cct ttg e Thr Pro Leu 750 t ttg ttg cta I Leu Leu Leu icaa aca Cct r Gln Thr Pro Iaca gca 9CC iThr Ala Ala 800 gtg ctC aat iVal Leu Asn 815 tca ggt cca Ser Guy Pro 830 eec tta tct Asn Leu Ser gga ace gag Gly Thr Giu gat ttt agc Asp Plie Ser 880 atg gat eta Met Asp Ile 895 atg ggg cac Met Guy His 910 egg cac aaa Arg His Lys ggt ctt eec Giy Leu Asn ctt ate get Leu Ile Asp 960 2113 2161 2209 2257 2305 2353 2401 2449 2497 2545 2593 2641 2689 2737 2785 2833 2881 ctg tct cct gat gat aaa gag ttt cag tct gtg gag gaa gag atg caa 2929 Leu Ser Pro Asp Asp Lys Giu Phe Gin Ser Val Giu Giu Giu Met Gin 965 970 975 agt aca gtt cga gag cac aga gat gga ggt cat gca 99t gga atc ttc 2977 Ser Thr Val Arg Giu His Arg Asp Gly Gly His Ala Gly Giy Ile Phe 980 985 990 aac aga tac aat att ctc aag att cag aag gtt tgt aac aag aaa cta 3025 Asn Arg Tyr Asn Ile Leu Lys Ile Gin Lys Val Cys Asn Lys Lys Leu 995 1000 1005 tgg-gaa aga tac act cac cgg aga aaa gaa gtt tct gaa gaa aac cac 3073 Trp Glu Arg Tyr Thr His Arg Arg Lys Giu Val Ser Giu Glu Asn His 1010 1015 1020 C1aac cat gcc aat gaa cga atg cta ttt cat ggg tct cct ttt gtg aat 3121 Asn His Ala Asn Glu Arg Met Leu Phe His Giy Ser Pro Phe Vai Asn 1025 1030 1035 1040 C1gca att atc cac aaa ggc ttt gat gaa agg cat gcg tac ata ggt ggt 3169 Ala Ile Ile His Lys Gly Phe Asp Glu Arg His Ala Tyr Ile Gly Gly 1045 1050 1055 atg ttt 9ga gct 99c att tat ttt gct gaa aac tct tcc aaa agc aat 3217 Met Phe Gly Ala Gly Ile Tyr Phe Ala Giu Asn Ser Ser Lys Ser Asn 1060 1065 1070 caa tat gta tat gga att gga gga ggt act ggg tgt cca gtt cac aaa 3265 Gin Tyr Vai Tyr Gly Ile Gly Gly Gly Thr Gly Cys Pro Val His Lys 1075 1080 1085 gac aga tct tgt tac att tgc cac agg cag ctg ctc ttt tgc cgg 9ta 3313 Asp Arg Ser Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val 1090 1095 1100 acc ttg gga aag tct ttc ctg cag ttc agt gca atg aaa atg gca cat 3361 Thr Leu Gly Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His 1105 1110 1115 1120 tct cct cca ggt cat cac tca gtc act ggt agg ccc agt gta aat ggc 3409 Ser Pro Pro Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly 1125 1130 1135 eta gca tta gct gaa tat gtt att tac aga gga gaa cag gct tat cct 3457 Leu Ala Leu Ala Glu Tyr Val Ile Tyr Arg Gly Giu Gin Ala Tyr Pro 1140 1145 1150 gag tat tta att act tac cag att atg agg cct gaa ggt atg gtc gat 3505 Giu Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Giu Gly Met Val Asp 1i55 1160 1165 gga 3508 Gly <210> 2 <211> 1169 <c222> PRT <213>. Homo sapiens <400>. 2 Ala Arg Ile Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys 1 5 10 is Ala Ser Ala Ala Ala Giu Ala Val Giu Pro Ala Ala Arg Glu Leu Phe 25 Glu Ala Cys Arg Asn Gly Asp Val Glu Arg Val Lys Arg Leu Val Thr 40 Pro Glu Lys Val Asn Ser Leu His Phe Ala Ala Gly 70 Leu Gin Asn Gly Ala Asn Pro Leu His Asn Ala Cys 100 Leu Leu Az-g His Gly Ala 115 -6- Arg Asp Thr Ala Gly 55 Phe Gly Arg Lys Asp Val Gin Ala Arg Asp 90 Ser Phe Gly His Ala 105 Asp Pro Asn Ala Arg 120 Lys Val Gly Val Ser Thr Glu Tyr Gly Leu Val Asn 110 Trp Asn 125 Thr Pro Leu His Glu Ala Ala Ile Lys Gly Ly's Ile Asp Val Cys Ile 130 135 Val Leu Leu Gin His Gly Ala Glu 145 150 140 Pro Thr Ile Arg Asn Thr Asp 155 Arg Thr Ala Leu Gly Glu Ala Asn 225 His Tyr Val Ser Asp 305 Pro Ser His Thr Giu Giu Ser 210 Arg Ala Gly Asn Lys 290 Pro Thr Leu Leu Tyr Lys 195 Asp Val Lys Hi s Ala 275 Asn Thr Pro Leu Ser 355 Lys 180 Met Gly Lys Asp Tyr 260 Met Arg Leu Gln Gln 340 Aeu Asp 165 Lys Met Arg Ile Lys 245 Giu Asp Val Leu ELeu 325 1lu Leu Ala Asp *Asp Glu Leu Ala Leu Leu 200 Lys Ser Thr 215 Val Gin Leu 230 Gly Asp Leu Val Thr Giu Leu Trp Gin 280 Glu Val Cys 295 Asn Cys His 310 Lys Giu ArgI Ala Arg Giu J Met Val Asn i 360 Pro Leu 185 Thr Pro Leu Val Leu 265 Ser 170 Glu Pro Leu Leu Pro 250 Leu iLys *Ala *Asn Leu 220 His His Lys Leu Leu 300 Al a Glu Thr Pro Ala Arg Val 205 Ala Gly Asn His His 285 Ser Ile Phe Arg Gin 365 Val Ser 190 Asn Ala Ala Ala Gly 270 Glu Tyr Asp Lys Ile 350 rhr *Leu 175 *Gly ICys Gly Asp Cys 255 Al a Ala Gly Leu Gly 335 Lys His c Gly 160 Thr Asn His Tyr Val 240 Ser Cys Ala Al1a Ala 320 Hiis .,ys alu Phe Thr Pro Ala Leu His Cys Ala Ala Ala Ser Pro Tyr Pro Lys Arg Lys Gin Ile Cys 385 Lys Glu Arg Lys Leu His Gly Ala Val Ala 410 Asn Giu Lys Ala Lys Thr 400 His Asn 415 As As Le Ii 46 GI Ar Ly GI2 Va 54! GI1 Val Leu Glu Asn 625 Asp Lys Val Ala Gly 705 Asn Tyr His Ala ;p Val ;p Asn u Gin 450 e Ser 5 n Gin 9 Gin s Leu n Ser 530 1 Glu SGly Ala 4 Trp i Ile 610 Arg I Ile C Lys G Asn C 6 Ala G 690 Ala A Ala A Asn A Glu A 7, His G 770 Va Le 43 Th Le Le Le CYa 51! Th2 Tyi Leu Glu L y s 595 'ys ~sp ;In ily ,ys 75 ly ,sp la la la 55 ly .1 Glu 420 u Gly r Cys u Gin u Leu u Leu 500 s Thr 7 Pro Leu Val Leu 580 Phe Lys I .Gly I Asp I 6 Cys L 660 Arg A Tyr A Val A Ser T 7: Cys V 1 740 Ala G Ala As Va GI Ar G1 G1 48! G1i Val Leu Leu Pro 565 Leu [hr jeu 'sn oeu 45 'eu sp sn Sn yr 25 al In Po 1 V n Tf 9 Le y Ph 47 n G1 iAl G1 Hi GI1 55' Lei Va Prc Let Thr 630 Leu Ala Thr Asn Ala 710 Gly Asn Lys Pro al Vai Ir Ser !u Leu 455 te Thr '0 u Gly a Ala n Ser s Phe 535 n His 0 u His L Lys I Leu I I Leu 615 Pro I Arg C Arg V Gin G 6 Leu G 695 Gin A His V Ala T Gly A 74 Thr L 775 L1 Lt 44 Li Al 11 Ly Va 52 Al Gi As, Hi 60C ;IT: Jeu ;ly ral ly 80 lu sp al hr rg 60 u -7- ys His Giu Ala 425 eu His Arg Ala 40 u Ser Tyr Gly .a Leu Gin Met 475 .e Ser Leu Gly 490 s Ala Gly Asp 505 1 Asn Cys Arg 0 a Ala Gly Tyr y Ala Asp Vai 555 n Ala Cys Ser 570 s Gly Ala Val 585 i Glu Ala Ala 3 His Gly Ala 3 Asp Leu Val I 635 Asp Ala Ala L 650 Lys Lys Leu S 665 Arg His Ser T Val Ala Giu T 7 Lys Gly Gly L, 715 Asp Val Ala A 730 Asp Lys Trp A: 745 Thr Gin Leu C~ Lys Asn Gin GI 78 Al Cy 46 G1 As Va Asj Asi 54C His ryz 1al kla sp ;20 ~ys 4 eu er 'hr yr 00 Cu la la Lu *5 Va a Ty 44 S As 0 y As n Se 1 Gl. p 114 52! I Arc mAla Gly Asn Lys 605 Pro Asp Leu Ser Pro 685 Leu Ile Leu Phe Ala 765 Gly 1i Asn Ala Leu 430 'r Cys Gly His p Pro Asn Ile n Giu Asn Val 480 r Giu Ala Asp 495 u Thr Val Lys 510 e Giu Gly Arg Val Ser Val Lys Asp Lys 560 His Tyr Glu 575 Val Ala Asp 590 Gly Lys Tyr Thr Lys Lys Gly Asp.Thr 640 Asp Aia Ala 655 Pro Asp Asn 670 Leu His Leu Leu Gin His Pro Leu His 720 Leu Ile Lys 735 Thr Pro Leu 750 Leu Leu Leu Gin Thr Pro Leu Asp Leu Val Ser Ala Asp Asp Val 5cr Ala Leu Leu Thr Ala Ala 785 790 795 800 Met Pro Pro 5cr Ala Leu Pro Ser Cys Tyr Lys Pro Gin Val Leu Asn 805 810 815 Gly Val Arg Ser Pro Gly Ala Thr Ala Asp Ala Leu Ser Ser Gly Pro 820 825 830 Ser Ser Pro Ser Ser Leu Ser Ala Ala Ser Ser Leu Asp Asn Leu Ser 835 840 845 Gly Ser Phe Ser Giu Leu Ser Ser Val Val Ser Ser Ser Gly Thr Giu 850 855 860 Gly Ala Ser Ser Leu Giu Lys Lys Giu Val Pro Gly Val Asp Phe Ser (N ~865 870 875 880 Ile Thr Gin Phe Val Arg Asn Leu Gly Leu Glu His Leu Met Asp Ile 885 890 895 (iPhe Giu Arg Glu Gin Ile Thr Leu Asp Val Leu Val Giu Met Gly His 900 905 910 Lys Giu Leu Lys Giu Ile Gly le. Asn Ala Tyr Gly His Arg His Lys 915 920 925 Leu Ile Lys Gly Val Giu Arg Leu Ile Ser Gly Gin Gin Gly Leu Asn 930 935 940 Pro Tyr Leu Thr Leu Asn Thr Ser Gly Ser Gly Thr Ile Leu Ile Asp 945 950 955 960 Leu Ser Pro Asp Asp Lys Giu Phe Gin Ser Val Glu Glu Giu Met Gin 965 970 975 Scr Thr Val Arg Giu His Arg Asp Gly Gly His Ala Gly Gly le Phe 980 985 990 Asn Arg Tyr Asn Ile Leu Lys Ile Gin Lys Val Cys Asn Lys Lys Leu 995 1000 1005 Trp, Giu Arg Tyr Thr His Arg Arg Lys Giu Val Ser Glu Glu Asn His 1010 1015 1020 Asn His Ala Aen Giu Arg Met Leu Phe His Gly Ser Pro Phe Val Asn 1025 1030 1035 1040 Ala Ile Ile His Lys Gly Phe Asp Giu Arg His Ala Tyr Ile Gly Gly 1045 1050 1055 Met Phe Gly Ala Gly Ile Tyr Phe Ala Giu Asn Ser Ser Lys 5cr Asn 1060 1065 1070 Gin Tyr Val Tyr Gly Ile Gly Gly Gly Thr Gly Cys Pro Val His Lys 1075 1080 1085 Asp Arg Scr Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val 1090 1095 1100 Thr Leu Gly Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His 1105 1110 1115 1120 Ser Pro Pro Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly 1125 1130 1135 Leu Ala Leu Ala Giu Tyr Val Ile Tyr Arg Gly Giu Gin Ala Tyr Pro 1140 1145 1150 -9- Glu Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Glu Gly Met Val Asp 1155 1160 1165 Gi y <210> 3 <c211> 3984 <c212> DNA <213> Homo sapiens <220> <221> CDS <222> (1)..(3981) <400> 3 atg geg gcg teg egt Met Ala Ala Ser Arg 1 5 cag etc cag ccc 9CC Gin Leu Gin Pro Ala ccc eca etc agc ect Pro Pro Leu Ser Pro acg gcc age ggc etg Thr Ala Ser Gly Leu so etg ccg gag ggg gat Leu Pro Glu Gly Asp ege Arg cca Pro ggC Gly gcc Ala gge Gly 70 tet eag Ser Gin ggg get Giy Ala etg gc Leu Ala 40 ccc ttc Pro Phe 55 agt egg Ser Arg cat His tea Ser 25 ceg Pro gee Ala gat Asp cat His 10 geg Ala ggg Gly tee Ser ecg Pro eae His ceg Pro ace Thr cg Pro ec Pro 75 eac His ecg Pro ace Thr egg Arg gac Asp cat His cg Pro eca Pro eae His agg Arg cat His cca Pro gee Al a gge Gly ec Pro eaa eaa Gin Gin ect cet Pro Pro tet ccc Scr Pro eta geg Leu Ala ega tee Arg Ser ceg Pro tgt Cys 9CC Ala ceg Pro tee Ser 145 age Ser eca Pro, gae Asp ace Thr get Al a teg Ser 130 cet Pro aca Thr ges Ala ceg Pro gte Val 9gg Gly 115 tee Ser gga Gly gca Ala gtg Val gt t Val gc Ala 100 gte Val tet Ser teg Ser eca Pro Ser gae Asp gee Ala get Ala tct Ser age 5cr etg Leu 165 999 Gly. ggt Gly gct Ala ccc Pro tee Ser t tg Leu 150 999 Gly gee Ala ecc Thr cee Pro aac Asn ceg Pro 135 geg Ala cct Pro cta Leu age Ser gtg Val eca Pro 120 act Thr gag Giu 9gg Giy C9g Arg tgt Cys gte Val 105 gee Ala tet Ser age Ser gca Ala gaa Glu tge Cys 90 eca Pro ggC Gly tee Ser ec Pro gea Ala 170 etg agt Ser geg Ala agt Ser tea 5cr gag Giu 155 9ga Gly etg ace Thr gtt Val ggC Gly tct Scr 140 9g Ala cet Pro gag Glu ecc Thr tct Ser agt Ser 125 tee Ser gcc Ala 999 Gi y gee Ala age Ser aet Thr 110 aac Asn teL 5cr gga Giy aca Thr tgt Cys 190 aes Thr tea Ser aat Asn cca Pro gt t Val 99g Gly 175 cge krg ate Ile tt Scr tea Ser tee Ser age Ser 160 gte Val1 sat Asn 48 96 144 192 240 288 336 384 432 480 528 576 180 185 999 gac gtg Gly Asp Val 195 tee egg gta Ser Arg Val aag agg Lys Arg 200 ctg gtg gac geg Leu Val Asp Aia gea Ala 205 aac gta aat Asn Val Asn gca Ala g t: Gi y 225 aa t Asn tgt Cys get Ala get Ala gga Gly. 305 etg Leu gac Asp gct t: Ala I aag t: Lys S 3 gtt c Val G 385 ggt g Gly G gtc a Val T etc t: Leu T. gaa gi Glu V~ 4 aae t: Asn Cj 465 aa Ly 21 ti Ph qt Va. tc Se: gal Asi get Ala 29C gct Ala kla 3aa. ;1u :ta. .eu :cg er 70 ag In ga. ly ca. hr 99 rp t0 lso g gac at s5 Asp Me 0 t: gga ag e Gly Ax c eac gc I His Al t: ttt gg r Phe Gl' 26 t cca aa.- SPro As, 275 att aai Ile Lyi gac cca Asp Prc gat cct Asp Prc ctc cta Leu Leu 340 ctg act Leu Thr 355 act cet Thr Pro ctt ctt Leu Leu ctt gtg Leu Val gaa ctg Glu Leu 420 cag -ttt Gin Phe 435 tgc tet Cys Ser cat gqc His Gly .g gce gyc Ala Gly 9g aag gat *g Lys Asp 230 t cgt gat a Arg Asp 245 c cat get y His Ala 0 t: 9cc agg ni Ala Arg a 999 aag 3 Gly Lys kaac att Asn Ile 310 tca gca Ser Ala 325 gaa. get 5 Glu Ala cct eta, a Pro LeuA tta cat c Leu His L 3 ctt cag c Leu Gln H 390 ect ctt c Pro Leu H 405 cta eta a~ Leu Leu L, act cca ci Thr Pro LI ttg tta ct Leu Leu Lt 45 aaa agt gc Lys Ser Al 470 cc As ga ga As a I 29! c ;ct aat 'sn ta eu 75 at is at is Ys 39 aag rg Lys L5 :t gta Il Val t: gga p Gly 9 9tt u Val t: aac p Asn 280 gat Asp 5 3aac SAsn gct g Ala V~ agg a Arg S 3 gtg a Val A 360 gea g Ala A 99t g9 Gly A: aat g~ Asn A cat gc His GI cae 98 His Gl 440 age ea Ser Hi gtg ga Val As t: SI 9, GI 99 gt: Va 26 tg Tr gt: kci rtc Tal .gt: 45 at sn eg la la La '9 5 t: p Ct tet ccc ci er Ser Pro LI aa eac tia ct Lu His Leu Le 235 t: etc ate cc .y Leu Ile Pi 250 9 agt ctg tt 1 Ser Leu Le 5 g aac tat ac pAsn Tyr Th 9 tgc att gtq, 1 Cys Ile Va' 301 t gat ggg am~ r Asp Gly Ly.- 315 ett aca ggt *Leu Thr Gl) 330 ggt aat gaa *Gly Asn Glvc tge cat gca Cys His Ala ggc tac aac Gly Tyr Asn .380 gat gtt eat Asp Val His 395 tgt tea tat Cys Ser Tyr 410 get tgt gtt Ala Cys Val get get tee Ala Ala Ser ggc get gat Gly Ala Asp 460 atg get eca Met Ala Pro 475 tq cac ttc: get eu His Phe Ala 20 :a cag atg ggt !u Gin Met Gly :g ctt cat aat 'o Leu His Asn 255 a ttg tge caa Leu Cys Gin 270 a ect etg cat r Pro Leu His 285 9 etg etg cag I Leu Leu Gin 1, tea gee etg B Ser Ala Leu gaa tac aag Glu Tyr Lys 335 igaa aaa eta. z iGlu Lys Leu b' 350 agt gat 999 c Ser Asp Gly 365 aga gtt ega, a Arg Val Arg I gca aaa gae a Ala Lys Asp L 4 gga cat tat 9 Gly His Tyr G 415 aat gee atg g~ Asn Ala Met Ai 430 aag aae cgt gi Lys Asn Arg Va 445 cet aeg tta gt Pro Thr Leu Va act ceg gag et Thr Pro Glu Le 48 gca Ala get Ala 240 gee Al a gga Gly gsa Glu cac His gac Asp 320 ~aaa itg let :ga Lrg .ta le sa ys 00 aa lu at 1 672 720 768 816 864 912 960 1008 1056 1104 1152 1200 1248 1296 1344 1392 1440 agg gag aga ttg act tat gaa Arg Giu Arg Leu Thr Tyr Giu 485 gcc Ala atc Ile gct Ala ctt Leu 545 ccc Pro ct 9 Leu act Thr ctc Leu ttc Phe 625 gag Giu gca Ala caa Gin cac His cac His 705 ctt aga Arc att Ile gtg Val 530 aga Arg ctg Leu cat His gct Ala ctg Leu 610 aca Thr agt Ser tct Ser aat A.sn ttc Phe 6 90 cac -His :at ga~ Gli aat Asr 515 9C Ala aaa Lys cat His aag Lys ttg Leu 595 Ceg Leu gca. Ala aca Thr aaa. Lys gtg Val 675 gca Ala ggt Gly aat 9 c~ 2Al~ so( ttc 1Phe tct Sei gga Gly gtt Val cat His 580 cat His agt Ser gca Ala cct Pro gct, Ala 660 aat Asn gca, Ala gcc Ala gcc Ala a gai a Asj aai Ly~ -ctc *Le. gcAla gca 565 ggc Gly aga. Arg tac Tyr cag Gin ata Ile 645 gga Gly tgt: Cys ggc Gly gat Asp tgt Cys 725 ctta gct p Leu Ala a caa ccg 5Gin Pro cat ccc His Pro 535 aat gtt Asn Val 550 gcc gas Ala Giu gce aag Ala Lys gcc gcc Ala Ala ggc tct Gly Ser 615 atg ggc Met Gly 630 cgt act Arg Thr gac ttg Asp Leu aga gac t Arg Asp I E tac aac c Tyr Asn 695 gtc cat g Val His A 710 tca. tat g -1i- ttt aaa ggt cat Phe Lys Giy His 490 aaa gtt aaa aaa Lys Val Lys Lys 505 cag tct cat gaa Gin Ser His Glu 520 aaa cgt aaa. eaa Lys Arg Lys Gin tct tta cta. caa gca Ser Leu Leu Gin Ala 49S aca ctc gct ct,3 Thr aca Thr gtg Val 540 aa As ag Arj atS Met cta Leu 600 gac mat ksn tct Ser ;aa ;lu :ta .eu ~gc Lrg icc la tgaa aaa aat aaa *a Glu Lys Asra Lys 555 gcc cat aat gat SAla His Asn Asp 570 Saat gca ctg gac Asn Ala Leu Asp 585 gca ggc cac ctg Ala Gly His Leu ccc tcc atc atc Pro Ser Ile Ile 620 gaa. gca gtg cag Glu Ala Val Gin 635 gat gtt gat tat Asp Val Asp Tyr 650 act gtg aag caa Thr Val Lys Gin 665 gag ggc cgg cat Giu Gly Arg His gtg tct gtt gta. Val Ser Val Val 700 aaa gac aag ggt Lys Asp Lys Gly 715 cac tat gag gtg His Tyr Giu Val 730 Leu gca Ala 525 aca Thr gat Asp gtc Val acc Thr cag Gin 605 tcc Ser cag Gin cga Arg ctt t Leu tcc a Ser 'I 685 gag t Glu 'T qgc t Giy L 3ct g kla G Al. 51' ctc Let gai Gi t tC Phe atq Met ct t Leu 590 a cc Thr t ta Leu att Ile :tc eu :gc :ys acg 'hr ac yr tg eu ag lu a Leu 3 cac .1 His attg xLeu atg Met Igaa Glu 575 ggt Gly tgc cys caa, Gln ctg Leu tta Leu 655 agc Ser I ccc t Pro I etg C Leu L gtq c Val P -7 ctt t Leu L 735 gaa Glu tgt Cys t ta Leu act Thr 560 gtt Val cag Gin cgc Atrg Gly agt Ser 64 0 3ag 3lu :ct ~er :ta .eu :ta. .eu cc ~ro ta eu 1488 1536 1584 1632 1680 1728 1776 1824 1872 1920 1968 2016 2064 2112 2160 2208 Leu His Asn 9ta agg cat Val Arg His Ser Tyr Gly get tct gte aat Ala Ser Val Asn gcg gac tta tgg Ala Asp Leu Trp aaa ttt acc Lys Phe Thr 750 2256 cet etc cat Pro Leu His 755 gaa gca gca get Giu Ala Ala Ala -12- aaa gga aag tat Lys Gly Lye Tyr 760 gaa ate tge aag etc Glu Ile Cys Lys Leu 765 2304 ett tta aaa cat Leu a ca Thr 785 cig Leu gca Al a ace Thr aac Asn gcc Ala 865 999 Gly aa t Asn aaa Lys ccc Pro get Ala. 945 tta Leu ate Ile gac Asp Leu 770 ect Pro aaa Lys aga Arg eag Gin ctg Leu 850 cag Gin cat His gca Ala gga Gi y ace Thr 930 gac Asp ce t Pro tea Ser aac Asn Lys ttg ILeu 999 Gly gtg Val gge Gly 835 gaa Glu gae Asp gtt Val aca Thr agg Arg 915 atg Met gat Asp ace Thr eca Pro etc a Leu *J 995 Hif ga t As; ga t Asp cag Gin 820 aga Arg gta. Val aag Lye gac Asp gat Asp 900 acg Thr aag Lays atc Ilie :gt ;ca kla let rhr gga Gly ttg Leu get Ala 805 aag Lys aat Asn get Ala ggt Gly ata Ile 885 aagI Lys cag Gin aac Asn aga 5 Arg 9 ttt a PheI 965 tee a Ser T ggc c Gly P gc~ Ali gta Val 790 get Ala etc Leu tea Ser gaa Giu 9gt Giy 870 g Ala tgg Trp, 2tg L eu :ag ;in Jet ~50 iaa ys hr ~ct 'ro, Igat eca Asp Pro 775 aag gaa Lye Giu *tig tig Leu Leu tgt ac Cys Thr aec ect *Thr Pro 840 tat ctt Tyr Leu 855 tta att Leu Ile get tta Ala Leu geg tt Ala Phe tge gee Cys Ala 920 gaa gge Glu Gly 935 ttg ctg Leu Leu cet eag Pro Gin eec tee Pro Ser tta gca 5 Leu Ala C 1000 aet aaa aag a Th 994 GI gal AS] cc~ Pr 82' ets Let eta Leu cet Prc ttg Leu act Thr 905 cte LeCu cag Gln ata Ile ;et kla .ge -ye )85 ;ag Jlu r Lys gac y Asp t get p Ala 810 1 gag cac His gag IGlu ct Leu ata Ile 890 ccc Pro etc Leu aeg Thr gat Asp act Thr 970 etc LeuI ttg S Leu Lys aca Thr 795 gee Ala aat Asn etg Leu cat His cat His 875 aaa Lye etc Leu cia Leu :ct Pro gce 955 Rta Jer A cce g A 71 9, at Al 99 Gl 86 aa As ta Ty Hi g0 lel It a ac aga sri Arg so at att sp Ile ig aag Lye *c aac *e Asn :a gca .a Ala 845 a get y Ala 0 t geg n Ala c aae r Asri t gaa s Glu g cat a His 925 g gat u Asp 0 g ec t Pro g agt 1. Ser :gee a I Ala S gga g Gly C 1005 ga As] ca GI 99( tgc Cyt 830C 99' Gly, ga t Asp gca Ala aeg Thr gea Ala 910 9gt G 1 y :tg Leu cea P'ro )cc kla Ige er 190 ~ga ;ly t gga p Gly 3 gac n Asp tgc SCys aga Arg tat Tyr gt t Val tet Ser tgt Cys 895 gee Ala gca Ala gca Ala gag Ser I 975 age a Ser :I gee t Ala S aa t Asn tta Leu 800 ctg Leu gac Asp aat Asn aat Asn tat Tyr 880 gi a Val cag 3ac A~sp Iea rhr ~cc l a 160 :tg ita ie cc ;er 2352 2400 2448 2496 2544 2592 2640 2688 2736 2784 2832 2880 2928 2976 3024 aat gca Asn Ala 1010 ggg gat ggc gee geg gga aca gaa agg aag gaa gga gaa gtt Giy Asp Giy Ala Ala Gly Thr Glu Arg Lye Glu Gly Glu Val 1015 1020 3072 -13- gct ggi ctt gac atg aat atc agc caa itt cta aaa sgc cit ggc ctt 3120 Ala Gly Leu Asp Met Asri Ile Ser Gin Phe Leu Lys Ser Leu Giy Leu cN11025 1030 1035 1040 gaa cac cit cgg gat sic ttt gas aca gaa cag air aca cia gat gtg 3168 Giu His Leu Arg Asp Ile Phe Giu Thr Giu Gin Ile Thr Leu Asp Val 1045 1050 1055 itg gct gat atg ggi cat gsa gag ttg aaa gaa ata ggc atc aat gca 3216 Leu Ala Asp Met Giy His Giu Giu Leu Lys Giu Ile Gly Ile Asn Ala 1060 1065 1070 tat ggg cac cgc cac aaa ts atc aaa gga gia gas aga crc iia ggi 3264 Tyr Giy His Arg His Lys Leu Ile Lys Giy Val Giu Arg Leu Leu Giy C11075 1080 1085 rlgga caa caa ggc acc sat cci tat ttg act itt cac tgt gii sat cag 3312 Gly Gin Gin Giy Thr Asn Pro Tyr Leu Thr Phe His Cys Val Asn Gin 1090 1095 1100 gga acg sit tig ctg gat cit gci cca gas gat aaa gsa tat cag ica 3360 Gly Thr Ile Leu Leu Asp Leu Ala Pro Giu Asp Lys Glu Tyr Gin Ser 1105 1110 1115 1120 gig gas gas gag aig caa agi act sit cga gaa cac ags gat ggt ggt 3408 Val Giu Giu Giu Met Gin Ser Thr Ile Arg Giu His Arg Asp Gly Gly 1125 1130 1135 sat gct ggc ggc sic tic sac aga tac ast gic stt cga sit caa ass. 3456 Asn Ala Giy Gly Ile Phe Asn Arg Tyr Asn Val Ile Arg Ile Gin Lys 1140 1145 1150 git gic sac sag sag tig sgg gag cgg tic tgc cac cga cag sag gaa 3504 Val Val Asn Lys Lys Leu Arg Giu Arg Phe Cys His Arg Gin Lys Giu 1155 1160 1165 gig ict gag gag sat csc sac cat cac sat gag cgc aig tig iii cat 3552 Val Ser Giu Glu Asn His Asn His His Asn Giu Arg Met Leu Phe His 1170 1175 1180 ggi ict cci tic sit sat gcc ati ati cat ass ggg iii gat gag cgs 3600 Gly Ser Pro Phe Ile Asn Ala Ile Ile His Lys Gly Phe Asp Giu Arg 1185 1190 1195 1200 cat gca tac ats gga gga stg itt ggg gcc ggg sit tat iii gct gaa 3648 His Ala Tyr Ile Gly Gly Met Phe Gly Ala Gly Ile Tyr Phe Aia Glu 1205 1210 1215 sac icc ica ass agc sac cas tat git tat gga sit gga gga gga aca 3696 Asn Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile Gly Gly Gly Thr 1220 1225 1230 ggc igc cci aca cac sag gac sgg ica igc tat sia igt cac aga caa 3744 Gly Cys Pro Thr His Lys Asp Arg Ser Cys Tyr Ile Cys His Arg Gin 1235 1240 1245 atg cic tic igi ags gtg acc cit ggg ass icc tti cig cag itt agc 3792 Met Leu Phe Cys Arg Val Thr Leu Gly Lys Ser Phe Leu Gin Phe Ser 1250 1255 1260 acc aig ass aig gcc cac gcg cci ccs ggg cac cac tcs gic sit ggi 3840 Thr Met Lys Met Ala His Ala Pro Pro Gly His His Ser Val Ile Giy 1265 1270 1275 1280 aga ccg agc gic sat ggg ctg gca tat gct gsa tat gic sic tac aga 3888 Arg Pro Ser Val Asn Gly Leu Ala Tyr Ala Giu Tyr Val Ile Tyr Arg 1285 1290 1295 -24- 99a gaa cag gca tac cca gag tat ctt atc act tac cag atc atg aag Gly Glu Gin Ala Tyr Pro Glu Tyr Leu Ile Thr Tyr Gin Ile Met Lys 1300 1305 1310 cca gaa gcc cct tcc cag acc gca aca gcc gca gag cag aag acc tag Pro Glu Ala Pro Ser Gin Thr Ala Thr Ala Ala Giu Gin Lys Thr 1315 1320 1325 3936 3984 <210> 4 <211> 1327 <212> PRT <213> Homo sapiens <400> 4 Met Ala Ala Ser Arg 1 5 Gin Leu Gin Pro Ala Pro Pro Leu Ser Pro Thr Ala Ser Gly Leu Leu Pro Giu Gly Asp krg Ser )ro Gly ;iy Leu Ja Pro 55 ;ly Ser Gin Ala Ala 40 Phe Arg His His His His Ala Pro Pro Pro Gly Thr Thr Pro Ser Pro Arg His Pro Pro Asp Arg His Gin Pro Pro Ala Ser Gly Leu Pro Arg, 70 Gly Thr Ser Cys Pro Asp Pro Vai Ser Thr Thr Ser Thr Ile Cyrs Ala Pro Ser 145 Scr Pro Gly Ala Gly 225 Thr Ala Ser 130 Pro Thr Ala Asp Lys 210 Phe Val Ala 100 Gly Val 115 Scr. Ser Gly Ser Ala Pro Val Ser 180 Val 5cr 195 Asp Met Gly Arg Ala Ala Pro Val Val Pro Ala Val Ser Thr Ser Ser Ala Ser 5cr Leu 165 Gly Arg Ala Lys Pro Asn Pro Ala Gly Ser Ser Leu 150 Gly Ala Val Gly Asp 230 Pro 135 Ala Pro Leu Lys Arg 215 Val Thr Giu Gly Arg Arg 200 Lys Val Gly 5cr Ser Ala Glu 185 Leu 5cr Glu Gly Ser Pro Ala 170 Leu Val Ser His Leu 250 5cr Glu 155 Gly Leu Asp Pro Leu 235 Ile Gly Ser 140 Al a Pro Giu Ala Leu 220 Leu Pro Ser 125 Ser Ala Gly Ala Ala 205 His Gin Leu 110 Asn 5cr Gly Thr Cys 190 Asn Phe Met His Asn Pro Val Gly 175 Arg Val Ala Gly Asn 255 Ser Ser Ser 160 Val Asn Asn Ala Ala 240 Ala Asn Val His Ala Arg Asp Asp 245 Cys Ser Phe Gly His Ala Giu Val Val Ser Leu Leu Leu Cys Gin Gly 260 265 270 Ala Asp Pro Asn 275 Ala Arg Asp ASn Trp Asn Tyr Thr Pro 280 285 Leu His Glu Al a Gi y 305 Leu Asp Ala Lys Val 385 Gly Val Leu Glu Ala Ile 290 Ala Asp Ala Asp Glu Leu Leu Leu 355 Ser Thr 370 Gln Leu Gly Leu Thr Glu Trp Gln 435 Val Cys 450 Lys Pro Pro Leu 340 Thr Pro Leu Val Leu 420 Phe 'er Gly Lys Asn Ile 310 Ser Ala 325 Glu Ala Pro Leu Leu His Leu Gln 390 Pro Leu 405 Leu Leu Thr Pro Leu Leu Ile 295 Arc Lys Ala Asn Leu 375 His His Lys Lieu eu 155 Asp Val Asn Thi Ala Val Arg Ser 345 Val Asn 360 Ala Ala Gly Ala Asn Al a His Gly 425 His Glu 440 Ser His -is- Cys Ile Val 300 Asp Gly Lys 315 Leu Thr Gly 330 Gly Asn Glu Cys His Ala Gly Tyr Asn 380 Asp Val His 395 Cys Ser Tyr 410 Ala Cys Val Ala Ala Ser Gly Ala Asp 460 Leu Ser Glu Glu Ser 365 Arg Ala Gly Asn Lays 145 ?ro Leu Ala Tyr Lys 350 Asp Val Lys His Ala 430 Asn Thr Gln Leu Lys 335 Leu Gly Arg Asp Tyr 415 Met Airg L,eu His Asp 320 Lys Met Arg Ile Lys 400 Glu Asp Val Val Asn 465 Arg Ala I le Ala Leu 545 Pro Leu Thr Cys Glu Arg Ile Val 530 Arg Leu His Ala His Arg Glu Asn 515 Ala Lys His Lys Leu 595 Gly Leu Ala 500 Phe Ser Gly Val His 580 His Lys Thr 485 Asp Lys Leu Ala Al a 565 Gly Arg Ser 470 Tyr Leu Gln His Asri 550 Ala Ala Ala Ala Val Asp Met Ala Pro Thr Pro Glu Leu Glu Ala Pro Pro 535 Val Glu Lys Al a Phe Lys Gln 520 Lys Asn Arg Met ILeu 600 Lys Val 505 Her Arg Glu Ala Asn 585 Ala Gly 490 Lys His Lys Lys His 570 Ala Gly 475 His Lys Glu Gln Asn 555 Asn Leu His Ser Thr Thr Val 540 Lys Asp Asp Leu Leu Leu Ala 525 Thr Asp Val Thr Gln 605 Leu Ala 510 Leu Glu Phe Met Leu 590 Thr Gln 495 Leu His Leu Met Glu 5.75 Gly Cys 480 Ala Glu Cys Leu Thr 560 Val1 Gln Arg Leu Leu Leu Ser Tyr Gly Her Asp Pro Ser Ile Ile Ser Leu Gln Gly 610 ir 620 Phe Thr Ala Ala 625 Glu Ser Thr Pro Met Gly Asn Glu Ala Val 630 635 Arg Thr Ser Asp Val Asp 650 Leu Leu 655 -16- Val Lys Ala Ser Lys Ala Gly Asp Leu Giu Thr 660 665 Gin Leu Cys Ser Ser 670 Gin His His 705 Leu Val Pro Leu Thr 785 Leu Ala Thr Asn Ala 865 Gly Asn Lys Pro Ala 945 Leu Ile Asp Asr Phe 690 His His Arg Leu Leu 770 Pro Lys Arg Gin Leu 850 Gin His Ala Gly Thr 930 Asp Pro Ser Asn Val Asn 675 Ala Ala Gly Ala Asn Ala His Gly 740 His Glu 755 Lys His Leu Asp Gly Asp Val Gin 820 Gly Arg 835 Glu Val Asp. Lys Val Asp Thr Asp 900 Arg Thr 915 Met Lys Asp Ile Thr Cys Pro Ala 980 Leu Thr Cyc G13 As; Cys 725 Ala Ala Gly Leu Ala 805 Lye Asn Ala Gly Ile 885 Lys Gin Asn Arg Phe 965 Ser 31y Arg r Tyr Val 710 Ser Ser Ala Ala Val 790 Ala Leu Ser Glu Gly 870 Ala Trp Leu Gin 4 Ala 950 Lys I Thr I Pro I Asp Leu Glu Gly Ar 1 Asr 695 His Tyr Val Ala Asp 775 Lys Leu Cys Thr Tyr 855 Leu Ala Ala cys Glu 935 Leu Pro ?ro ,eu 680 1 Arg Ala Gly Asn Lys 760 Pro Glu Leu Thr Pro 840 Leu Ile Leu Phe Ala I 920 Gly Leu I Gin 3 Ser C Ala C Val Lys His Vai 745 Gly Thr Gly Asp Pro 825 Leu Leu Pro Leu [hr 905 .eu .,n le la ys 485 ;lu Ser Asp Tyr 730 Ala Lys Lys Asp Ala 810 Glu His Glu Leu Ile 890 Pro Leu Thr Asp Thr 970 Leu I Leu Val Lys 715 Glu Asp Tyr Lys Thr 795 Ala Asn Leu His His 875 Lys Leu Leu Pro .la 955 al er ~la Hi Va 70 GI Va Le G1 As 78 As Ly Ii Al G1 864 As Ty2 Hi2 Ala Leu 940 Met Val Ala Jia1 .s Ser 685 1i Glu y Gly .1 Ala u Trp u Ile 765 n Arg 0 p Ile s Lys Asn s Ala 845 y Ala Ala Asn Glu 2 His C 925 Asp I Pro I Ser Ala S 9 Gly G 1005 Th TY Let Glu Lys 750 Cys Asp Gin Gly Cys 830 3 iy Asp kla rhr kla 910 ;ly ,eu ,ro la ;er 1iy r Pro Leu Val Leu 735 Phe Lys Gly Asp Cys 815 Arg Tyr Val Ser Cys 895 Ala Ala Ala Glu I Ser I 975 Ser I Ala S Leu Leu Pro 720 Leu Thr Leu Asn Leu 800 Leu Asp Asn Asn Tyr 880 Val GIn ksp hr kla ,eu Ele er 995 1000 Asn Ala Gly Asp Gly Ala Ala Gly Thr Giu Arg Lys Glu L020 Gly Giu Val 1010 1015 1 Ala Gly Leu Asp met Asn Ile Ser Gin Phe Leu Lys Ser Leu Gly Leu 1025 1030 1035 1040 Glu His Leu Arg Asp Ile Phe Giu Thr Glu Gin Ile Thr Leu Asp Val 1045 1050 1055 Leu Ala Asp Met Gly His Giu Giu Leu Lys Glu Ile Gly Ile Asn Ala 1060 1065 1070 Tyr Giy His Arg His Lys Leu Ile Lys Gly Val Giu Arg Leu Leu Gly 1075 1080 1085 Giy Gin Gin Gly Thr Asn Pro Tyr Leu Thr Phe His Cys Val Asn Gin 1090 1095 1100 Gly Thr Ile Leu Leu Asp Leu Ala Pro Giu Asp Lys Giu Tyr Gin Ser C11105 1110 1115 1120 Vai Glu Giu Glu Met Gin Ser Thr Ile Arg Giu His Arg Asp Gly Gly 1125 1130 1135 Asn Ala Gly Gly Ile Phe Asn Arg Tyr Asn Val Ile Arg Ile Gin' Lys 1140 1145 1150 Val Val Asn Lys Lys Leu Arg Glu Arg Phe Cys His Arg Gin Lys Glu 1155 1160 1165 Val Ser Glu Glu Asn His Asn His His Asn Giu Arg Met Leu Phe His 1170 1175 1180 Gly Ser Pro Phe Ile Asn Ala Ile Ile His Lys Gly Phe Asp Giu Arg 1185 1190 1195 1200 His Ala Tyr Ile Gly Gly met Phe Gly Ala Giy Ile Tyr Phe Ala Giu 1205 1210 1215 Asn Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile Gly Gly Gly Thr 1220 1225 1230 Gly Cys Pro .Thr His Lys Asp Arg Ser Cys Tyr Ile Cys His Arg Gin 1235 1240 1245 Met Leu Phe Cys Arg Val Thr Leu Gay Lys Ser Phe Leu Gin Phe Ser 1250 125.5 1260 Thr Met Lys Met Ala His Ala Pro Pro Gly His His Ser Val Ile Gly 1265 1270 1275 1280 Arg Pro Ser Val Asn Gly Leu Ala Tyr Ala Giu Tyr Val Ile Tyr Arg 1285 1290 1295 Gly Glu Gin Ala Tyr Pro Giu Tyr Leu Ile Thr Tyr Gin Ile Met Lys 1300 1305 1310 Pro Giu Ala Pro Ser Gin Thr Ala Thr Ala Ala Glu Gin Lys Thr 1315 1320 1325 <210> <211> 460 <212> DNA <213> Homo sapiens <400>: gaactgtctt cagtagttag ttcaagtgga acagagggtg cttccagttt ggagaaaaag gaggttccag gagtagattt tagcataact caattcgtaa ggaatcttgg acttgagcac 120 catggata tatirnagag agaacagatc actttggatg tattagttga gatggggcac 180 aaggagctga aggagattgg aatcaatgct tatggacata ggcacaaact aattaaagga 240 gtcgagagac ttatctccgg acaacaaggt cttaacccat atttaacttt gaacacctct 300 -Is- ggtagtggaa caattcttat agatctgtct cctgatgata aagagtttca gtctgtggag 360 gaagagatgc aaagtacagt tcgagagcac agagatggag gtcatgcagg tggaatcttC 420 aacagataca atattctcaa gattcagaag gtttgtaaca 460 <210> 6 <211> 42 <212> PRT <213> Homo sapiens <400> 6 Giy Thr Ile Leu Ile 1 5 Val Giu Giu Giu Met Asp Leu Ser Gin Ser Thr Pro Asp Asp I .10 Lys Giu Phe Gin Ser Vai Arg Giu His Arg Asp Gly Gly 25 His Ala Gly Gly Ile Phe Asn Arg Tyr Asn <210> 7 <211> 564 <212> DNA <213> Homo sapiens <400> 7 tgctatttca atgcgtacat gcaatcaata cttgttacat tgcagttcag ggcccagtgt tgtagtttta atctcttgaa attttcagtt ccnaatgtta tgggtctcct agg tggtatg tgtatatgga ttgccacagg tgcaatgaaa aaatggccta tttgttcatc ttgacaagac tgggaagtta tattttgttc tttgtgaatg tttggagctg attggaggag agnctgctct atggcacatt gcattagctg ttcaaaantg ftttgCCtta caaatagtaa cctt caat tatcca gcatttattt gtactgggtg tttgccgggt ctcctccagg aatatgttat ctaggggagg acgggntttt agagattttc caaaggcttt tgctgaaaac tccagttcac aaccttggga tcat cact ca ttacagagga catactttaa ttaaaatttt ttattaccct gatgaaaggc tcttccaaaa aaagacagat aagtctttcc gtcactggta gaacaggtaa ctttttatta at ttgggggt tacccggnt t 120 180 240 300 360 420 480 540 564 <210> 8 <211> 118 <212> PRT <213> Homo sapiens <400> B Leu Phe His 1 Asp Giu Arg Giy Ser Pro Phe Val Asn Ala Ile Ile His Lys Gly Phe Ala Tyr Ile Gly Gly Met Phe Gly Ala Gly Ile Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn Gin Tyr 40 His Lys Asp Arg Val Tyr Giy Ile Gly Gly Gly Thr Gly Cys Pro Val 55 Cys Tyr Ile Cys His Arg Xaa Leu Leu Phe Cys Arg Val Thr Leu Gly Lys Ser Phe Leu 70 75 s0 Gin Phe Ser Ala Lys Met Ala His Ser Pro Pro Giy His His Ser Val Thr Gly Arg Pro Ser Val Asri Giy Leu Ala Leu Ala Giu Tyr Vai 100 105 110 Ile Tyr Arg Gly Giu Gin 115 <210> 9 <211> 397 <212> DNA <213> Homo sapiens <400> 9 aacagagtta tcaacagaac aatacaarttt acattgcttt tgtattgttc tccagaggct gatgggagcc <210> <211> 343 <212> DNA <213> Homo <400> cttatcctga aaatagttat tctacgtttt ataaaaatgt ttttctaaat ggttgtctgt acttgaacct taattttact catttgtaaa gtaatataaa atctatactt atgttcagtt tttatctgtc tttatatgtt aatacaatac actgtaaata tCtgttttag catcttacat gttagttggg at aggaaat c atgcattgat tgtgttcttt agagcttttg aactgcagcg cgtcatgatt gaaagattga tttctca tctaacaaac aaaacacagc tactagccca gtttacaaaa gagtgatctt gttatcagat tgtaatgccc atttacactg gtatttattt ttttttcata tacatttgat ttaatttgcc sapiens gtatttaatt tttaagaaac actcctttgc gaacgaagtt atttnctgtt actaaattat acttaccaga taattccact tgaaaaaaaa ttaacattct ttttcagcac aaacagggtt ttatgaggcc gaacct aaaa tcatct tgcc gacttgataa tttaacagat aactggaccc tgaaggtatg tcatcaaagc cacaggcctg agctttaata gccattccag ttt gtcgatggat agcagtggcc tggcaaaagg atgtacagtg ggtaaactgg <210> 11 <211> 334 <212> DNA <213> Homo sapiens <400> 11 gcagttCtaa agctcttatt aacacagtat atgcataaca tttaacctgg gtacattatt aacagat tta tacagtttta tgtattagta tataaaaggt #atggcatct aaagctttat tattacaaag caaatgaaat aaattagttc tcaagttaac gttaaagtgc caagtcagaa caatgtaaat tgtattcagt tgt tgagggc tctgtttata tgaaaaaaca tgt t aaatactggg gtaaatgctg attacagttt atttagtaca ggaaatattt ctagtacaaa tgttttaaag gttagaatca gacaacccag agaaaacact <210> 12 <211> 353 <212> DNA <213> Homo sapiens <400> 12 cagcaaagga tagtttctta gtaattaaat aggccattta ttcattgcac ctgtggcaaa g taaaacg ta aaataactat actcaggata cactgggcct tgaactgcag tgaacaagat gaggccactg ttatccatcg agcctgttct accagtgact gaaagacttt ctgtctttgt ctgctttgat accatacctt cctctgtaaa gagtgatgac cccaaggtta gaactggaca gattttaggt caggcctcat taacatattc ctggaggaga cccggcaaaa cccagtacct tcagtggaat aatctggtaa agctaatgct atgtgccatt gagcagctgc tct 120 180 240 300 353 <210> 13 <211> 436 <212> DNA <213> Homio sapiens <400> 13 ttttttttgc agtaCaaaag ttttaaagaa tagaatcaat caacccagtt taggaaaaca gtttcacatt agttctaaaa ctcttattta cacagtattg gcataaeata taacctggga Ctggtacat t tttatccnt t cagatttata cagttttaca tattagtaaa taaaaggttc tgggcatctg atttaaaggc tggccacggc t tacaaagca aatgaaattg attagttctg aagt taactc t taaagtgct tttfltccaag ctgtggggcn atgtaaataa tattcagtgt ttgagggcat tgtttataat ggaaaaaaca gtcaggantg aggatggat t atactgggct aaatgctgtg tacagtttgt ttagtacaga gggaaatatt tttaaacttc ttttttccgg ccaagggtgt taaacg <210> 14 <211> 392 <212> DNA <213> Homo sapiens <400> 14 tgctatttca atgcgtacat gcaatcaata Cttgt tacat tgcagttcag ggcccagtgt atgtagtttt tgggtctcct aggtggtatg tgtatatgga t tgccacagg tgcaatgaaa aaatggccta aattttgttt tttgtgaatg caattatcca tttggagctg gcatttattt attggaggag gtactgggtg cagctgctct: tttgccgggt atggcacatt ctcctccagg gcattagctg naatatgtta catcttccaa aa caaaggcttt tgctgaaaac tccagt tcac aaccttggga tcatcactca t ttacagagg gatgaaaggc tcttccaaaa aaagacagat aagtctttcc gtcactggta agaacaggta <210> <211> 317 <212> DNA <213> Homo sapiens <400> ttttttttgc agtacaaaag ttttaaagaa taggaatcaa gacaacccag tttaggaaaa agttctaaaa ctcttattta cacagtattg tgcataacat tttaaccggg cnctgta cagatttata cagttttaca tattagtaaa ataaaaggtt gaatgggcat ttacaaagca aatgaaattg attagttctg caagt taact ctgttaaagt atgtaaataa tattcagtgt ttgagggcat ctgtttataa gctgaaaaaa atactgggct aaatgCtgtn tacagtttgt tttaggtaca cnggganata <210> 16 <211> 485 <212> DNA <213> Homo sapiens <400> 16 tgcagttcta aagctcttat gaacacagta aatgcataac gtt taacctg ctgtacatta tttgccacag gccactggct ttatc aaacagattt ttacagtttt ttgtattagt atataaaagg gaatggcatc ttaaagcttt gcctgtgggg gctttgatga atattacama acaaatgaaa aaaattagt t ttcaagttaa tgttaaagtg atcaagtcag caagatgatt t t ttagggt t gcaatgtaaa ttgtattcag ctgttgaggg ctctgtttac ctgaaaaaac aatgttaaac ttttttcagc cagtgggaat taaatactgg tgtaaatgct cattacagtt aatttagtac aggaaatatt ttcgttcaca aaaggagtaa tagtt tccta gctagtacaa gtgttttaaa tgttagaatc agacaaccca tacgaaaaca tttttatcct aacgtagagg aaataacnat <210> 17 <211> 291 <212> DNA <213> Homo sapiens c400> 17 ttflcctgcag tggtaggccc ggct tatcct ataaatagtt cctctacgtt ttcagtgcaa agtgtaaatg gagtatttaa. attttaagaa ttactccttt tgaanatggc acattctcct gcctagcatt agctgaatat ttacttacca gattatgagg actaattcca ctgaacctaa gctgaaaaaa aatcatcttg ccaggtcatc gttatttaca cctgaaggta aatcatcaaa cccacaggcc actcagtcac gaggagaaca tggtcgatgg gcagcagtgg t <210> 18 <211> 371 <212> DNA <213> Homo sapiens <400> 18 cgtagaggcc taactattta actgctgctt tgatganttt tanggttcan gtggaattng tttcttaaaa tccatcgacc ataccttcag gcctcataat ctggtaagta attaaatact 120 caggataagc tgggcctacc aactgcaggn tgttacaagg tacatatttg ctgttctcct ctgtaaataa agtgactgaa gtgatgcctg aagactttcc caagggttac tcttgtcttt tgtngacctn a catattcagc taatgctagg ccatttacac gggggagaat gtgccatttt cattgcactg ccgggcaaaa gagcagctgc ctgtgggiaa gggcaccccq taccctcctc caattccata <210> 19 <211> 341 <212> DNA <213> Homo sapiens <400> 19 gaaagataca cgaatgctat aggcatgcgt caaaaggcaa acaaaggaca accttggggg ctcaccggag t tcatgggtc acataggtgg tcaatatgta gatcttgttt aagtcttttc aaaagaagtt tcCttttgtg tatgtttgga tatgggaatt acatttggcc ctggcagttt tctgaagaaa aatgcaatta gctggcattt gggagggag9 acaggcaggc cagttgccat accacaacca tccacaaagg attttgctgg gtactggggt tggctct ttt g tgccaatgaa ctttgatgaa aaaactcttc gtccagtttc tgcccgggtn <210> <211> 385 <212> DNA <213> Homo sapiens <400> tactaaatta actgtaatgc gcat ttacac cagtatttat aaaatttttt gatctttaca tggggtttat taaacagagt cctcaacaga tgaatacaat t tacattgct catatgtat t tttggattcc ccgggnttta taacttgaac actaatttta ttcatttgta ttgtaatata gttcatttat ngggggctat ntttg cttttatatg ctaatacaat aaactgtaaa aatctgtttt atttcatctt ggttcaggtt ttatgcattg aangtgttct taagagct tt aggaactgca acatcgtcat gttaggttgg attctaacaa ttaaaacaca tgtactagcc ggcggtttac ggattgaggt gggaaagggt <210> 21 <211> 335 <212> DNA <213> Homo sapiens <400> 21 gaaggtatgg catcaaagca acaggcctgt ctttaataat cattccgggt nttttatatq tcgatggata gcagtggcct ggcaaaagga gtacagtgtt taaactgggg ttatggcctt aatagttatt ctacgt tt ta taaaaatgtg ttctaaatat ttgtctgtac 9gttcttaac ttaagaaact ctcctttgct aacgaagttt ttcctgtttt taaattatta caana aattccactg gaaaaaaaat aacattctga ttcagcactt aacagngtta aacctaaaat catcttgccc cttgataaag taacagatgc act tggaacc <210> 22 <211> 388 <212> DNA <213> Homo sapiens <400> 22 gttttactcc aatgtgaacq aaatatttcc tgtactaaat aaactgtaat caggcattta ctagcccagt t ttgctgaaa aagtttaaca tgttttttca tataaacaga gccct caaca cactggaata atttatttac aaaaatcatc ttctgacttg gcactttaac gttaacttga gaactaattt caatttcatt atgctttg ttgcccacag ataaagcttt agatgccatt accttttata tactaataca tgttaaaact gcctgtggaa aataatgtac ccaggttaaa tgttatgcat atactgtgtt ggtaantagg naagga taaa agtgttttct ctgggttgtc tgattctaac ctttaaaaca agcttttgta <210> 23 <211> 401 <212> DNA <213> Homo sapiens <400> 23 gttttactcc aatgtgaacg aatatttcct gtactaaatt aactgtaatg acaggcattt tttttgtact tttgctgaaa aagttaacat gttttttcag a taaacagag ccctcaacag acactggaat nggccccgtn aaaaatcatc tctgacttga cacttztaaca ttaacttgaa aactantttt acaattttca ttttatttta ttgCccacag taaagcttta gatgccattc ccttttatat acttaataca ttttgttaaa cattgctttg gcctgtggaa ataatgtaca caggttaaac gttatgcatt atactgtgtt actggttaaa 9 naagga taaa gtgttttcta tgggttgtct gattctaaca ctttrlaaaac t taaggnggc <210> 24 <211> 354 <212> DNA <213> Homo sapiens <400> 24 taattttact catttgtaaa gtaatataaa atctatactt atgttcagtt ttatctgtca aatacaat ac actgtaaata tctgttttag catcttacat gttagttggg ttagaaatct tgtgttcttt agagcttttg aactgcagcg cgtca tgatt aaagattgag t tctnat tta aaaacacagc tactagccca gtttacaaaa gagtgatct t ttatcagatt agaacttatg atttacactg gtatttattt ttttttcata tacatt tgat taatttgccg aatatgctga aatacaatt t acattgcttt tgtattgttc tccagaggct atgggagcct agat <210> <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> tgtaaaacga cggccagt <210> 26 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 26 ggaaacagct atgaccatg <210> 27 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 27 tttgccgggt aaccttgg <210> 28 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 28 ccaaggttac ccggcaaa <210> 29 CK1<211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 29 gtaggcccag tgtaaatg 18 <210> c=KI<211> 18 <212> DNA ~KI<213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> catttacact gggcctac 1 <210> 31 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 31 gagtaagttg cagggcatgt <210> 32 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Priier <400> 32 acatgccctg caacttactc <210> 33 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 33 gaatcaccgc agttactaaa <210> 34 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 34 -24- tttagtaact gcggtgattc <c210> <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> ggcctgaagg tatggtcgat <210> 36 (N2 <211> tfl<212> DNA <213> Artificial Sequence CK~ <220> <223> Description of Artificial Sequence:Primer <400> 36 atcgaccata ccttcaggcc <210> 37 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 37 tgagggcatt acagtttgtt <210> 38 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 38 taatacgaac tcactatagg g 21 <210> 39 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 39 atacactcac cggagaaa 18 <210> <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer c400> tttctccggt gagtgtat c210> 41 c2ll> 1691 c212> DNA <213> Artificial Sequence c220> c221> CDS <222> <220> <223> Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence <400> 41 atg cta ttt cat ggg tct Met Leu Phe His Gly Ser 1 5 cct ttt gtg Pro Phe Val gca att atc cac Ala Ile Ile His aaa ggc Lys Giy ttt gat gaa agg Phe Asp Glu Arg tat ttt gct gaa Tyr Phe Ala Glu gga gga ggt act Gly Gly Gly Thr cat gcg tac ata ggt His Ala Tyr Ile Gly 25 aac tct tcc aaa agc Asn Ser Ser Lys Ser ggg tgt cca gtt cac Gly Cys Pro Val His 55 ctg ctc ttt tgc cgg Leu Leu Phe Cys Arg ggt atg ttt gga Gly Met Phe Gly aat caa tat Asn Gin Tyr aaa gac aga Lys Asp Arg gct ggc att Ala Gly Ile tat gga att Tyr Gly Ile tgt tac att Cys Tyr Ile tgc cac Cvs His agg cag Arg Gin gta Val ttg gga aag tct Leu Gly Lys Ser ctg cag ttc agt Leu Gin Phe Ser tca gtc act ggt Ser Val Thr Gly 100 gtt att tac aga Val Ile Tyr Arg 115 gca atg Ala Met aaa atg gca cat tct cct cca ggt Lys Met Ala His Ser Pro Pro Giy cat cac His His agg ccc agt Arg Pro Ser gga gaa cag Giy Giu Gin gta aat ggc cta gca tta gct gaa Val Asn Gly Leu Ala Leu Ala Glu 105 110 gtaatgtagt tttatttgtt catcttcaaa tat Fyr aatgctaggg cttaactgga aatagtaaag tctctttttt gaactgtttg atttcctaaa ctcttataaa ctgtgttttg taggt atcgg aggcatactt ttttttaaaa agaattttct actcttacca agagtaagtt aacaagaaga taattgaaat ctctcagtga aatcaccgca taacttttta attttatttg tataaccttt ttctctcctt gcagggcatg ttttattcaa cttgtattta gagccaaaag gttactaaaa ttaatctctt gagataattt acctagatt t ctttccttgt tccctttacc atttcgccag acagcctgtc tagttctaga tcagacatga gaat tgacaa cagatttgga cctaaatgt t gtgtgtacct attaactatt tcgttccgga catagcaaag gcagtgttgt ttttagtctt gacatattgc aagttacaaa aatattttgt atttttttgt tcaattgtaa tttttct tag aagtatataa gaactgggag atctgatact tatgaactta gtattcatct tagacttgct gattgaaaat ctgaagaact gtactcaggg 987 -26- taaagatgtt CK1 tcctccctaa accattattt gattatgagg ctgaacctaa aatcatcttg tgacttgata ctttaacaga aacttgaacc ctaattttag rN2~ tcatttgtaa ttgagaaaat gattaggaat gaatttatct cctgaaggta aatcatcaaa cccacaggcc aagct ttaat tgccattcca ttttatatgt taatacaata aactgtaaat gtccctagat acttccggaa ttctcttcca tggtcgatgg gcagcagtgg tgtggcaaaa aatgtacagt ggttaaactg tatgcattga ctgtgttctt aagagctttt gattctgatc tacaacagta agtctgttta tctttcaaga ggcttatcct gagtatttaa ataaatagtt attttaagaa cctctacgtt ttactccttt ggataaaaat gtgaacgaag gttttctaaa. tatttcctgt ggttgtctgt actaaattat ttctaacaaa ctgtaatgcc taaaacacag catttacact gtactagccc agtatttatt atttagaacc 1047 aaatttttgt 1107 ttacttacca 1167 actaattcca 1227 gctgaaaaaa 1287 tttaacattc 1347 tttttcagca 1407 aaacagagtt 1467 ctcaacagaa 1527 gaatacaatt 1587 tacattgctt 1647 tgtaatataa tcctgtttta gaagtgcaaa aaaaaaaaaa aaaa <210> 42 <211> 119 <212> PRT <213> Artificial Sequence <223>. Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence 1691 <400> 42 Met Leu Phe H is Gly Ser Pro Phe Val Asn Ala Phe Asp Glu Arg Tyr Phe Ala.,Glu Gly Gly Gly Thr His Ala Tyr Asn Ser Ser Gly Cys Pro 55 Ile Gly Gly met 25 Lys Ser Asn Gin 40 Val His Lys Asp Cys His 6s Leu Gin Ser Val Ile Ile His Lys Giy Phe Gly Ala Gly Ile Tyr Val Tyr Gly Ile Arg Ser Cys Tyr Ile Leu Gly Lys Ser Phe Pro Pro Giy His His Ala Leu Ala Glu Tyr 110 Arg Gin Leu Phe Ser Ala Thr Gly Arg Leu Phe Cys Arg Val Thr 70 75 Met Lys Met Ala His Ser 90 Pro Ser Val Asn Gly Leu 105 Val Ile Tyr 115 Arg Giy Glu Gin <210> <211> <212> c213> <220> <221> c222> <220> 43 1692 DNA Artificial Sequence CDS .(357) -27- c223>. Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence c400> 43 atg cta ttt cat 999 tct cct ttt gtg aat gca ait atc cac aaa 99c Met Leu Phe His Gly Ser Pro Phe Val. Asn Ala Ile Ile His Lys Gly 1 5 10 ttt gat gaa agg cat gcg tac ata 99t ggt atg itt gga gct ggc att Phe Asp Glu. Arg His Ala Tyr Ile Gly Gly Met Phe Giy Ala Gly Ile 25 tat ttt gct gaa aac ici tcc aaa agc aai caa tat gta tat gga att Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile 40 gga gga ggt act ggg tgt cca gtt cac aaa gac aga tct igi tac att Gly Giy Gly Thr Gly Cys Pro Val His Lys Asp Arg Ser Cys Tyr Ile 55 tgc cac agg cag ctg ctc ttt tgc cgg gia acc tig gga aag tct ttc Cys His Arg Gin Leu Leu Phe Cys Arg Val. Thr Leu Gly Lys Ser Phe 70 75 ctg cag tic agi gca atg aaa atg gca cat ict cct cca gi cat cac Leu Gin Phe 5cr Ala Met Lys Met Ala His Ser Pro Pro Gly His His 90 tca gic act ggt ag9 ccc agt gta aat ggc cia gca tta gci gaa tat Ser Val Thr Giy Arg Pro Ser Val. Asn Gly Leu Ala Leu Ala Giu Tyr 100 105 110 gtt att tac aga gga gaa cag gtaatgiagt tttaittgt catciicaaa Vai Ile Tyr Arg Gly Glu. Gin 115 48 96 144 192 240 288 336 387 aatgctaggg ci taacigga aatagtaaag tctctttt gaactgttig aittcctaaa ctcitataaa cigigittig taggtatcgg iatgaacita taaagatgii tcciccctaa accaitatit gaiiatgagg ctgaacciaa aaicatctig tgaciigaia aggcatacit tttitaaaa agaattiict acictiacca agagtaagtt aacaagaaga iaattgaaat ctcicagtga aatcaccgca gtattcaict t tgagaaaat gattaggaai gaaiitatct cctgaaggta aaicatcaaa cccacaggcc aagct ttaai taaciiitta attitattig tataaccttt ttctcccit gcagggcatg titattcaa cttgtattta gagccaaaag gi tactaaaa tagacitgct giccctagai acttccggaa ttccttcca tggtcgatgg gcagcagtgg ttaatctcii gagataaittt acctagatit cticcittt iccCtitacc atttcgccag acagccigtc tagitctaga icagacatga gatigaaaat gaticigatc agictgttia ggcttatcct ataaatagtt -ctctacgtt gaattgacaa cagattigga cctaaatgtt gigtgiacct attaaciatt tcgttccgga catagcaaag gcagtgttgi ttttagtcti ctgaagaact tacaacagta tctttcaaga gagiatttaa attaagaa tiactcctti gtgaacgaag tatitccigi gacatitgC 447 aagttacaaa 507 aaiattttgi 567 atttittigt 627 tcaatigiaa 687 titticitag 747 aagtataiaa 807 gaactgggag 867 aicigataci 927 gtacicaggg 987 atttagaacc 1047 aaaiiittgt 1107 itactiacca 1167 aciaattcca 1227 gctgaaaaaa 1287 titaacattc 1347 tttitcagca 1407 tgiggcaaaa ggataaaaai aatgtacagt gttttctaaa -28- ctttaacaga tgccattcca ggttaaactg ggttgtctgt actaaattat aacttgaacc ttttatatgt tatgcattga ttctaacaaa ctgtaatgcc ctaattttac taatacaata ctgtgttctt taaaacacag catttacact tcatttgtaa aactgtaaat aagagctttt gtactagccc agtatttatt tgtaatataa atctgtttta gaactgcaaa aaaaaaaaaa aaaaa <210> 44 <211> 119 <c212> PRT <213> Artificial Sequence <c223> Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence <400> 44 Met Leu Phe His 'Gly Ser Pro Phe Val Asn Ala Ile Ile His 1 5 10 Phe Asp Glu Arg His Ala Tyr Ile Gly Gly Met Phe Gly Ala 25 30 Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn Gin Tyr Val Tyr 40 45 Gly Gly Giy Thr Gly Cys Pro Val His Lys Asp Arg Ser Cys 55 60 Cys His Arg Gin Leu Leu Phe Cys Arg Vai Thr Leu Gly Lys 70 75 Leu Gin Phe Ser Ala Met Lys Met Ala His Ser Pro Pro Gly 90 Ser Val Thr Gly Arg Pro 5cr Val Asn Gly Leu Ala Leu Ala 100 105 110 Val Ile Tyr Arg Gly Glu Gin 115 aaacagagtt 1467 Ctcaacagaa 1527 gaatacaatt 1587 tacattgctt 1647 1692 Gly Ile Ile Ile Phe His Tyr <210> 211> 582 <212> DNA <213> Artificial Sequence <220> <221> CDS <222> <220> <223> Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence <400>. gaa aga tac act cac cgg aga aaa gaa gtt tct gaa gaa aac cac aac Glu Arg Tyr Thr His Arg Arg Lys Giu Val Ser Glu Glu Asn His Asn 1 5 10 cat gcc aat gaa cga atg cta ttt cat ggg tct cct ttt gtg aat gca His Ala Asn Glu Arg Met Leu Phe His Gly Ser Pro Phe Val Asn Ala 25 att atc cac aaa ggc ttt gat gaa agg cat gcg tac ata ggt ggt atg Ile Ile His Lys Gly Phe Asp Giu Arg His Ala Tyr Ile Gly Gly Met 40 -29- ttt gga gct ggc att tat ttt gct gaa aac tct tcc aaa agc aat caa Phe Gly Ala Gly Ile Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn Gin 55 tat gta tat gga att gga gga ggt act ggg tgt cca gtt cac aaa gac Tyr Val Tyr Gly Ile Giy Gly Gly Thr Gly Cys Pro Val His Lys Asp 70 75 aga tct tgt tac att tgc cac agg cag ctg ctc ttt tgc cgg gta ac Arg Ser Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val Thr 90 ttg gga aag tct ttc ctg cag ttc agt gca atg aaa atg gca cat tct Leu Gly Lys Ser The Leu Gin Phe Ser Ala Met Lys Met Ala His Ser 100 105 110 cct cca ggt cat cac tca gtc act ggt agg ccc agt gta aat ggc eta Pro Pro Gly His His Ser Val Thr Giy Arg Pro Ser Vai Asn Giy Leu 115 120 125 gca tta gct gaa tat gtt att tac aga gga gaa cag gct tat cct gag Ala Leu. Ala Giu Tyr Val Ile Tyr Arg Giy Glu Gin Ala Tyr Pro Glu 130 135 140 tat tta att act tac cag att atg agg cct gaa ggt atg gtc gat gga Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Glu Gly Met Val Asp Gly 145 150 155 160 taaatagtta ttttaagaaa Ctaattccac tgaacctaaa atcatcaaag cagcagtggc ctctacgttt tactcctttg ctgaaaaaaa aaaaaaaaaa aa <210> 46 <211> 160 <212> PRT <213> Artificial Sequence <223> Description of Artificial Sequence: Sequence not specified as protein-coding is vector sequence <400> 46 Giu Arg Tyr Thr His Arg Arg Lys Giu Val Ser Glu Giu Asn His Asn 1 5 10 His Ala Asn Giu Arg Met Leu Phe His Gly Ser Pro Phe Val Asn Ala 25 Ile Ile His Lys Gly Phe Asp Giu Arg His Ala Tyr Ile Gly Gly Met 40 Phe Gly Ala Gly Ile Tyr Phe Ala Glu Asn 5cr Ser Lys Ser Asn Gin s0 55 Tyr Val Tyr Gly Ile Gly Gly Gly Thr Gly Cys Pro Val His Lys Asp 70 75 Arg Ser Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val Thr 90 Leu Gly Lye Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His Ser 100 105 .110 Pro Pro Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly Leu 115 120 125 Ala Leu Ala Giu Tyr Val Ile Tyr Arg Gly Glu Gin Ala Tyr Pro Giu 130 135 140 Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Giu Gly Met Val Asp Gly 145 150 155 160 192 240 288 336 384 432 480 540 582 <210> 47 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Prjmer <400> 47 ctccggacaa caaggtctta acc <:210> 48 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 48 ccacctatgt acgcatgcc <210> 49 <211> 356 <212> DNA <213> Homo sapiens <400> 49 tccggacaac cttatagatc acagttcgag ctcaagat tc gaagtttctg tttgtgaatg aaggtcttaa tgtctcctga agcacagaga agaaggtttg aagaaaacca caattatcca cccatattta tgataaagag tggaggtcat taacaagaaa caaccatgcc caaaggcttt actt tgaaca tttcagtctg gcaggtggaa ctatgggaaa aatgaacgaa gatgaaaggc cctctggtag tggaggaaga tct tcaacag gatacactca tgctatttca atgcgtacat tggaacaatt gatgcaaagt atacaatatt ccggagaaaa tgggtctcct aggtgg <210> <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> atttaaccct cactaaaagg g <210> 51 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 51 aaaggctccc atcggcaaat <210> <211> <212> <-213> <220> 52 DNA Artificial Sequence -31- <223> Description of Artificial Sequence:Primer CK1 <400> 52 gttgagggca ttacagtttg <210> 53 <211> <212> DNA <c213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer C1<400> 53 aaaacgtaga ggccactgct <210> 54 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 54 tggtgtagac tgacgccctt <210> <211> <212> DNA <213> Artificial Sequence <22 0> <223> Description of Artificial Sequence:Primer <400> tccggtgagt gtatctttcc <210> 56 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 56 ctcctttgtc ttgggcattc <210> 57 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 57 atctgctctg ccctcttgtt <210> 58 <211> <212> DNA <213> Artificial Sequence -32- <220> <223> Description of Artificial Sequence:Primer <400> 58 gggtatcgcg gcaatttaca 2 <210> 59 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 59 aacaagaggg cagagcagat <210> (N2 <211> <212> DNA <213> Artificial Sequence <220>. <223> Description of Artificial Sequence:Primer <400> tgccccatct caactaatac <210> 61 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 61 gtaatgccct caacagaact <210> 62 <211> <212> DNA <213> Artif icial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 62 ggcgtcagtc tacaccactt <210> 63 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 63 taaattgccc 9cgataccca <210> 64 <211> <212> DNA <213> Artificial Sequence CK1 <220> c223> Description of Artificial Sequence:Primer <400> 64 cactcagtca ctggtaggcc <210> <211> <212> DNA <213> Artificial Sequence CK1 <220> <223> Description of Artificial Sequence:Primer tn<400> atctgctctg ccctcttgtt <210> 66 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 66 tagttgagat ggggcacaag <210> 67 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 67 aaacgtagag gccactgctg <210> 68 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 68 cgggtaacct tgggaaagtc <210> 69 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 69 gggctttact gctttacaga <210> <211> <212> DNA c213> Artificial Sequence <220> <223> Description of Artificial Sequence:Priner <400> gtaagggctg ctgacagtga <c210> 71 <211> <212> DNA <213> Artificial Sequence cN~1 <220> <223> Description of Artificial Sequence:Primer <400> 71 CK1ttactccagc agagggcact <210> 72 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Seqluence:Priner <400> 72 ctgacgccct tcaatgtctc <210> 73 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 73 ggtactaagg ccacaattca <210> 74 <211> c212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 74 gggtatcgc9 gcaatttaca <210> <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400. gttgagggca ttacagtttg C9<210> 76 <211> C1<212> DNA <c213> Artificial Sequence *<220> <223> Description of Artificial Sequence:Primer <400> 76 taacaagagg gcagagcaga <210> 77 <211> Cl<212> DNA <c213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer agtcgtg agggcattac <210> 78 <.211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 78 ggcctaccag tgactgagtg <210> 79 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 79 gggctagagg acctgaagag <210> <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> agtgccctct gctggagtaa <210> 81 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 81 ggcgtcagtc tacaccactt S<210> 82 <211> <212> DNA <213> Artificial Sequence S<220> O <223> Description of Artificial Sequence:Primer <400> 82 tgaattgtgg ccttagtacc S<210> 83 <211> <212> DNA 1 <213> Artificial Sequence <220> 0 <223> Description of Artificial Sequence:Primer <400> 83 atgcccaaga caaaggagga <210> 84 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 84 gtaatgccct caacagaact <210> <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> atctgctctg ccctcttgtt <210> 86 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 86 cgggtaacct tgggaaagtc <210> 87 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 87 ccggacaaca aggtcttaac <210> 88 <c211> 3353 <212> DNA .c213> Homo sapiens <220> <221> CDS <c222> (1)..(2352) <400> 88 tgt gaa ctg ttg cta aga aa Cys Glu Leu Leu Leu Arg Ly 1 S gaa ttc ttg act cct ctg ca Glu Phe Leu Thr Pro Leu Hi gtt gtt gaa gta gtg gtg aa, Val Val Giu Val Vai Val Ly aat ctt ggt cag act tct ctj Asn Leu Gly Gin Thr Ser Lei 5! caa acc tgc cgc cta ctc ctc Gin Thr Cys Arg Leu Leu Let 70 tcc ctt cag ggc ttt act gct Ser Leu Gin Giy Phe Thr Ala caa ctc ctc caa gag ggt atc Gin Leu Leu Gin Glu Gly Ile 100 caa ttg ctg gaa gct gca aag Gin Leu Leu Glu Ala Ala Lys 115 ctg tgt act gtt cag agt gtc Leu Cys Thr Val Gin Ser Vai 130 135 tct aca cca cit cat ttt gca Ser Thr Pro Leu His Phe Ala 145 150 gaa tat ctg cta, cag cat gga Glu Tyr Leu Leu Gin His Gly 165 ggc ctt gta cct ttg cac aat Giy Leu Val Pro Leu His Asn 180 gca gaa ctt cit gtt aaa cat Ala Glu Leu Leu Val Lys His 195 tgg9 aaa itt aca cct tta cat Trp Lys Phe Thr Pro Leu His 210 215 a gga gc S Gly Al C gtg gc, s Val. AL 2. a cat ga s His Gil 40 a cac agi .1 His Arc agc tat xSer Ty2 tta cac; Leu Gin tca tra Ser Leu 105 gct gga Ala Gly 120. aac tgc Asn Cys gct ggg Ala Gly gct gat Ala Asp gca igt Ala Cys 185 99a gca Gly Ala 200 gaa gca Giu Ala a aac atc a Asn Ile 10 a tct gag a Ser Giu 5 1 gca aag Ala Lys agct gca Ala Ala ggg tgt Gly Cys 75 iatg gga Met Gly 90 ggt aat Gly Asn gat gtc Asp Val aga gac Arg AspI tat aac a Tyr Asn 155 gtg cat g Val His A 170 tct tat g Ser Tyr G gia gtt a Val Val A gca gca a Ala AlaL aat gaa aag act aaa Asn Glu Lys Thr Lys 1s aaa gct cat aat gat Lys Ala His Asn Asp gtt aat gct ctg gat Val Asn Ala Leu Asp tat tgi ggt cat cta Tyr Cys Gly His Leu gat cci aac ait ata Asp Pro Asn Ile Ile aat gaa aat gta cag Asn Glu Asn Val Gin tca gag gca gac aga Ser Giu Ala Asp Arg 110 ?aa act gta aaa aaa 1lu Thr Val Lys Lys 125 Itt gaa ggg cgt cag lie Giu Gly Arg Gin 140 iga gtg tcc gtg gig ~rg Val Ser Val Val 160 ~ci aaa gat aaa gga la Lys Asp Lys Gly 175 'ga cat tat gaa gti ly His Tyr Glu Val 190 at gia gci gat tia sn Val Ala Asp Leu 205 aa gga aaa tat gaa ys Giy Lys Tyr Giu 48 96 144 192 240 288 336 384 432 480 528 576 624 672 att tgc Ile Cys 225 agg gat Arg Asp att caa Ile Gin aag ggt Lys Giy eat tgc Asn Cys 290 aaa Lys 99a Giy gat Asp tgt Cys 275 cgc Arg ctt ctg Leu Leu aat act Asn Thr 245 ctg ctt Leu Leu 260 tta gcc Leu Ala gat acc Asp Thr ctc Leu 230 cc t Pro agg Arg aga Arg caa Gin cag Gin ttg Leu gga Giy gtg Val ggc Gly 295 cat His ga t Asp gat Asp aag Lys 280 age Arg gg t Giy ctt Leu gca Ala 265 aeg Lys cat His -38- gce gec cct Ala Asp Pro 235 gtt eea gat Vai Lys Asp 250 gct ttg cta Aia Leu Leu ttg tct tct Leu Ser Ser tca ace cct Ser Thr Pro 300 aca Thr g Gi y gat Asp cct Pro 285 tta Leu aaa Lys gat Asp gc t Ala 270 gat Asp cat His aee Lys ace Thr 255 gcc Ale eat Asn t te Leu eec Asn 240 get Asp aag Lys gte Val gca Ala gct Ale 305 gct Ale gce Aila eat Asn gee Giu cat His 385 get Asp ccc Pro ggt tat eat eat tte gee gtt gce gag Gly Tyr Asn Asn Leu Giu Val Ale Giu get Asp gca Ala gca Ale gce Ala 370 gga Gi y tta Leu cca Pro gtg Val t ct Ser tgt Cys 355 gcc Ale gct Ala gtt Val tct Ser eat Asn tec Tyr 340 gtc Vel cee Gin gac Asp tca Ser gct Aila 310 gcc cee gac Ala Gin Asp 325 ggg cat gte Gly His Val eat gcc acg Asn Ale Thr eag gge cga Lys Gly Arg 375 ccg act ctt Pro Thr Leu 390 gca get get Ale Asp Asp 405 ctg ccc tct Leu Pro Ser gga gcc act Gly Ala Thr ctt tct gca Leu Ser Ale 455 ctg tct tce Leu Ser Ser tat ttg tte cee cec gga Tyr Leu Leu Gin His Gly 315 320 ctt ett cct tte cat eat a Lys get Asp gec Asp 360 ace Thr eee Lys gtc Val tgt Cys gce Ala 440 gcc Ala gte eIa gge gga Gly Gil 330C gte gca Val Ala 345 ae tg Lys Trp cag ctt Gin Leu eat ceg Asn Gin agc gct Ser Ale 410 tec aeg Tyr Lys 425 Leu. Ile gct cta Ala Leu gct ttc Ale Phe tgt gct Cys Ale 380 gee gge Giu Gly 395 ctt ctg Leu Leu cct cae Pro Gin ctc tct Leu Ser ctt gec Leu Asp 460 Pro cte Leu ace Thr 365 t tg Leu caa Gin ace Thr gtg Val tce Ser 445 ILeu ate Ile 350 cct Pro t tg Leu ace Thr gce Ala ctc Leu 430 ggt Giy Hig 331 Lys t tg Leu cta Leu cct Pro gcc Ala 415 eat Asn cca Pro Asn tat *Tyr Icac His *gcc Ala tta Leu 400 etq Met gg t Gly tct Ser ggg Gly ggt Gly 480 720 768 816 864 912 960 1008 1056 1104 1152 1200 1248 1296 1344 1392 1440 1488 420 gtg Val agc Ser eg t Ser 465 get Asp egc 8cr gt t Val gct Ale egt Ser agt Ser Asn Leu Ser tc ggt~ a aca oao Ser Ser Gly Thr Giu 475 gct tcc agt ttg Ale Ser Ser Leu aee aeg gag gtt Lys Lys Glu Val gge gte get ttt Gay Val Asp Phe agc eta Ser Ile 495 act caa Thr Gin gag aga Glu Arg gag ctg Giu Leu 530 att aaa Ile Lys 545 tat tta Tyr Leu tct ect Ser Pro aca gtt Thr Val aga tac~ Arg Tyr 610 gaa aga Glu Arg 625 cat 9CCj His Ala I att atc c Ile Ile H ttt gga 9 Phe Gly A 6 tat gta t Tyr Val TI 690 aga tct t Arg Ser C 705 ttg gga a Leu Gly L. Cct cca g' Pro Pro G gca tta g~ Ala Leu A: 7! tt Ph ge G1 aa L~y GI' ac Th~ gat Asi cga Arg 595 aat Asn tac r'yr iat ~sn :ac 'ct la ;75 at yr gt ag ys ly la 55 C gt Va a ca' GI~ 9 gac s GIa a gtc y Val r Le. gat Asp 580 gag Glu att Ile act Thr gaa Glu aa a Lys 660 ggC Gly gga Gi y tac Tyr tct Ser cat His 740 gaa Glu a agg aat 1 Arg Asn 0 9 etc act n Ile Thr g att gga a Ile Gly gag aga Glu Arg 550 aac acc Asn Thr 565 aaa gag Lys Giu cac aga His Arg, ctc aeg Leu Lys cac cgg His Arg 630 cga atg Arg MetI 645 ggc ttt Gly Phe att tat t Ile Tyr P att gga g Ile Gly G 6 att tgc c Ile Cys H 710 ttc ctg C Phe Leu G 725 cec tca g His Ser V tat gtt ai Tyr Val I; Ct Le tt Le at 11 53 ct Le tic Se: t t PhE get Asi att Ile 61.5 k.rS :ta eu 3at Isp :tt 3 he ga liy 95 ac is ag In tic tt le -39- :t gga ctt gag cac cta u Gly Leu Giu His Leu 505 g gat gta tta gtt gag Asp Val Leu Vai Glu 520 aat gct tat gga cat Asn Ala Tyr Giy His 5 540 t atc tcc gga caa caa u Ile Scr Gly Gin Gin 555 t ggt agt gga aca att r Gly Ser Giy Thr Ile 570 t cag tct gtg gag gaa e Gin Ser Val Giu Giu 585 gga ggt cat gca ggt SGiy Gly His Ala Giy 600 cag aag gtt tgt aac Gin Lys Val Cys Asn 620 aaa gaa gtt tct gaa S Lys GIuL Val Ser Giu C 635 ttt cat ggg tct cct t Phe His Gly Ser Pro P 650 gaa egg cat gcg tec a Glu Arg His Ala Tyr I 665 gct gaa aac t'ct tcc a Aia Giu Asn Ser SerL 680 6 ggt act ggg tgt cca g Gly Thr Gly Cys Pro V 700 agg cag ctg ctic ttt t' Arg Gin Leu Leu Phe C 715 ttc agt gca etg aaa al Phe Ser Ala Met Lys Mi 730 act ggt agg ccc agt gi Thr Giy Arg Pro Ser v~ 745 tac aga gga gaa cag gc Tyr Arg Gly Giu Gin Al 760 7 etg ga Met As 52 atg gg Met Gi 525 egg ca Arg Hi ggt ct Giy Le ctt at 4 Leu Ii gag atc Giu Mel 5 9( ~g atc 3iy Ii 605 aag aaa .sys .LyE ;aa aac flu Asn :tt gtg ~he Val ta ggt le Giy 670 aa agc ys Ser tt cac ai His 9c cgg ys Arg tg gca et Ala :a aat 11 Asn 750 ~t tat .a Tyr it eta ttt ;p Ile Phe .0 19 cac aag y His Lys C aaa cta S Lys Leu t aac cca u Asn Pro 560 a gat ctg e Asp Leu 575 Scaa agt Gin Ser ttc aac Phe Asn icta tg Leu Trp cac aec His Asn 640 eat gca Asn Ala 655 ggt atg Gly met aat caa Asn Gin aae gac Lys Asp gte acc Val Thr 720 cat tct His 735 ggc cte Giy Leu cct gag Pro Giu 1536 1584 1632 1680 1728 1776 1824 1872 1920 1968 2016 2064 2112 2160 2208 2256 2304 tat tta att act tac cag att atg agg cct gaa ggt atg gte gat gga 2352 Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Giu Giy Met Vai Asp Giy 770 775 780 taaatagtta ctctacgttt gataaaaatg ttttctaaat gttgtctgta tctaacaaac aaaacacagc tactagccca gtttacaaaa .gagtgatctt ttatcagatt agaacttatg ccaaagagct tttctagctt Ctcctgtttt aacataagta ctattctaat ttttaagaaa tactcctttg tgaacgaagt atttcctgtt ctaaattata tgtaatgccc atttacactg gtatttattt ttttttcata tacatttgat taatttgccg aatatgctga ctaactatga tcatgt tgga t tagagaaac ggatgttaca taccttaaat ctaattccac ctgaaaaaaa ttaacattct ttttcagcac aacagagt ta t caacagaac aatacaattt acattgcttt tgtattgttc t ccagaggct atgggagcct agatttaatt taggtcctga aaattttctg taaatcttgc tttccagggt ctaaagggga tgaacctaaa atcatcttgc gacttgataa tttaacagat acttgaacct taattttact cat ttgtaaa gtaatataaa atctatactt atgttcagtt ttatctgtca tgtgatacct ttactaaaga cagtccttct tgttgaacaa gggaagggta aaaaaaaaat atcatcaaag ccacaggcct agctttaata gccattccag tttatatgtt aatacaatac actgtaaa ta tctgttttag catcttacat gttagttggg ttagaaatct ttgtatgtat agcttcttta gtgaaaatta ttattgtgtt atcctaaatc cagcagtggc 2412 gtggcaaaag 2472 atgtacagtg 2532 gttaaactgg 2592 atgcattgat 2652 tgtgttcttt 2712 agagcttttg 2772 aactgcagcg 2832 cgtcatgatt 2892 aaagattgag 2952 ttctcattta 30i2 gagacacatt 3072 ctggcctcaa 3132 gagcaaagtg 3192 cttttcatgg 3252 atttcccaat 3312 3353 <210> 89 <211> 784 <212> PRT :213> Homo sapiens <400> 89 Cys Giu Leu Leu Leu 1 5 Giu Phe Leu Thr Pro Arg Lys Gly Ala Asn Ile Asn Giu Lys Thr Lys Vai Val Giu Asn Leu Giy Gin Thr Cys Val Vai Gin Thr Leu His Vai Ala Ser Giu 25 Val Lys His Giu Aia Lys 40 Ser Leu His Arg Ala Ala Lys Val1 Tyr Asp Aia His Asn Asp Asn Ala Leu Asp Cys Giy His Leu Gly Cys Arg Leu Leu Ser Tyr Pro Asn Ile Leu Gin Gly Thr Aia Leu Gin Met Gly Asn Giu Asn Vai Gin Giu Ala Asp Arg 110 Gin Leu Leu Gin 100 Gin Leu Leu Giu 115 Giu Giy Ile Ser Leu Gly Asn Ser 105 Aia Ala Lys Ala Gly Asp Val Giu Thr Val Lys Lys 120 125 -41- Arg Asp Leu Cys Thr Val Gin Ser Val Asn Cys 130 135 Ile Giu Gly Arg Gin 140 Ser Thr Pro Leu His 145 Glu Gly Ala Trp Ile 225 Arg Ile Lys Asn Ala 305 Ala Ala Asn Glu His 385 Asp Pro I Val 3 Ser I 4 Tyi Leu Glu Lys 210 Cys Asp 'Gin Gly Cys 290 Gly Asp Ala Ala Ala 370 Gly Leu ?ro krg )ro s50 Leu Val Leu 195 Phe Lys Gly Asp Cys 275 Arg Tyr. Val Ser. Cys 355 Ala C Ala 3 Val I 5cr 4 Ser P 435 Ser S Le Prc 18 Let Thi Leu Asn Leu 260 Leu Asp Asn Asn ryr 340 Jal ;in 4 sp er la 20 'ro er u Gin 165 Leu a Val Pro Leu Thr 245 Leu Ala Thr Asn Ala 325 Gly Asn Lys Pro Ala 2 405 Leu I Gly 3 Leu S Phe Ala Ala 150 His Gly Ala His Asn Ala Ser Asp 170 Ser Tyr Gly His Tyr Giu Val 190 Lys Leu Leu 230 Pro Arg Arg Gin Leu 310 Gin His Ala Gly hr 390 ksp ?ro la ier His His 215 Gin Leu Gly Val Gly 295 Glu Asp Val Thr Arg 375 Leu I Asp Ser C Thr I 4 Ala 455 Gi' 204 G1 Hi AsI Asr Lys 280 Arg Val Lys Asp Asp 360 rhr Lys Ial 'ys la 440 la Y Ala Val Val Asn Val Ala Asp Leu .i Ala 5 Gly Leu Ala 265 Lys His Ala Gly Val 345 Lys Gin Asn er Tyr 425 Asp Ser Val Al Ali Val 25C Ala Leu Ser Glu Gly 330 Ala Trp Leu Gin Ala 410 Lys Ala Ser Ser I Ala i Asp 235 Lys Leu Ser Thr Tyr 315 Leu Ala Ala Cys Glu 395 Leu Pro 4 Leu Leu Ser Ly 22 Pr Asl Leu Ser Pro 300 Leu Ile Leu Phe Ala 380 Gly Leu Gin Ser ksp 460 3er 205 s Gly Thr Gly a Asp Pro 285 Leu Leu Pro Leu Thr 365 Leu Gin Thr 2 Val I 4 Ser C 445 Asn I Gly T Lys Lys Asp Ala 270 Asp His Gin Leu Ile 350 Pro Leu rhr kla ,eu 130 ;ly eu :hr Tyr Lys Thr 255 Ala Asn Leu His His 335 Lys Leu Leu Pro Ala I 415 Asn Pro Ser C Glu C Glu Asn 240 Asp Lys Val Ala Gly 320 Asn Tyr His Ala Leu 400 Met ,ly 3er fly Ser Phe Ser Giu Leu Ser Ser Val 465 470 475 480 Ala Ser Ser Leu Lys Lys Giu Val Pro 490 Gly Vai Asp Phe Ser Ile 495 -42- Giu His Thr Gin Phe Val 500 Arg Asn Leu Gly Leu Leu Met Asp Ile Phe 510 505 Giu Giu Ile 545 Tyr Ser Thr Arg Giu *625 His Ile Phe Tyr Arg 705 Leu Pro Ala Arg Leu 530 Lys Leu Pro Vai Tyr 610 Arg Ala Ile Giy Val 690 Ser 3iy Pro Leu Giu 515 Lys Giy Thr Asp Arg 595 Asn Tyr Asn His Ala 675 Tyr Cys; Lys Giy Ala Gir Giu Vai Leu Asp 580 Giu Ile Thr Giu Lys 660 Gly Gly Tyr Ser His 740 Glu Ile Thr Leu Asp Val Leu Val Git 520 Ile Giu Asn 565 Lys His Leu His Arg 645 Gly Ile Ile Ile Phe 725 His Tyr Gly Arg 550 Thr Glu Arg Lys Arg 630 Met Phe Tyr Gly Cys 710 Leu Ser Ile 535 Leu Ser Phe Asp Ile 615 Arg Leu Asp Phe Gly 695 His Gin Val Asn Ala Tyr Gly Ile Ser *Giy Ser Gin Ser 585 Gly Gly 600 Gin Lys Lys Giu Phe H is Giu Arg 665 Ala Giu 680 Gly Thr Arg Gin Phe Scr Thr Giy 745 Gly Gly 570 Val His Val Val Gly 650 His Asn Giy Leu 730 Gin Thr Giu Aia Cys Ser 635. Ser Ala Ser Cys Leu 715 His 540C Gin Ile Giu Gly Asn 620 Giu Pro Tyr Ser Pro 700 Phe Met 525 Arg Gly L.eu Giu Gly 605 Lys Giu Phe Ile Lys 685 Val1 Cys Gly His Leu Ile Met 590 Ile Lys Asn Val Gly 670 Ser His Arg *His Lys Asn Asp 575 Gin Phe Leu His Asn 655 Gly Asn Lys Val Lys Leu Pro 560 Leu Ser Asn Trp Asn 640 A-1 a M4et ksp L'hr 720 Met Lys met Ala His Ser 735 krg Pro 5cr Vai Asn Gly Leu 750 755 Val Ile Tyr 760 Arg Gly Giu Gin Ala Tyr Pro Giu 765 Tyr Leu 770 Ile Thr Tyr Gin Met Arg Pro Giu Met Val Asp Giy <210> <211> 3799 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (3)..(2270) <400> aa gct cat aat gat git gtt gaa gta gtg gtg aaa cat gaa gca aag Ala His Asn Asp Val Val Glu Val Val Val Lys His Giu Ala Lys 1 5 10 gtt aat gct ctg Vai Asn Ala Leu aat Ctt ggt cag Asn Leu Gly Gin -43- act tet Thr Ser eta cac aga get gca Leu His Arg Ala Ala tat Tyr ga t Asp aa t Asn tea Ser gaa Giu at t Ile aga Arg get Ala gga Gly 160 aat Asn aaa Lys ect Pro gat Asp eta Leu 240 tct C Ser I tg Cy! cct Prc gaa Giu gag Glu act Thr gaa Giu gtg Val aaa Lys 145 cat His 9ta Val gga Giy aca rhr ?ga 1 y ;at ksp :ct ggqt s Gly aac SAsn so aat Asn gea Ala gta Val 999 Gly tee Ser 130 gat Asp tat Tyr get Ala aaa Lys aaa Lys 210 gata Asp I get g Ala ;z gat a ca Hi 3 ati Ill gti Va gac Asi aaa Lys egt Arg 115 gtg Val aaa Lys gaa Glu gat A.sp tat Tyr 195 iaa ys ca rhr ;cc lia iat t cta eaa ace tgc s Leu 5 t ata e Ile Scag I Gin -aga Arg aaa Lys 100 *cag Gin gtg Val gga Gly gtt Val ttat Leu I 180 gaa a Giu I aae a Asn gat a Asp I aag a Lys L 2 gta a Val A eta etc ctg agc Leu Leu Leu Sex ttt act get tta Phe. Thr Ala Leu 55 caa etc etc eaa Gi1 ca~ Gli 81 etq Let. tet Ser gaa Glu Gly a 165 :gg rrp itt le 99 Lrg tt le ag ys 45 at sn n~ Lei 7' 1 tt 5 iLei tgt ICY *Thi tat .Tyr ett Leu 150 gaa Giu aaa Lys tge Cys gat Asp eaa Gin 230 99 t Gly tge Cys I t Leu ctg Leu act Thr cca Pro etg Leu 135 gta Val Gin gaa Glu gtt Val ett Leu 120 eta Leu cet Pro gag Giu get Ala cag Gin 105 cat His cag Gin ttg Leu ggt Gly gca Ala 90 agt Ser ttt Phe cat His cac His ate Ile aag Lys gte Val gca Ala gga Gly aat tea Ser get Ala aae Asn get Ala get Ala 140 gca tat Tyr 4 eag Gin tta Leu gga Gly tge Cys 999 Gly 125 gat Asp tgt 999 Gi y atg Met ggt Gly gat Asp aga Arg, 110 tat Tyr gtg Val tct tgt Cys gga Gly aat Asn gte Val gac Asp aae Asn cat His tat 143 191 239 287 335 383 431 479 527 575 623 671 719 767 815 Asn Ala 3cr Tyr 155 ett ctt gtt Leu Leu Val ttt aca cet Phe Thr Pro 185 aaa ett etg Lys Leu Leu 200 gga aat act Gly Asn Thr 215 gat etg ett Asp Leu Leu tgt tta gee Cys Leu Ala ege gat aee Arg Asp Thr 265 aaa cat gga Lys His Gly 170 tta cat gaa Leu His Glu etc cag cat Leu Gin His ect ttg gat Pro Leu Asp 220 agg gga gat Arg Gly Asp 235 aga gtg aag Arg Val Lys 250 eaa gge aga Gin Gly Arg gca Ala gca Al a ggt Gly 205 ett Leu gea Ala aag Lys eat His gta Val gea Ala 190 gca Ala gtt Val1 get Ala t tg Leu tea Ser 270 1 ro Asp Asn 260 cet tta eat Pro Leu His gca get ggt tat Ala Ala Gly Tyr aat tta gaa gtt Asn Leu Glu Val gca gag tat Ala Giu Tyr 285 -44- ttg tta caa cac gga gct gat gtg aat 9CC caa gac Leu Leu Gin His Giy Ala Asp Val Asn Ala Gin Asp att Ile c ta Leu 320 ttc Phe gct Ala gga Gly ctg Leu caa Gin 400 tct Ser gac Asp agt Ser gta Val cta Leu 480 gag Glu cat His caa Gin att Ile cct Pro 305 cta Leu aca Thr ttg Leu can Gin aca Thr 385 gtg Val tca Ser aac Asn gga Gly gat Asp 465 atg Met atg Met agg Arg ggt Gly Ct t Leu 545 290 t ta Leu ata Ile cct Pro t tg Leu aca Thr 370 gcn Ala ctc Leu ggt Gly tta Leu aca Thr 450 ttt Phe gat Asp ggg Gly cac His ctt Leu 530 ata Ile cat His nag Lys t tg Leu cta Leu 355 cct Pro gcc Ala nat Asn cca Pro t Ct Ser 435 gag Glu agc Scr ata Ile cac His an Lys 515 aac Asn gat Asp aa t Asn tat Tyr cac His 340 gCC Ala tta Leu atg Met ggt Gly tct Ser 420 999 Gly ggt Gly ata Ile ttt Phe ag Lys 500 cta Leu cca Pro ctg Leu 9C8 Ala aa t Asn 325 gaa Glu cat His ga t Asp ccc Pro gtg Val 405 agc Ser agt Ser gct Ala act Thr gag Glu 485 gag Giu att Ile tat Tyr tct Ser gca Al a 310 gca Al a gca Ala gga Gly t ta Leu cca Pro 390 aga Arg cca Pro t tt Phe tcc Ser caa Gin 470 aga Arg ctg Leu aa Lys4 tta Leu cCt Pro 550 295 tct Scr tgt Cys gcc Al a get Ala gtt Val 375 tct Ser agc Ser t ca Ser t ca Ser agt Ser 455 ttc Phe gaa Giu aag Lys gga Gly ac t rhr 535 gat Asp tac Tyr gte Val caa Gin gac Asp 360 t ca 5cr gct Ala cca Pro age Ser gaa Glu 440 ttg Leu gta Val cag Gin gag Glu gtc Val 520 ttg Leu gat Asp 999 Gi y at Asn aag Lys 345 ccg Pro gca Ala ctg Leu gga Gly ctt Leu 425 ctg Leu gag Giu agg Arg atc Ile att Ile 505 gag 31 u aac ksn Lys cat His 9CC Ala 330 gga Gly act Thr gat Asp ccc Pro 9CC Ala 410 tet Ser tct 5cr aa Lys ant Asn act Thr 490 gga Gly aga Arg acc Thr gag Gi u gta Val 315 acg Thr cga Arg ctt Lecu gat Asp tct Ser 395 act Thr gca Ala tca 5cr ag Ljys Ct t Leu 475 ttg Leu ate Ile Ctt Lcu tet 5cr ttt Phe 555 an Lys 300 gat Asp gac Asp aca Thr a. Lys gtc Val. 380 tgt Cys gcn Al a gee Ala gtn Val gag Glu 460 gga Gly gat Asp aat Asn atc Ile ggt Gly 540 cag Gln g9a gga ctt Gly Gly Leu 9ta gca Val Ala aaa tgg Lys Trp cag ctt Gin Leu 350 nat cag Asn Gin 365 agc gct Scr Ala tac nag Tyr Lys gat gct Asp Ala ngc agt Ser 5cr 430 gtt agt Val 5cr 445 gtt cca Val Pro ctt gag Leu Giu gtn ttn Val Leu gct tat Ala Tyr 510 tcc ggn 5cr Giy 525 agt gga Ser Gly tct gtg Ser Val4 gct Ala gct Ala 335 tgt Cys gna Giu Ct t Leu cct Pro etc Leu 415 ctt Leu tca Ser gga Gly cac His gt t Val 495 gga Gly can Gln aca Thr gag Glu 911 959 1007 1055 1103 1151 1199 1247 1295 1343 1391 1439 1487 1535 1583 1631 1679 gaa gag atg caa agt aca gtt cga, gag cac aga gat gga ggt cat gca Giu Giu met Gin Ser Thr Val Arg Giu His Arg Asp Giy Gly His Ala 560 565 570 575 qgt 99a. atc ttc aac aga tac aat att Gly Gly Ile Phe Asn Arg Tyr Asn Ile aac aag aaa Asn Lys Lys gaa gaa aac Giu Giu Asn 610 Cct ttt gtg Pro Phe Val 625 tgg gaa aga tac Trp Glu Arg Tyr act Thr 600 gaa Glu ctc aag att Leu Lys Ile 585 cac cgg aga His Arg Arg cga atg cta Arg Met Leu aaa Lys cag aag gtt tgt Gin Lys Val Cys aac cat gcc Asn His Ala 590 gaa gtt tct Glu Val Ser 605 cat ggg tct His Gly Ser agg cat gcg Arg His Ala aat gca att Asn Ala Ile aaa ggc ttt Lys Gly Phe tac Tyr 640 tcc Ser ata Ile ggt ggt atg Gly Gly met gga get ggc att Gly Ala Gly Ile gct gaa aac Ala Glu Asn t ct Ser 655 aaa agc aat Lys Ser Asn gta tat 99a Val Tyr Gly gga ggt act Gly Gly Thr ggg tg1t Gly Cys 670 cca gtt cac Pro Val His aga tct tgt Arg Ser Cys tgc cac agg Cys His Arg ttt tgc cgg gta Phe Cys Arg Val 690 aaa. atg gca. cat Lys Met Ala His 705 agt gta aat ggc Ser Val Asn Gly 720 acc ttg gga Thr Leu Gly ttc ctg cag Phe Leu Gin cag ctg etc Gin Leu Leu 685 agt gea. atg 5cr Ala Met ggt agg ccc Gly Arg Pro 1727 1775 1823 1871 1919 1967 2015 2063 2111 2159 2207 2255 2310 2370 2430 2490 2550 2610 2670 2730 2790 2850 tct cct 5cr Pro cat cac tca His His Ser gaa tat gtt Giu Tyr Val 730 gtc act Val Thr 715 cta gca tta gct Leu Ala Leu Ala 725 att tac aga gga Ile Tyr Arg Giy cag qct tat Gin Ala Tyr ect gag tat tta att act tac cag Pro Giu Tyr Leu Ile Thr Tyr Gin 740 745 att atg agg cct gaa. Ile Met Arg Pro Giu 750 ggt atg gtc gat gga taaatagtta ttttaagaaa ctaattccac tgaacctaaa Gly Met Val Asp Gly 755 atcatcaaag ccacaggcct agctttaata gccattccag tttatatgtt aatacaatac actgtaaata tctgttttag catcttacat cagcagtggc gtggcaaaag atgtacagtg gttaaactgg atgcattgat tgtgttcttt agagcttttg aac tgcagcg cgtcatgatt ctctacgttt gataaaaatg ttttctaaat gttgtctgta tctaacaaac aaaacacagc tactagceca gtttacaaaa gagtgatctt tactcctttg tgaacgaagt atttcctgtt ctaaattata tgtaatgec atttacactg gtatttattt ttttttcata tacatttgat ctgaaaaaaa ttaacat tct ttttcagcac aacagagt ta tcaacagaac aatacaattt acattgcttt tgtattgttc tccagaggct atcatettgc gacttgataa tttaacagat acttgaacct taattttact catttgtaaa gtaatataaa atctatactt atgttcagtt gttagttggg tgttgcagac tagtaccaca caaatctagc atagccaaag agaagataca catacatgga gatgttattg gattaatttg tcttcggtag taaaaagctg atgttgaagg cagttataag tgcaaaggaa gttttgtaca aaagattgag tg ttga ttga ccatctttaa gct ttactga aattttcatg aaactgt tgc CttttCggtc caaggagcag acttgggtca ttgagaattt aaggagaccc ataatgtttc caagggactg gatcaataaa tgtacataat ttatcagatt ccttactaaa agtctagtgt actcagaaca tataagagct ctgtactaat tgaatttgtg agtgccctct tgaattcaac ggtctacatt cacacatctt tctgtttgca cttgtttttg aagacttcat atatttactt taatttgcca t cccgaaat c ttagtcccct ttgttctctt agctaaatat gggtatagta C tggcatcca gctggagtaa aaccagttac tatcaaatga ctcactgtca aagaagatgc taagttatct ttgaatgtaa CCtgctttca ttaaacctta taaaaaatga tttCcttcaa tgagaatgtg agtatatcct gagcagt tga tggtacttac tcgcaattat ttgcctttca ggaaagagtg Scagccctta ctctggctag caact ttat t atggtgtgaa cattagtaat tggggttttc 2910 attgtggcct 2970 aactttccaa 3030 aagattttaa 3090 gctctttcga 3150 agaactaaca 3210 tgttcagtag 3270 tcttgcagca 3330 tcatacaatt 3390 tcacaaactc 3450 cttctgcaaa 3510 aatgtttgtg 3570 cttgtgaaat 3630 atactgatgt 3690 ctgagatggt 3750 tctaccattt tataattaga aggagatgta ggggtgggag tggggaggg 3799 <210> 91 <211> 756 <212> PRT <213> Homo sapiens <400> 91 Ala His Asn. Asp Vai 1 5 Val Glu Val Val Val 10 Leu Gly Gin Thr Ser Lys His Giu Leu His Arg Ala Lys Val Asn Ala Leu Cys Gly His Pro Asn Ile Asp Asn Leu Gln Thr Cys Arg 40 Leu Leu Leu Ser Ala Ala Tyr Gly Cys Asp Met Giy Asn Ile Ser Leu Gin Gly Phe Thr Ala so Glu Asn Val Gin Gin Leu Leu Gin Giu Gly Leu Gly Asn Ala Asp Arg Gin Leu Leu Giu Ala Thr Val Lys Glu Gly Arg 115 Val Ser Val 130 Leu Ser Cys Thr Val Gin 105 Thr Pro Leu His 120 Tyr Leu Leu Gln Ala Lys 90 Ser Val Phe Ala His Gly Al a Gly Asp Val Glu Asn Cys Arg Asp Ile 110 Ala Gly Tyr Asn Arg 125 Ala Asp Val His Ala Val Glu LYS Asp Lys Giy Gly Leu Val Pro Leu His Asn Ala Cys Ser Tyr Gly 145 150 155 160 His Tyr Glu Val Ala Glu Leu Leu Val -47- Lys His Gly Ala Val Val Asn 170 175 165 Val Ala Asp Leu Trp Lys Phe Thr Pro Leu His Glu Ala Ala Ala Lys Gly Thr Gly 225 Asp Ala Ala Lys Pro Leu Leu Pro 305 Leu Thr Leu Gin Thr 385 Val Ser Asn Gly Asp 1 465 Met Asp His Gln 290 Leu Ile Pro Leu Thr 370 Ala Leu Giy 1,eu C'hr Iso ~he ~sp Asn Leu 275 His His Lys Leu Lou 355 Pro, AlaI Asn Pro Ser 435 Giu SerI Ile I Val 260 Ala Gly Asn Tyr His 340 Ala Leu Met Giy Ser 420 31y ;lY Ele ~he *Arg Lys 245 *Asn Ala *Ala Ala Asn 325 Glu His Asp Pro Val 405 Ser P Ser P Ala S Thr G 4 Giu A 485 Cys Lys Asp Gly 215 Gin Asp 230 Gly Cys Cys Arg Gly Tyr Asp Val 295 Ala Ser 310 Leu 200 Asn Leu Leu Asp Asn 280 Asn Tyr 185 Leu Thr Leu Ala Thr 265 Asn Ala Gly Leu Pro Arg Arg 250 Gin Lou GIn His Gin Leu Gly 235 Val Gly Glu Asp His Asp 220 Asp Lys Arg Val Lys 300 Asp Gi y 205 Leu Ala Lys His Ala 285 Gly 190 Ala Val1 Ala Lou Ser 270 Glu -Gly Asp Lys Leu Ser 255 Thr Tyr Leu Pro Asp Lou 240 Ser Pro Lou Ile Val Val Ala Ala Leu 315 320 Ala Cys Val Ass Ala Thr Asp Lys Trp Ala Phe kla G 1 y eu ?ro 90 rg 'ro 'he er in 70 rg Ala Ala Val 375 Ser Ser Ser Ser Ser 455 Phe Glu Gin Asp 360 Ser Ala Pro Ser Giu 440 Lou Val Gln Lys 345 Pro Ala Lou Gly Lou 425 Lou Giu Arg Ile 330 Gly Thr Asp Pro Ala 410 Ser Ser Lys Asn Thr 490 Arg Lou Asp Ser 395 Thr Ala Ser Lys Lou 475 Leu Thr Lys Val 380 Cys Ala Ala Val Glu 460 Gly Asp Asn Ass 365 Ser Tyr Asp Ser Val1 445 Val Lou Val1 Ala 335 Lou Cys Ala 350 Gin Giu Gly Ala Lou Lou Lys Pro Gin 400 Ala Lou Ser 415 Ser Lou Asp 430 Ser Scr Ser *Pro Gly Val Giu His Lou 480 Lou Val Glu 495 Tyr Gly His 510 Met Gly His Lys 500 Giu Lou Lys Giu I1e Gly Ile 505 Arg His Lys Lou Ile Lys Gly Val 515 520 Giu Arg Lou Ile Ser Gly Gin Gin 525 -48- Gly Leu ASn Pro Tyr Leu Thr Leu Asn Thr Ser Gly Ser Giy Thr Ile 530 535 540 Leu Ile Asp Leu Ser Pro Asp Asp Lys Giu Phe Gin Ser Val Giu Giu 545 550 555 560 Glu Met Gin Ser Thr Val Arg Giu His Arg Asp Giy Giy His Ala Giy 565 570 C Gay Ile Phe Asn 580 Lys Lys Leu Trp 595 Arg Tyr Asn Ile Leu Lys Ile Gin Lys Val Cys Asn Glu Arg Tyr His Arg Arg Lys Giu Val Ser Giu 605 His Gly Ser Pro Giu Asn 610 His Asn His Ala Giu Arg Met Leu Phe 620 Asp Giu 635 Vai Asn Ala Ile His Lys Giy Phe Arg His Ala Ile Gly Gly Met Gly Ala Giy Ile Tyr 650 Phe Ala Giu Asn Ser Ser Lys 5cr Asn Val His Lys 675 Tyr Val Tyr Gly Ile Gly Giy Gly Thr Gly Cys Pro 665 670 Asp Arg Ser Cys Ile Cys His Arg Leu Leu Phe Cys Arg 690 Val Thr Leu Gly Ser Phe Leu Gin Ser Ala Met Lys Aia His 5cr Pro Gly His His 5cr Thr Gly Arg Pro Val Asn Gly Leu Ala 725 Leu Ala Giu Tyr Ile Tyr Arg Gly Giu Gin 735 Ala Tyr Pro ,Giu Tyr Leu 740 Ile Thr Tyr 745 Gin Ile Met Arg.Pro Glu Giy 750 Met Val Asp Gly 755 <210> <211> <212> <213> 92 2971 DNA Homo sapiens <400> 92 tgtgaactgt CCtCtgcacg gaagcaaagg tgtggtcat c tcccttcagg gagggtatct ggagatgtcg gaagggcgt c gaatatctgc ttgcacaatg gcagtagt ta ggaaaatatg agggatggaa cttaggggag aagtigtctt ttacatttag gctgatgtga tgctaagaaa tggcatctga ttaatgctct tacaaacctg gctttactgc cattaggtaa aaactgtaaa agtctacacc tacagcatgg catgttctta atgtagctga aaatttgcaa atactccttt atgcagcttt Ctcctgataa cagctggtta atgcccaaga aggagcaaac gaaagctcat ggataatctt ccgcctactc tttacagatg ttcagaggca aaaactgtgt acttcatttt agctgatgtq tggacattat tttatggaaa acttctgctc ggatcttgtt gctaga tgct tgtaaat tgc taataattta caaaggagga atcaatgaaa aatgatgttg ggtcagactt ctgagctatg ggaaa tgaaa gacagacaat actgttcaga gcagctgggt catgctaaag gaagttgcag tttacacctt cagcatggtg aaagatggag gccaagaagg cgcga taccc gaagttgcag Cttattcctt agactaaaga attcttgact ttgaagtagt ggtgaaacat ctctacacag agctgcatat ggtgtgatcc taacattata atgtacagca actcctccaa tgctggaagc tgcaaaggct gtgtcaactg cagagacatt ataacagagt gtccgtggtg ataaaggagg ccttgtacct aacttcttgt taaacatgga tacatgaagc agcagcaaaa cagaccctac aaaaaaaaac atacagatat tcaagatctg gttgtttagc cagagtgaag aaggcagaca ttcaacacct agtatttgtt acaacacgga tacataatgc agcatcttac 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 -49- gggcatgtac aaatgggctt ttgttgctac gatttagttt ctgccctcrtt gatgctctct aacttatctc gcttccagtt aggaatcttg gtattagttg aggcacaaac tatttaactt aaagagtttc ggtcatgcag aagaaactat catgccaatg ggctttgatg gaaaactctt gttcacaaag ttgggaaagt cactcagtca agaggagaac atggtcgatg agcagcagtg ctgtggcaaa taatgtacag aggttaaact ttatgcattg actgtgt tet taagagcttt agaactgcag atcgtcatga ggaaagattg Iatgtagcagc :tcacaccttt Icccatggagc cagcagatgz gttacaagcc cttcaggtcc iggagtttttc tggagaaaaa gact tgagca agatggggca taa ttaaagg tgaacacctc agtctgtgga gtggaatct t gggaaagata aacgaatgct aaaggcatgc ccaaaagcaa acagatcttg Ctttcctgca ctggtaggcc aggcttatcc gataaatagt gcctctacgt agga taaaaa tgttttctaa gggttgtctg attctaacaa ttaaaacaca tgtactagcc cggt ttacaa ttgagtgatc agttatcaga :tctactaata :gcacgaagca -tgacccgact ktgtcagcgct tcaagtgctc atctagccca agaactgtct ggaggttcca cctaatggat caaggagctg agtcgagaga tggtagtgga ggaagagatg caacagatac cactcaccgg atttcatggg gtacataggt tcaatatgta ttacatttgc gttcagtgca cagtgtaaat tgagtattta tattttaaga tttactcctt tgtgaacgaa atatttcctg tactaaatta actgtaatgc gcatttacac cagtatttat aattttttca tttacatttg tttaatttgc aagtataatc gcccaaaags cttaaaaatc cttctgacag aatggtgtga tcaagccttt tcagtagtta ggagtagat t atatttgaga aaggaga t g Cttatctccg acaattctta caaagtacag aatattctca agaaaagaag tCtCCttttg ggtatgtttg tatggaattg cacaggcagc atgaaaatgg qgcctagcat attacttacc aactaar tcc tgctgaaaaa gtttaacatt ttttttcagc taaacagagt cctcaacaga tgaatacaai ttacattgct tatgtattgt attccagagg C icatgtgtcaa gacgaacaca aggaaggaca pagccatgcc gaagcccagg ctgcagccag gttcaagtgg ttagcataac gagaacagat gaatcaatgc gacaacaagg tagatctgtc t tcgagagca agattcagaa tttctgaaga tgaatgcaat gagctggcat gaggaggtac tgCtcttttg cacattctcc tagctgaata agattatgag actgaaccta aaatcatctt ctgacttgat actttaacag taacttgaac actaatttta ttcatttgta ttgtaatata tcatctatac ctatgttcag tgccacggac 1080 gCtttgtgCt 1140 aacaccttta 1200 cccatctgct 1260 agccactgca 1320. Cagtcttgac 1380 aacagagggt 1440 tcaattcgta 1500 cactttggat 1560 ttatggacat 1620 tcttaaccca 1680 tcctgatgat 1740 cagagatgga 1800 ggtttgtaac 1860 aaaccacaac 1920 tatccacaaa 1980 ttattttgct 2040 tgggtgtcca 2100 ccgggtaacc 2160 tccaggtcat 2220 tgttatttac 2280 gcctgaaggt 2340 aaatcatcaa 2400 gcccacaggc 2460 aaagctttaa 2S20 atgccattcc 2580 cttttatatg 2640 ctaatacaat 2700 aaactgtaaa 2760 aatctgtttt 2820 ttcatcttac 2880 ttgttagttg 2940 2971 <210> 93 <211> <212> DNA <213> Artificial Sequence <220> <223> Description Of Artificial Sequence:Primer <400> 93 gggcggaaag acgtagttga <210> 94 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 94 gcggctgttc accttctcag <210> <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> acgcaagtga tggcagaaag <210> 96 ri<211> <212> DNA <213> Artificial Sequence 220> <223> Description of Artificial Sequence:Primer <400> 96 tcacttgcgt ggcagttgac <210> 97 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 97 gcggcaggtt tgtagatgac <210>'98 <211> 1568 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1567) <400> 98 g gcc agg atc atg tcg ggt cgc cgc tgC gcc ggc ggg gga gcg gcc tgc 49 Ala Arg Ile Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys 1. S 10 gcg agc gcc gcg gcc gag gcc gtg gag ccg gcc gcc cga gag ctg ttc 97 Ala Ser Ala..Ala Ala Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe 25 gag gcg tgc cgc aac ggg gac gtg gaa cga gtc aag agg ctg gtg acg 145 Glu Ala Cys Arg Asn Gly Asp Val Glu Arg Val Lys Arg Leu Val Thr 40 cct gag aag gtg aac agc cgc gac acg gcg ggc agg aaa tcc acc ccg 193 Pro Glu Lys Val Asn Ser Arg Asp Thr Ala Gly Arg Lys Ser Thr Pro 55 ctg cac ttc gcc gca ggt ttt ggg cgg aaa gac gta gtt gaa tat ttg 241 Leu His Phe Ala Ala Gly Phe Gly Arg Lys Asp Val Val Glu Tyr Leu 70 75 ctt cag aat ggt gca aat gtc caa gca cgt gat gat ggg 99c ctt att 289 Leu Gln Asn Gly Ala Asn Val Gln Ala Arg Asp Asp Gly Gly Leu Ile 90 cct ctt cat aat 9ca tgc tct ttt ggt cat gct gaa gta gtc aat ctc 337 Pro Leu His Asn Ala Cys Ser Phe Gly His Ala Glu Val Val Asn Leu 100 105 110 ctt ttg cga cat ggt gca gac ccc aat gct cga gat aat tgg aat tat 385 Leu Leu Arg His Gly Ala Asp Pro AsYI Ala Arg Asp Asn Trp Asn Tyr 115 120 125 act cct ctc cat gaa gct gca att aaa gga aag att gat gtt tgc att 433 Thr Pro Leu His Glu Ala Ala Ile Lys Gly Lys Ile Asp Val Cys Ile 130 135 140 gtg Val 145 agg Arg ggt Gly gaa Glu gca Ala aa c Asn 225 cat His tat Tyr gta Val tct Ser gac Asp 305 ccc Pro tcg Ser cat His aca Thr ata Ile( 385 ctc Let ac~ Th2 gai Gi gaa Gl. agt Ser 210 aga Arg gct Ala ggt Gly aat Asn aag Lys 290 cca Pro aca Thr t tg Leu :tc Leu 3ca kla 370 :gt :ys g tta i Leu I gca Ala Stat Tyr Iaaa Lys 195 gat Asp gta Val aaa Lys cat His gca Ala 275 aac Asn aca Thr cca Pro ctg Leu C tct c Ser I 355 ttg c Leu H~ gaa c Giu L cac Gir ttc Leu aag Lys 180 atg Met ggc Gly aag Lys gat Asp tat Tyr 260 atg M.et a99 Arg :tg Leu zag ;In :aa ;1n :tg jCu :at 'is ~tg *eu cat gg His Gi' gat tt Asp Let 165 aaa gat Lys AsI atg gct -Met Ala aga aag Arg Lys att gta Ile Val 230 aaa ggt Lys Gly 245 gaa gta Glu Val gac ttg Asp Leu gtt gaa Val Glu ctc aat Leu Asn 310 tta aaa Leu Lys 325 gct gca Ala Ala gaa atg Glu Met tgt gct Cys Ala ttg cta Leu Leu 390 a gct gag cca y Ala Glu Pro I gca gat cca j Ala Asp Pro *gaa ctc tta Glu Leu Leu 185 *cta ctc aca Leu Leu Thr 200 tca act cca Ser Thr Pro 215 *cag ctg tta Gin Leu Leu gat ctg gta Asp Leu Val act gaa ctt Thr Glu Leu 265 tgg caa ttc Trp Gin Phe 280 gta tgt tct Val Cys Ser 295 tgt cac aat Cys His Asn gaa aga tta 5 Giu Arg Leu cga gaa gct S Arg Giu Ala 345 gtg aat ttc a Val Asn Phe L 360 gCt gca tct c Ala Ala Ser P 375 aga aaa gga g Arg Lys Gly acc atc cga aat Thr Ile Arg Asn 155 tct gcc aaa qca Ser Ala Lys Ala 170 gaa agt 9CC agg Glu Ser Ala Arg cca tta aat gtc Pro Leu Asn Val 205 tta cat ttg gca Leu His Leu Ala 220 ctg caa cat gga Leu Gin His Gly 235 cca tta cac aat Pro Leu His Asn 250 ttg gtc aag cat Leu Val Lys His act CCt Ctt cat rhr Pro Leu His 285 Ctt ctc tta agt Leu Leu Leu Ser 300 iaa agt gct ata .sys Ser Ala Ile 315 ;ca tat gaa ttt la Tyr Giu Phe 130 ;at gtt act cga tsp Val Thr Arg iag cat cct caa ~ys His Pro Gin 365 ca tat ccc aaa 'ro Tyr Pro Lys, 380 'ca aac atc aat .1a Asn Ile Asn 395 aca Thr gtg Val agt Ser 190 aac Asn gat gga Asp Gly 160 ctt act Leu Thr 275 ggc aat Gly Asn tgc cac Cys His gca Alz gct Ala gcc Ala ggt Gly 270 gag Giu tat Tyr gac Asp aaa Lys at c Ile 350 a ca Thr aga Arg gaa 1 u 998 IGly gat Asp tgt Cys 255 gcc Ala gca Ala ggt Gly ttg Leu ggC Giy 335 aaa Lys cat His aag Lys aag Lys tat Tyr gtc Val 240 tct Ser tgt Cys gct Ala gca Ala gCt Ala 320 cac His aaa Lys gaa Giu caa Gln act Thr 400 481 529 577 625 673 721 769 817 865 913 961 1009 1057 1105 1153 1201 1249 aaa gaa ttc ttg Lys Glu Phe Leu cct ctg cac gtg Pro Leu His Val tct gag aaa gct Ser Glu Lys Ala cat aat His Asn 415 gat Asp gat Asp cta Leu ata Ile 465 eag Gin aga Arg aaa Lys gtt Val aat Asn caa Gin 450 tcc Ser caa Gin caa Gin ctg Leu gtt Val ctt Leu 435 acc Thr ctt Leu etc Leu ttg Leu tgt Cys 515 gaa Glu 420 ggt Gly tgc Cys cag Gin etc Leu ctg Leu 500 act rhr gta Vai cag Gin cgc Arg ggc Gly eaa Gin 485 gaa Glu gtt Val gtg Val act Thr eta Leu ttt Phe 470 gag Glu get Ala cag Gin gtg Val tct Ser etc Leu 455 act Thr ggt Gly gca Ala agt Ser aaa Lys cta Leu 440 cts Leu get Ala atc Ile aag Lys gtc Val 520 cat His 425 cac His age Ser tta Leu tea Ser get Ala 505 aac Asn -52- gaa gca Glu Ala aga get Arg Ala tat 999 Tyr Gly eag atg Gin Met 475 tta ggt Leu Gly 490 gga gat Gly Asp tge a Cys aag Lys gca Ala tgt Cys 460 gga Gly aat Asn gte Val gtt aat Val Asn 430 tat tgt Tyr Cys 445 gat ect Asp Pro aat gaa Asn Glu tea gag Ser Glu gaa act Glu Thr 510 get Ala ggt Gly aae Asn aat Asn gca Ala 495 gta Val ctg Leu cat His att Ile gta Val 480 gac Asp aaa Lys 1297 1345 1393 1441 1489 1537 1568 <210> 99 <211> 522 <212> PRT <213> Homo sapiens <400> 99 Ala Arg Ile Met Ser Gly Arg Arg 1 5 Cys Ala Gly Gly Gly Ala Ala Cys 10 Ala Ser Ala Ala Ala Giu Ala Val Giu Pro Ala Ala Arg Glu Leii Phe Glu Pro Leu Leu Pro Leu Thr Val 145 Ala Glu His Gin Leu Leu Pro 130 Leu 20 Arg Vai Ala Gly Asn 100 His His Gin I Asn Asn Ala Ala Ala Gly Glu His Asp 165 Gly Ser Gly 70 Asn Cys Ala Ala Gly 150 25 Asp Val Glu Arg Asp Thr 55 Phe Giy Arg Val Gin Ala Ser Phe Gly 105 Asp Pro Asn 120 Ala Ile Lys 135 Ala Glu Pro Arg Ala Lys Arg 90 His Ala Gly Thr Val Gly Asp 75 Asp Ala Arg Lys Ile 155 Lys Arg Val Asp Glu Asp Ile 140 Arg Arg Lys Val Gly Val Asn 125 Asp Asn Leu Ser Glu Gly Val 110 Trp Val Thr Val Thr Tyr Leu Asn Asn Cys Asp Thr Pro Leu Ile Leu Tyr Ile Gly 160 Arg Thr Ala Leu Leu Ala Asp Pro Ser Ala Lys Ala Val Leu Thr 170 175 Gly Giu Tyr Lys Asp Giu Leu Leu Glu 185 Ser Ala Arg Ser Gly Asn 190 Glu Giu Lys Met Met Ala Leu Leu 195 200 -53- Thr Pro Leu Asn Val Asn CyS His 205 Ala Asn 225 His Tyr Val Ser Asp 305 Pro Ser His Thr Ile 385 Lys Asp Asp Leu Ile 465 Gin Arg Lys Ser 210 Arg Ala Gly Asn Lys 290 Pro Thr Leu Leu Ala 370 ys Glu Val Asn Gin 450 Ser Gin Gin Leu Asp Val Lys His Ala 275 Asn Thr Pro Leu Ser 355 Leu Glu Phe Val Leu 435 Thr Leu C Leu I Leu I Cys 1 515 Gly Lys Asp Tyr 260 Met Arg Leu Gin Gin 340 Leu His Leu Leu Glu 120 fly -ys fin ,eu ~eu i00 hr Arg Lys Ile Lys 245 Glu Asp Val Leu Leu 325 Ala Glu Cys Leu Thr 405 Val Gin Arg Gly 3 Gin C 485 Glu P Val C Val 230 Gly Val Leu Glu Asn 310 Lys Ala Met Ala Leu 390 Pro Val Thr .eu ?he 170 ;lu la Inn Ser Thr Pro Leu His Leu Ala Ala Gly Tyr 215 220 Gin Leu Lem Leu Gin His Gly Ala Asp Val Asp Thr Trp Val 295 Cys Glu Arg Val Ala 375 Arg Leu Val Ser Leu 455 Thr 2 Gly Ala I Ser N Leu Glu Gin 280 Cys His Arg Glu Asn 360 Ala Lys His Lys Leu 440 Leu Val Leu 265 Phe Ser Asn Leu Ala 345 Phe Ser Gly Val His 425 His Ser Prc 250 Leu Thr Leu Lys Ala 330 Asp Lys Pro Ala Ala 410 Glu Arg yr 235 240 Leu His Asn Ala Cys Ser 255 Val Pro Leu Ser 315 Tyr Val His Tyr Asn 395 Ser Ala Ala Gly Lys Leu Leu 300 Ala Glu Thr Pro Pro 380 Ile Glu Lys Ala Cys 460 Gly His His 285 Ser le Phe Arg Gin 365 Lys Asn Lys Val Tyr 445 Asp Asn Gly 270 Glu Tyr Asp Lys lle 350 Thr Arg Glu Ala Asn 430 :ys Pro ;lu Ala Ala Gly Leu Gly 335 Lys His Lys Lys His 415 Ala Gly Asn Asn Cys Ala Ala Ala 320 His Lys Glu Gin Thr 400 Asn Leu His Ile Val 480 kla Leu Gin Met 475 Ile Ser Leu Gly Asn Ser Glu Ala Asp 490 jys Ala Gly 505 Fal Asn Cys 495 Asp Val Glu Thr Val Lys 510 c210> 100 <211> 4127 c212> DNA <213> Homo sapiens -54- <220> <221> CDS <222> (3508) <220> c221> 3 'LTR <222> (3509) (4127) <400> 100 g 9cc agg atc atg tcg ggt cgc cgc tgc 9CC ggc ggg gga 9cg 9CC tgc 49 Ala Arg Ile Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys 1 5 10 1s gcg agc gcc gcg gcc gag 9CC gtg gag Ala Ser Ala Ala Ala Glu Ala Val Glu CC9 9CC 9CC Pro Ala Ala 25 gag Glu CCt Pro Ctq Leu ct t Leu cct Pro Ctt Leu act Thr gt9 Val 145 agg Arg ggt Gly gaa Glu gca Ala aac Asn 225 gcg Ala gag Glu cac His cag Gln ctt Leu ttg Leu Cct Pro 130 Ctg Leu aca Thr gaa Glu gaa Glu agt Ser 210 tgc cgc Cys aag Lys ttc Phe aat Asn cat His cga Arg 115, ctC Leu t ta. Leu gca Ala tat Tyr aaa Lys 195 gat Asp aac 999 gac gtg gas cgi Asn Gly Asp Val Glu Arl Arc gtg Val 9CC Ala 99t. Gly aat Asn 100 cat His cat His cag Gin ttg Leu aag Lys atg Met 39C ;ly 40 aac ag~ Asn Se~ gca ggt Ala Gl~ gca aat Ala Asr 85 gca tgc Ala Cys ggt gca Gly Ala gaa gct Glu Ala cat gga His Gly 150 gat tta Asp Leu 165 aaa gat Lys Asp atg gct Met Ala aga sag Arg Lys C gc gac r Arg Asp 55 tttt 999 SPhe Gly 9tc caa Val Glri tct ttt Ser Phe gac CCC Asp Pro 120 gca att Ala Ile 135 gct gag Ala Glu gca gat Ala Asp gaa ctc Glu Leu cta ctc Leu Leu 200 tca actc Ser Thr 1 215 -acg Thr Cgg Arg gca Ala ggt Gly 105 aat Asn aaa Lys CCa Pro cca Pro tta Lieu L85 ica rhr :ca ?ro gcs Ali aaa Lys cgt Arg 90 cat His gct Ala gga Gly acc Thr tct Ser 170 gaa Glu cca Pro tta agtc aag ;Val Lys ggc agg IGly Arg gac gta Asp Val 75: gat gat Asp Asp gct gas Ala Glu cga gat Arg Asp aag att Lys Ile 140 atc cga Ile Arg 155 9CC aaa Ala Lys agt 9CC Ser Ala tta sat Leu Asn cat ttg His Leu 220 cgs gag Arg Glu agg ctg Arg Lieu ass tcc Lys Ser gtt Val 999 Gly gta Val at Asn 125 9gat Asp sat Asn gca Ala a99 A.rg gtc /a 1 205 ;ca kla *gaz 99C *Gl gtC Val 110 tgg Trp gtt Val aca Thr gtg Val agt Ser 190 aac Asn gca Al a tat ttg Tyr Leu ctt att Leu Ile sat ctc Asn Leu aat tat Asn Tyr tgc att Cys Ile gat gga, Asp Gly 160 ctt act Leu Thr 175 ggc sat Gly Asn tgc cac Cys His gga tat Gly Tyr gat gtc Asp Val 240 97 145 193 241 289 337 385 433 481 529 577 625 673 721 aga gta aag stt gta krg Val Lys Ile Val 230 cag ctg tta ctg Gin Leu 1,eu Leu cat gga gct His Gly Ala cat gct aaa His Ala Lys gat aaa ggt gat Asp.-Lys Gly Asp 245 ctg gta cca tra cac aat Leu Val Pro Leu His Asn 250 9CC tgt tct Ala Cys Ser 255 tat ggt cat tat gaa gta act gaa ctt ttg gtc aag cat ggt 9CC tgt Tyr Giy His Tyr Glu Val Thr Giu Leu Leu Val Lys His Gly Ala Cys 260 265 270 gra aat gca atg gac Vai Asn Ala Met Asp ttg tgg caa ttc act ccr ct' Leu Trp tcr Ser gac Asp 305 ccc Pro tcg Ser cat His aca Thr ata Ile 385 aaa Lys gat Asp gat Asp. cta Leu ata Ile 465 cag Gin aag Lys 290 cca Pro aca Tbr t tg Leu ctc Leu gca Ala 370 tgt Cys gaa Giu gtt Val aat Asn caa Glin 450 tcC Ser caa 31n 275 aac Asn aca Thr cca Pro cr9 Leu tct Ser 355 t tg Leu gaa Giu ttc Phe gtt Vai ct Leu 435 acc Thr crt C Leu C crc c Leu L agg Arg ct9 Leu cag Gin caa Gin 340 cr9 Leu cat His cr9 Leu t tg Leu ;aa 31U 420 3gt :gc :ag ;In :tc Igtt Val crc Leu tta Leu 325 gct Ala gaa Giu tgt Cys r tg Leu act Thr 405 gta Val cag Gin cgc Arg ggc Gly 1 4 caa g Gin G 485 gaa Git aat Asn 310 aaa Lys gca Ala atg Met gct Ala cra Leu 390 ~cr Pro gtg at ['hr mta :tt ~he 70 iag iiu gra IVal 295 rgt CyS gaa Giu cga Arg gtg Val gct Ala 375 aga Arg ctg Leu gtg Val tct Ser ctc Leu I 455 act g Thr .2 ggt a Gly I Gin Phe Thr 280 tgr rct ctt Cys Ser Leu cac aat aaa His Asn Lys aga tta gca Arg Leu Ala 330 gaa gct gat Glu Ala Asp 345 aat ttc aag '.sn Phe Lys 360 gca tct cca klia Ser Pro iaa gga gca ,ys Gly Ala :ac gtg gca is Vai Ala 410 kaa cat gaa .ys His Glu 425 ta cac aga eu His Arg2 40 tg agc tat S *eu Ser Tyr C ct tta cag a Pr crc Let agt Se2 315 tat Tyr grt Val car His tat Tyr aac Asn 395 tct Ser gca Icr kla fly *Lei *ttj j Lei 30( gct Ai gaz Glt act Thr ccr Pro ccc Pro 380 arc Ile gag Glu aag Lys gca Al a tgt C 1 's 460 gga Gly t car gag u His Giu 285 agt tat a1 Ser Tyr 0 tata gac Ile Asp trt aaa Phe Lys cga atc -Arg -le 350 caa aca Gin Thr 365 aaa aga Lys Arg aat gaa Asn Giu aaa gct Lys Ala gtt aat Val Asn 430 tat tgt Tyr Cys C 445 gat oCr a Asp Pro *1 aat gaa a Asn Giu P gca Ala ggt Gly t tg Leu ggC Gly 335 aaa, Lys cat His aag Lys aag Lys ca t His 415 Ikia jgt ;iy iac LSf ~at snf Ala gca Ala gct Ala 320 cac His aa Lys gaa Giu caa Gin act Thr 400 aa t Asn ct 9 Leu cat His art Ile gra Val 865 913 961 1009 1057 1105 1153 1201 1249 1297 1345 1393 1441 1489 1537 ia iLeu Gin Met Ltc tca tta ggt aat rca gag gca gac le Ser Leu Gly Asn Ser Glu Ala Asp 490 495 aga caa ttg Arg Gin Leu ctg Leu 500 gaa gct gca Glu Ala Ala sag gcr Lys Ala 505 gga gat gtc Gly Asp Val gaa act gra ass Giu Thr Val Lys 510 aaa cti Lys Lei cag tci Gin Sej 531 gtg gai Val Gli 545 gga. ggc Gly Gl) git gca Val Ala tta tgg Leu Trp gaa att Glu Ile 610 aac agg Asn Arg 625 gat att Asp Ile aag aag Lys Lys gta aat Val Asn gca gct Ala Ala 690 gga gct Gly Ala 705 aat gca Asn Ala tat aat Tyr Asn cac gaa His Glu 9CC cat Ala His 770 3 tgt act a. Cys Thr 515 aca cca r Thr Pro i tat ctg i Tyr Leu ctt gta Leu Val gaa ctt Glu Leu 580 aaa ttt Lys Phe 595 tgc aaa Cys Lys gat gga Asp Gly caa gat Gin Asp I ggt tgt t Gly Cys I 660 tgc cgc 9 Cys Arg A 675 ggt tat a Gly Tyr A gat gtg a Asp Val A gca tct t Ala Ser T 7 gca tgt g Ala Cys V 740 gca gcc c Ala Ala G 755 gga gct gi Gly Ala A! 9t Va ct Le ct Le ccl Pr 56! ct Let aca Thz ctt Leu aat Asn :tg jeu ta .eu Fat sp at rsn at .sn ac yr 25 tc al aa in ac sp t cz 1 G) t ca u Hi a ca u GI 55 t tt D Le gt I Va cc. Pri Ct Lei act Thl 63C Ctt Leu gcc Ala acc Thr aat Asn 9CC Ala 710 999 Gly aat Asn aag Lys ccg Pro lg agt gt .n Ser Va 52 It ttt gc .s Phe Al 535 9 Cat gg n His Gl 0 g cac aa u His As t aaa ca 1 Lys Hic t tta Cat 0 Leu Hi 60( 9 ctc cac u Leu Gir 615 t cct ttg 7 Pro Leu agg gga Arg Gly aga gtg Arg Val caa ggc Gin Gly 680 tta gaa Leu Glu 695 caa gac Gin Asp cat gta His Val gcc acg Ala Thr gga Cga Gly Arg 760 act ctt Thr Leu 775 -56- c aac tgc aga gac 1i Asn Cys Arg Asp 0 a gct 999 tat aac a Ala Gly Tyr Asn 540 a gct gat gtg cat y Ala Asp Val His 555 t gca tgt tct tat n Ala Cys Ser Tyr 570 t gga gca gta gtt a Gly Ala Val Val 585 t gaa gca gca gca s Glu Ala Ala Ala cat ggt gca gac His Gly Ala Asp 620 F gat ctt gtt aaa Asp Leu Val Lys 635 gat gca gct ttg Asp Ala Ala Leu 650 aag aag ttg tct t Lys Lys Leu Ser S 665 aga cat tca aca c Arg His Ser Thr P 6 gtt gca gag tat t Val Ala Giu Tyr L 700 aaa gga gga ctt a Lys Gly Gly Leu I 715 gat gta gca gct c Asp Val Ala Ala L 730 gac aaa tgg gct t Asp Lys Trp Ala P 745 aca cag ctt tgt 94 Thr Gin Leu Cys A: 7( aaa aat cag gaa g Lys Asn Gin Giu G 780 at 11 52 ag Ar gC Al 99 Gi' aa As aaz Lyg 605 cCt Pro gat ksp :ta jeu :ct er :ct 4 ro .85 tg ,eu tt le ta eu tc he. ct la ;a Ly t gaa 999 cgt e Glu Gly Arg S a gtg tcc gtg g Val Ser Val t aaa gat aaa a Lys Asp Lys 560 a cat tat gaa y His Tyr Glu 575 t gta gct gat Val Ala Asp 590 gga aaa tat Gly Lys Tyr aca aaa aaa Thr Lys Lys gga gat aca Gly Asp Thr 640 gat gct 9cc Asp Ala Ala 655 .cct gat aat Pro Asp Asn 670 tta cat tta Leu His Leu tta caa cac Leu Gin His Cct tta cat Pro Leu His 720 cta ata aag Leu Ile Lys 735 aca cct ttg Thr Pro Leu 750 ttg ttg cta Leu Leu Leu caa aca cct Gin Thr Pro 1585 1633 1681 1729 1777 1825 1873 1921 1969 2017 2065 2113 2161 2209 2257 2305 2353 tta gat tta gtt tca gca gat gat gtc Leu Asp Leu Val Ser Ala Asp Asp Val 785 790 -57- agc gct Ser Ala 795 Ctt ctg aca gca gcc Leu Leu Thr Ala Ala 800 2401 atg ccc Met Pro ggt gtg Gly Val tct agc Ser Ser ggg agt Gly Ser 850 ggt gct Gly Ala 865 ata act Ile Thr ttt gag Phe Giu a ag gag Lys lu: cta. att 1.eu Ile 930 cca tati Pro Tyr 945 ctg tet Leu Seri agt aca S Ser Thr A~ aac aga t Asn Arg 9 tgg gaa a Trp Giu 1010 aac cat Asn His A 1025 cca tet Pro Scr aga agc Arg Ser 820 eca tca Pro Ser 835 ttt tca Phe Ser tcc sgt Ser Ser caa ttc Gin Phe aga gaa Arg Giu 900 ctg aag Leu Lys 915 ~a gga5 Lys Gly I tta actt L.eu ThrI :ct gat g ?ro Asp A8 ;tt cgs g l Arg G 980 :ac aat a yr Asn I ~95 iga tac a Lrg TyrT cc sat g l1a Asn G g A 8 P2 tt Le Va 88 ca I 4a t ai ci 58 ai et la 05 cig ccc tet Leu Pro Ser tgt tac aag cct esa gtg ctc aat Cys Tyr Lys Pro Gin Val Leu Asn 810 815 ca 95 gcc act ro Gly Ala Thr ge Ctt tct gca er Leu Ser Ala 840 ia ctg tet tca Lu Leu Ser Ser 855 :g gag aaa sag ~u Glu Lys Lys 870 a agg sat ctt ~I Arg Asn Leu I5 g ate act ttg n Ile Thr Leu g att gga ate Ile Gly Ile 920 gag aga ctt I Glu Arg Leu 935 g sac aec tct u Asn Thr Ser 950 t aaa gag ttt p Lys Glu Phe 9 cac aga gat 5 ui His Arg AspC t etc sag att c e Leu Lys Ile C 1000 tcac egg ags a r His Arg-Arg L 1015 cga stg cts t Arg Met LeuP 1030 ge Al. 82~ get Alj gt8 Val gaS GIL gga Gly gat Asp 905 at Asn ate Ile ~gt Gly :ag jga fly ~85 :ag fIn Laa ~ys .tt 'he gat get etc tet tea Asp Ala Leu 5cr Ser 5 830 cage agt ett gac sac a Ser Ser Leu Asp Asn 845 i gtt agt tea agt gga IVal Ser Ser Ser Gly 860 gtt eca gga gts gat Val Pro Gly Val Asp 875 ctt gag cac eta atg *Leu Glu His Leu Met 890 *gta tta gtt gag atg 4Val Leu Val Giu met 910 get tat gga cat agg Ala Tyr Gly His Arg 925 tee gga esa cas ggt 5cr Gly Gin Gin Gly 940 agt gga sea att ett Ser Gly Thr Ile Leu 955 tet gtg gag gas gag Ser Val Giu Glu Glu 970 ggt cat ges ggt gga Gly His Aia Gly Gly 990 aag gtt tgt aae aaga Lys Val Cys Asn Lys 1 1005 gaa gtt tet gsa gaa a Giu Val Ser Glu Giu 1020 cat ggg tct cet ttt g His Gly Ser Pro Phe V 1035 ggt ces Gly Pro tta tet Leu Ser sea gag Thr Giu ttt age Phe Ser 880 gat ata Asp Ile 895 ggg cac Gly His cac aaa His Lys ctt sac Leu Asn ata gat Ile Asp 960 atg ea 'let Gin 975 Ite tte Ilie Phe ~aa eta .ys Leu Lac cac ~sn His rtg aat !al Asn 1040 2449 2497 2545 2593 2641 2689 2737 2785 2833 2881

2929. 2977 3025 3073 3121 ges att ate cac aaa gge ttt Ala Ile Ile His Lys Gly Phe 1045 gat gas agg cat geg tac ats ggt ggt Asp Glu Arg His Ala Tyr Ile Giy Gly 1050 1055 3169 -58- erg ttt 9ga gct Met Phe Gly Ala 1060 caa tat 9te tat Gin Tyr Vai Tyr 1075 get aga tct tgt Asp Arg Ser Cys ggc att tat Gly Ile Tyr ttt Phe 1090 act ttg Thr Leu 1105 gge art gga. gga Gly Ile Gly Gly 1080 tat att tgc cat Tyr Ile Cys His 1095 tct ttc ttg tag Ser Phe Leu Gin 1110 tat cat tte gtt Hlis His Ser Val 9cr gaa. eact ct tcc aaa agc eat Ale Glu Asn Ser Ser Lys Ser Asn 1065 1070 ggt act ggg tgt cca gtt cac aa Giy Thr Gly Cys Pro Val His Lys 1085 egg tag ttg ctc ttt tgc tgg gte Arg Gin Leu Leu Phe Cys Arg Val 1100 ttt egt gte. atg aae erg gte car Phe Ser Ale Met Lys Met Ala His 1115 1120 att ggt egg ccc agt gte. eat ggc Thr Giy Arg Pro Ser Val Asn Gly 1130 1135 tac age gge. gee ceg gtt tat cct 99a. eag Gly Lys tct ct tca ggt Scr Pro Pro Giy 1125 ta gte tta gct gaa tat gtt err Leu Ala Leu Ala Glu Tyr Val Ile Tyr Arc GIv (flu Glny Ala. Tyr P- 1140 1145 1-1;;0 gag tat tre art act tat tag ett erg egg cct gee ggt. erg gtc get Glu Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Giu Gly Met Val Asp 1155 1160 1165 gga taaategtta ttttaegaaa cttrtcetc tgeaccteea etctcaaag Gly cagcagtggc ttacgttt tactcctttg ttgaaaaeaaa atcetcttgc ttaceggcc gtggceaeag gataaaaatg tgaacgeegr ttaacattct gacttgetaa egttteat atgtetagtg ttttttear atttcctgtt tttttagcac tttaacagat gttatta gtteeettgg gttgtctgta ctaatata aacegagtte ecttgeecct tttatatgt etgcerrgat .tctaacaaac tgtaatgccc tceacagaec taattttact aatecata tgtgttctrt eeeacacegc atttacecrg aetatearrr ctrtgtaaa. actgtaaat agagctttg tectagccte gtatttattt ecattgctrr gtaarateaa tttgtttta aactgcagcg gttracaaaa ttttttcara tgtarrgttt atctatecrt cetcttate, cgtctgatt gagtgatcrt tecarttgat tttagaggct atgttcegrr gttagttgg aeegattgag ttatcagatt taatttgtt 3217 3265 3313 3361 3409 3457 3505 3558 3618 3678 3738 3798 3858 3918 3978 4038 4098 4127 :t a 9 t g <210> 101 <c211> 1169 <212> PRT <c213> Homo sapiens <400> 101 Ala Arg Ile Met Ser Gly Arg 1 5 Ale Ser Ala Ale Ala Glu Ala Giu Ala Cys Arg Asn Gly Asp Pro Glu Lys Vai Asn Ser Arg 55 Arg Cys Ala Gly Gly 10 Val GlU Pro Ala Ala 25 Val Glu Arg Val Lys 40 Asp Thr Ala Gly Arg Gly Ale Ala cys Arg Glu Leu Phe Arg Leu Val Thr Lys Ser Thr Pro 59- Lys Asp Val His Phe Ala Ala Phe Gly Arg Val Giu Tyr Leu Leu Gin Asn Gly Ala Asn Val Gin Ala Pro Leu His Asn Ala Cys Ser Arg Asp Asp Gly Gly Leu Ile 90 His Ala Giu Val Val Asn Leu Phe Gly 105 Pro Asn 120 Leu Leu Arg His 115 Thr Pro Leu His 130 Val Leu Leu Gin 145 Arg Thr Ala Leu Gly Glu Tyr Lys IS0 Glu Glu Lys Met 195 Ala Ser Asp Gly 210 Asn Arg Val Lys 225 His Ala Lys Asp Tyr Gly His Tyr 260 Val Asn Ala.Met 275 Ser Lys Asn Arg 290 Asp Pro Thr Leu 305 Pro Thr Pro Gin Ser Leu Leu Gin 340 His Leu Ser Leu 355 Thr Ala Leu His 370 Ile Cys Glu Leu 1 385 Gly Ala Asp Ala Arg Asp Gi. His As; 165 Lys Met Arg Ile Lys 245 Giu Asp Val Leu Lieu 325 kia f7lu .ys ~eu IAl Gi' Lei Asl Ala Lys Val 230 Gly Val Leu Giu Asn 310 Lys Ala Met Ala Leu 390 aAla 135 r Ala 0 iAla Leu Ser 215 Gin Asp Thr Trp Val 295 Cys Giu Arg Val Ala 375 Arg I Leu H~ Ile Lys Gly Lys Ile Giu Asp Leu Leu 200 Thr Leu Leu Glu Gin 280 Cys His krg flu ~sn J60 la ~ys [is *Prc *Pro Leu 185 Thr Pro Leu Val Leu 265 Phe Ser Asn Leu Ala 345 Phe Ser Gly Val Thr Ser 170 Glu Pro Leu Leu Pro 250 Leu Thr Leu Lys Ala 330 Asp' Lys Pro Ala Ala S 410 Ile 155 Ala Ser Leu His Gin 235 Leu Vai Pro Leu Scr 315 Tyr Jal iis ryr ~sn 95 140 Arg Lys Ala Asn Leu 220 His His Lys Leu Leu 300 Ala Giu Thr Pro Pro 380 Ile Asr 121 Asj Asn Ala Arg Val 205 Ala Gly Asn His His 285 5cr Ile Phe Arg .In .,ys ~sn 110 1 Trp, .Val Thr Val Ser 190 Asn Ala Al a Ala Gly 270 Giu Tyr Asp Lys Ile 350 Thr I Arg I Glu I Asr Cys Asp Leu 175 Gly Cys Gi y Asp Cys 255 Ala Ala Gly Leu fly 335 .sys ijs ~ys ~yS ITyr Ile Gly 160 Thr Asn His Tyr Val 240 Ser Cys Ala Ala Ala 320 His Lys Giu Gin Thr 400 Lys Giu Phe Leu Thr Pro 405 er Glu Lys Ala His Asn 415 Asp Val Val Glu Val 420 Val Val Lys Glu Ala Lys Val Asn Ala Leu 430 Asp Leu Ile 465 Gin Arg Lys Gin Val 545 Gly Asn Leu 435 Gin Thr 450 Ser Leu Gin Leu Gin Leu Leu Cys 515 Ser Thr 530 Glu Tyr Giy Leu Gly Cys Gin Leu Leu 500 Thr Pro Leu Val Gin Arg Gly Gin 485 Glu Val Leu Leu Pro 565 Thr Leu Phe 470 Glu Ala Gin His Gin 550 Leu Ser Leu His 440 Leu Leu Ser 455 Thr Ala Leu Gly Ile Ser Ala Lys Ala 505 Ser Val Asn 520 Phe Aia Aia 535 His Gly Ala His Asn Ala Arg Ala Tyr Gly Gin Met 475 Leu Gly 490 Gly Asp Cys Arg Gly Tyr Asp Val 555 Cys Ser 570 Ala Cys 460 Gly Asn Val Asp Asn 540 His Tyr Tyr 445 Asp Asn Ser Glu Ile 525 Arg Al Gly Cyi Pro Glu Glu Thr 510 Glu Vai Lys His Gly His Asn Ile Asn Val 480 Ala Asp 495 Vai Lys Gly Arg Ser Vai Asp Lys 560 Tyr Glu 575 Vai Leu Glu Asn 625 Asp Lys Val Ala Gly 705 Asn Tyr His Aia I Ala Trp Ile 610 Arg Ile Lys Asn Ala 690 Ala Ala Asn Giu His 770 Glu Leu 580 Lys Phe 595 ys Lys Asp Gly Gln. Asp Gly Cys 660 Cys Arg 675 Gly Tyr Asp Val Ala Ser Ala Cys 740 Ala Ala 755 Gly Ala Leu Val Lys His Thr Leu Asn Leu 645 Leu Asp Asn Asn Tyr 725 Val Aln ksp Pro Leu Thr 630 Leu Ala Thr Asn Ala 710 Gly Asn Lys Pro Leu Leu 615 Pro Arg Arg Gin Leu 695 Gin His Ala Gly Thr I 775 His 600 Gin Leu Gly Val Gly 680 Glu Asp Val rhr rg Gly 585 Glu His Asp Asp Lys 665 Arg Val Lys Asp* Asp 745 Thr Ala Val Val Asn Val Ala Asp Ala Gly Leu Ala 650 Lys His Ala Gly Val 730 Lys Gln Ala Ala Val 635 Ala Leu Ser Glu Gly 715 Ala Trp Leu Ala Asp 620 Lys Leu Ser Thr Tyr 700 Leu Ala Ala Cys Lys 605 Pro Asp Leu Ser Pro 685 Leu Ile Leu Phe Ala 765 590 Gly Thr Gly Asp Pro 670 Leu Leu Pro Leu Thr 750 Leu Lys Lys Asp Ala 655 Asp His Gin Leu Ile 735 Pro Leu Tyr Lye Thr 640 Ala Asn Leu His His 720 Lys Leu Leu jeu Lys Asn Gin Glu Gly Gin Thr Pro 780 Asp Leu Val Ser Ala Asp 790 Asp Val Ser Ala 795 Leu Leu Thr Ala Ala 800 -61- Met Pro Pro Ser Ala Leu Pro Ser Cys Tyr Lys Pro Gin Val Leu Asn c~1805 810 815 Gly Val Arg Ser Pro Gly Ala Thr Ala Asp Ala Leo Ser Ser Gly Pro 820 825 830 Ser Ser Pro Ser Ser Leo Ser Ala Ala Ser Ser Leu Asp Asn Leo Ser 835 840 845 Giy Ser Phe Ser Glu Leu Ser Ser Val Val Ser Ser Ser Gly Thr Giu 850 855 860 Gly Ala Ser Ser Leu Giu Lys Lys Glu Val Pro Gly Val Asp Phe Ser 865 870 875 880 Ile Thr Gin Phe Vai Arg Asn Leu Gly Leu Glu His Leu Met Asp Ile cN1885 890 895 Phe Giu Arg Glu Gin Ile Thr Leu Asp Val Leu Val Giu Met Gly His 900 905 910 Lys Glu Leo Lys Gu Ile Gly Ile Asn Ala Tyr Gly His Arg His Lys 915 920 925 Leu Ile Lys Gly Val Giu Arg Le Ile Ser Gly Gln Gin Gly Leo Asn 930 935 940 Pro Tyr Leo Thr Leu Asn Thr Ser Gly Ser Gly Thr Ile Leo Ile Asp 945 950 955 960 Leu Ser Pro Asp Asp Lys Glu Phe Gin 5cr Val Glu Glu Gl Met Gin 965 970 975 Ser Thr Val Arg Glu His Arg Asp Gly Gly His Ala Gly Gly Ile Phe 980 985 990 Asn Arg Tyr Asn Ile Leo Lys Ile Gin Lys Val Cys Asn Lys Lys Leo 995 1000 1005 Trp Giu Arg.,Tyr Thr His Arg Arg Lys Glu Val Ser Giu Glu Asn His 1010 loi5 1020 Asn His Ala Asn Giu .Arg Met Leo Phe His Gly Ser Pro. Phe Val Asn 1025 1030 1035 1040 Ala Ile Ile His Lys Gly Phe Asp Glu Arg His Ala Tyr Ile Gly Gly 1045 1050 1055 Met Phe Gly Ala Gly Ile Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn 1060 1065 1070 Gin Tyr Val Tyr Giy Ile Giy Gly Giy Thr Gly Cys Pro Val His Lys 1075 1080 1085 Asp Arg Ser Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val 1090 1095 1100 Thr Leu Giy Lys Ser Phe Leo Gin Phe Ser Ala Met Lys Met Ala His 1105 1110 1115 1120 Ser Pro Pro Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly 1125 1130 1135 Leo Ala Leu Ala Giu Tyr Val Ile Tyr Arg Gly Glu Gin Ala Tyr Pro 1140 1145 1150 Glu Tyr Leu Ile Thr Tyr Gin Ile Met Arg Pro Giu Giy Met Val Asp 1155 1160 1165 Gly <210> 102 <211> 32 <212> DNA. <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 102 gagcattggg gtctgcacca tgtcgcaaaa 99 32 (KI<210> 103 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 103 ccatcctaat aegactcact atagggc 27 <210> 104 <211> 647 <212> DNA <213> Homo sapiens <220> <221> CDS <222> <400> 104 g gag ctg gca gga 999 gcc ttg cca gct tcc gcc 9cc gcg tcg ttt cag 49 Glu Leu Ala Gly Gly Ala Leu Pro Ala Ser Ala Ala Ala Ser Phe Gln 1 5 10 gac ccg gac ggc gga ttc gog ctg cct ccg ccg ccg cgg ggc agc cgg 97 Asp Pro Asp Gly Gly Phe Ala Leu Pro Pro Pro Pro Arg Gly 5cr Arg 25 ggg gca 999 agc cca geg agg ggc gcg cgt ggg cgc ggc cat ggg act 145 Gly Ala Gly Ser Pro Ala Ar9 Gly Ala Arg Gly Arg Gly His Gly Thr 40 gcg ccg gat ccg gtg aca gca ggg agc caa gcg gcc cgg gcc ctg agc 193 Ala Pro Asp Pro Val Thr Ala Gly Ser Gln Ala Ala Arg Ala Leu Ser s0 55 9c9 tct tct cog ggg ggc ctc gcc ctc org oto gcg ggg ccg 999 otc 241 Ala Ser Ser Pro Gly Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu 70 75 otg ctc cgg ttg ctg gcg ctg ttg ctg gct gtg gcg gcg gcc agg ato 289 Leu Leu Arg Leu Leu Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile 90 atg tog ggt cgc 090 tgo gcc 90 999 gga gcg 9CC tgc gcg ago gcc 337 Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala 100 105 110 gcg gcc gag gcc gtg gag ccg gcc goc cga gag otg ttc gag 909 tgc 385 Ala Ala Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys 115 120 125 cgc aac ggg gac gtg gaa cg Arg Asn Gly Asp Val Glu Anl 130 13~ gtg aac agc cge gae acg gec Val Asn Ser Arg Asp Thr Al~ 145 I50 9CC gca ggt ttt 999 egg aaz Ala Ala Gly Phe Gly Arg Lys 165 gqt gca aat gtc caa gca cgt Gly Ala Asn Val Gin Ala Arg 180 aat gca tge tet ttt ggt eat Asn Ala Cys Ser Phe Gly His 195 cat ggt gea gac ccc aat get His Gly Ala Asp Pro Asn Ala 210 215 <210> 105 <211> 215 <212> PRT <213> Homo sapiens <400> 105 Glu Leu Ala Gly Gly Ala Leu 1 5 Asp Pro Asp Gly Gly Phe Ala q te aag Val Lys ggc agg Gly Arg gac gta Asp Val gat gat Asp Asp 185 get gaa Ala Glu 200 c Pro Ala Leu Pro 1 -63- agg etg Arg Leu aaa tee Lys Ser 155 gtt gaa Val Glu 170 999 gge Gly Gly 9ta gte Val Val gtg aeg Val Thr 140 ace eeg Thr Pro tat ttg Tyr 1.eu ett att Leu Ile aat etc Aen Leu 205 cet Pro etg Leu ett Leu ect Pro 190 ett Leu gag aag Glu Lys cac ttc His Phe 160 eag aat Gin Asn 175 ctt cat Leu His ttg ega Leu Arg 433 481 529 577 625 Gly Ala Ala Pro Ala Ser Leu Leu Met 5cr Ala Ala Arg Asn 130 Val Asn 145 Ala Ala Gly Ala Gly 5cr Asp Pro Ser Pro Arg Leu Gly Arg 100 Glu Ala 115 Gly Asp Ser Arg Gly Phe Asn Val 180 Pro Val Gly Leu Arg Val Val Asp Gly 165 .,in Ala Thr Gly 70 Ala Cys Glu Glu Thr 150 Arg Ala Arg Ala 55 Leu Leu Ala Pro Arg 135 Ala Lys Gly 40 Gly Ala Leu Gly Ala 120 Val Gly Asp Ala Arg Gly Arg Ser Leu Leu Gly 105 Ala L~ys Arg Val Gln Leu Ala 90 Gly Arg Arg Lys Val 170 Al a Leu Val Ala Glu Leu Ser 155 Glu Ala Ala Ala Al a Leu Val 140 Thr Tyr Gly Arg Gly Ala Cys Phe 125 Thr Pro Leu Ala Pro Ala Ala 110 Glu Pro Leu Leu Leu Gly Arg Ser Ala Glu His Gin 175 His Gly Thr Arg Asp Asp 185 Gly Gly Leu Ile Pro Leu His 190 Asn Ala Cys Ser Phe Gly His Ala 195 200 Glu Val Val Asn Lou Leu Lou Arg 205 His Gly Ala Asp Pro Asn Ala 210 215 c2lO> 106 <~211> 4406 <212> DNA <213> Homo sapiens <220> <221> CDS <c222> (2)..(3787) (N2 <400> 106 g gag ctg gca gga 9gg99 C gc tg cca gct icc gcc 9CC gcg tcg itt cag 49 Glu Leu Ala Gly Gly Ala Leu Pro Ala Ser Ala Ala Ala Ser Phe Gln In1 5 10 gac ccg gac ggc gga tic gcg ctg cct ccg .ccg ccg cgg 99c agc cgg 97 Asp Pro Asp Gly Gly Phe Ala Leu Pro Pro Pro Pro Arg Gly Ser Arg 25 999 gca ggg agc cca gcg agg ggc gcg cgt 999 cgc ggc cat 999 act 145 Gly Ala Gly Ser Pro Ala Arg Gly Ala Arg Gly Arg Gly His Gly Thr 40 gcg ccg gat ccg gig aca gca 999 agc caa gcg 9cc cgg 9CC cig agc 193 Ala Pro Asp Pro Val Thr Ala Gly Ser Gin Ala Ala Arg Ala Leu Ser s0 55 geg tct ict ccg ggg gc ctc gc cetc cig ctc gcg ggg ccg ggg cic 241 Ala Ser Ser Pro Gly Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu 70 75 cig cic cgg tig ctg gcg cig tig cig gct gig gcg gcg, gcc agg atc 289 Leu Leu Arg Leu Leu Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile 90 aig tcg ggi ,cgc cgc tgc gcc ggc ggg gga gcg gcc tgc gcg agc 9cc 337 Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala 100 105 110 gcg gcc gag 9cc gig gag ecg qcc 9cc cga gag cig tic gag gcg tgc 385 Ala Ala Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys 115 120 125 cgc aac ggg, gac gig gaa cga gic aag agg cig gig acg cci gag aag 433 Arg Asn Gly Asp Val Glu Arg Val Lys Arg Leu Val Thr Pro Glu Lys 130 135 140 gig aac agc cgc gac aeg gcg ggc agg aaa icc acc ccg ctg cac tic 481 Val Asn Ser Arg Asp Thr Ala Gly Arg Lys Ser Thr Pro Leu His Phe 145 150 155 160 gcc gca ggt iii ggg cgg, aaa gac gia git gaa tat tig cit cag aai 529 Ala Ala Gly Phe Gly Arg Lys Asp Val Val Glu Tyr Leu Leu Gin Asn 165 170 175 ggi gca aat gic caa gca cgt gat gat ggg ggc cit ati cci cit cat 577 Gly Ala Asn Val Gin Ala Arg Asp Asp Gly Gly Leu Ile Pro Leu His 180 185 190 aat gca igc ict iii ggt cat gct gaa gia gte aat etc cii tig cga 625 Asn Ala Cys Ser Phe Gly His Ala Glu Val Val Asn Leu Leu Leu Arg 195 200 205 cat ggt gca gac ccc aat gct cga gat aai tgg aai tat act cci cic 673 His Gly Ala Asp Pro Asn Ala Arg Asp Asn Trp Asn Tyr Thr Pro Leu 210 215 220 cat His 225 089 Gin t tg Leu aag Lys atg Met gaa Gi u cat His ga t Asp aaa Lys atg Met got gca Ala Ala gga gct Gly Ala tta gca Leu Ala 260 gat gaa Asp Glu 275 gct cta Ala Leu gga Gly acc Thr tot Ser gaa Glu cca Pro aag Lys atc Ile gcc Ala agt Ser 280 tta att Ile cga Arg aaa Lys 265 9C Ala aat gat gtt Asp Val 235 aat aca Asn Thr 250 gca gtg Ala Val agg agt Arg Ser gtc aac Val Asn t go Cys ga t Asp ctt Leu ggc Gi y tgc Cys 300 gga Gly gat Asp att gtg Ile Val 998 899 Gly Arg act ggt Thr Gly 270 aat 988 Asn Glu 285 cac gca His Ala tat aac Tyr Asn gto cat Val His ctg tta Leu Leu 240 aca gca Thr Ala 255 988 tat Giu Tyr gaa 888 Giu Lys agt gat Ser Asp 290 295 99C Gly 305 aag Lys gat Asp tat Tyr atg Met 899 Arg 385 ctg Leu aga Arg att Ile 888 Lys 988 Giu gac Asp 370 gtt Val ctc Leu t ta Leu gCt Ala gaa Glu 450 tgt Cys 889 tca act cca Lys gta Val g9t Gly gta Val 355 ttg Leu 988 Gi u aat Asn 888 Lys 9ca Ala 435 atg Met gct Ala Ser Thr Pro 310 cag ctg tta Gin Leu Leu 325 gat ct9 gta Asp Leu Vai 340 gca Ala 998 Gly 330 335 cca tta cac aat 9CC Pro Leu His Asn Ala 345 tgt tct tat ggt cat Cys Ser Tyr Gly His 350 act Thr tgg Trp gta Val tgt Cys 988 Glu 420 cga Arg gtg Val gC t Al a 988 ctt ttg Glu Leu Leu caa ttc act Gin Phe Thr 375 tgt tct ott Cys Ser Leu 390 cac aat 888 His Asn Lys 405 898 tta gca Arg Leu Ala 988 gct gat Glu Ala Asp aat ttc aag Asn Phe Lys 455 9C8 tct cca Ala Ser Pro gtc Val 360 cct Pro ctc Leu agt Ser tat Tyr gtt Val1 440 cat His tat Tyr aag Lys ctt Leu tta Leu gct Ala 988 Giu 425 act Thr Oct Pro ccc Pro cat His cat His a9t Scr ata Ile 410 ttt Phe cga Arg 99 t Gly gag Giu tat Tyr 395 gao Asp 888 Lys atc Ile C Ala 908 Ala 380 ggt Gly t tg Leu 990 Gly 888 Lys cat His 460 889 Lys tgt gta. Cys Val 365 got tot Ala Ser 908. 980 Ala Asp gCt CCC Ala Pro cac tog His Scr 430 888 cat Lys His 445 988 aCa Glu Thr 088 ata Gin Ile aat gca Asn Ala 889 aac Lys Asn CC8 808 Pro Thr 400 808 008 Thr Pro 415 ttg ctg Leu Leu ctc tot Leu Ser 908 tt9 Ala Leu tgt 988 Cys Giu 721 769 817 865 923 961 1009 1057 1105 1153 1201 1249 1297 1345 1393 1441 1489 088 aca Gin Thr aaa aga Lys Arg 475 470 Ctg ttg Ota 898 Leu Leu Leu Arg 888 998 908 880 atc aat Lys Gly Ala Asn Ile Asn 485 490 988 889 act 888 Giu Lys Thr Lys 988 ttc Giu Phe 495 tt Le Gl 99 Gi tg Cy 54 ca4 Ct(4 Lei ctc Lei act Thi cca Prc 625 Ct 9 Leu gta Val ctt Leu ttt Phe aaa Lys 705 gga Gly ga t Asp tgt Cys :g act cct !u Thr Pro a gta gtg u Val Val 515 t cag act y Gin Thr 530 c c9C cta s Arg Leu 5 g 99C ttt n Gay Phe :caa gag j Gin Glu Igaa gct 1 Glu Ala 595 gtt cag Val Gin 610 LCtt catt Leu His I cta cag c Leu Gin H~ cct: ttg C Pro Leu H 6 ctt gtt a Leu ValL 675 aca cct t Thr Pro L 690 Ctt ctgq c Leu Leu Li aat act ci Asn Thr P~ ctg ctt ac Leu Leu A3 74 tta 9CC ag Leu Ala A~ 755 cl Li gt tc Se Ct Le ac Th gg 58' gcl agt :tt :at 'is a c ris 60 aa ys ta eu tc t L0 'a tg cac g3tg gcs ti eu His Val Ala Si 00 :9 ass cat gas gc 1i Lys His Giu A] 5: :t cta cac aga gc r Leu His Arg Al 535 c ctg agc tat gg u Leu Ser Tyr Gi 550 t: gct Itta cag at r Ala Leu Gin Me 565 It atc tca tta 99 y Ile Ser Leu Gi 0 a sag gct gga gal iLys Ala Gly Asl 601 gtc sac tgc agi *Val Asn Cys Arc 615 *gca gct ggg tat *Ala Ala Giy Tyz 630 gga gct gat gt:S *Gly Ala Asp Val 645 aat gca tgt tct Asn Ala Cys Ser cat gga gca gta His Gly Ala Val 680 cat gaa gca gca His Glu Ala Ala 695 cag cat ggt gca Gin His Gly Ala 710 ttg gat ctt gtt Leu Asp Leu Val 725 gga gat gca gct Gly Asp Ala Ala gtg aag aag ttg Val Lys Lys Leu 760 -66- gag aaa gct C er Giu Lys Ala H 505 :a sag gtt ast g La Lys Val Asn A It gca tat tgt 91 .a Ala Tyr Cys G'. 5, 9 tgt gat cct a y Cys Asp Pro A., 555 g gga sat gas sa t: Gly Asn Glu AE 570 t: sat tca gag gc y Asn Ser Glu Al 585 t gtc gaa act gt: P Val Glu Thr Va Igac stt gas gg IAsp Ile Giu Gi 62 sac aga gtg tc, Asn Arg Val Se: 635 1cat gct: asa gal His Ala Lys ASi 650 tat gga cat tat Tyr Gly His Ty2 665 gtt sat gta gct Val Asn Val Ala gcs 555 995 aaa Ala Lys Gly Lys 700 gac cct: aca aaa Asp Pro Thr Lys 715 aaa gat gga gat Lys Asp Gly Asp 730 ttg cta gat gct Leu Leu Asp Ala 745 tct tct cct gat Ser Ser Pro Asp at sat gat gtt is Asn Asp Val 510 ct ctg gat aat ls Leu Asp Asn 525 31: cat cta caa ly His Leu Gin ic att ata tcc ;n Ile Ile Ser it gta cag caa in Val Gin Gin 575 !a gac a9S Caa a Asp Arg Gin 590 a ass ass ctgt 1 Lys Lys Leu 605 9 Cgt Ca9 tct a y Arg Gin Ser 1 0 C gtg gtg gsa t: r Val Val Glu 6 ass gga ggc c SLys Gly Gly L 655 gas gtt gca g 7Glu Val Ala G 670 gat tta tgg a IAsp Leu Trp, L, 685 tat gas stt t: Tyr Glu Ile C as aac agg ga Lys Asn Arg AE aca gat stt ca Thr Asp Ile Gl 735 9CC asg sag gg Ala Lys Lys GI 750 ast gts aat tg Asn Val Asn Cy 765 gtt Val ct t Leu aCC Thr ctt Leu 560 Cc Leu t tg :gt 'ys ica 'hr .at yr tt eu a lu vs t: '0 'a It y C s 1537 1585 1633 1681 1729 1777 1825 1873 1921 1969 2017 2065 2113 2161 2209 2257 2305 cgc gat Arg Asp 770 acc caa ggc Thr Gin Gly aga cat tca aca cct tta cat Arg His Ser Thr Pro Leu His tta gca gct ggt Leu.Ala Ala Gly 775 tat aat aat tta Tyr Asn 785 gtg aat Val Asn tct tac Ser Tyr tgt gtc Cys Val 9CC caa Ala Gin 850 gct gac Ala Asp 865 gtt tca Val Ser tct gct Ser Mla agc cca Ser Pro tca agc Ser Ser 930 tca gaa Ser Giu 945 agt ttg Ser Lou ttc gta Phe Val gas cag Giu Gin aag gag Lys Glu 1010 Asr gcc Ala 999 Gly aat Asn 835 aag Lys ccg Pro gca Ala ctq Lou gga Gly 915 ctt Leu ctg Leu gag Glu agg Arg atc Ile 9 95 att Ile Leu caa cat *His 820 9CC Ala gga Gly act Thr gat Asp ccc Pro 900 gcc Ala tct Ser tct Ser aas Lys at Asn 980 act Thr gga Gly ga Glu gac Asp 805 gta Val acg Thr cga. Arg Ct t Lieu gat Asp 885 tct Ser act Thr gca Mla tca Ser sag Lys 965 Ctt Leu ttg Leu atc Ile gtt gca gag Val Ala Glu 790 aaa gga gga Lys Gly Gly gat gts. gca Asp Val Ala gac aaa tgg Asp Lys Trp 840 aca cag ctt Thr Gin Lou 855 aaa aat cag Lys Asn Gin 870 gtc agc gct Val Ser Ala tgt tac sag Cys Tyr Lys gca gat gct Ala Asp Ala 920 9cc agc agt Ala Ser Ser 935 gts gtt agt Val Val Ser 950 gag gtt cca Glu Val Pro gga ctt gag Gly Leu Glu gat gta tta 5 Asp Val Leu A 1000 aat gct tat Asn Ala Tyr C 1015 tat Tyz Ct t Leu gct Ala 825 gct Ala tgt Cys gaa Giu ct t Leu cct Pro 905 ctc Lou ctt Leu t ca Ser 3ga 3 ly :ac ij S 985 Itt al. ;ga fly 780 ttg tta caa cac gga gct Leu Leu Gin His Gly Mla 795 stt cct tta cat sat gca Ile Pro Leu His Asn Ala 810 815 cta cta ata aag tat sat Lieu Lou Ile Lys Tyr Asn 830 ttc aca cct ttg cac gaa Phe Thr Pro Lieu His Glu 845 gct ttg ttg cta gcc cat Ala Lou Lou Lieu Ala His 860 gga caa aca cct .tta gat Gly Gin Thr Pro Leu Asp 875 ctg aca gca gcc stg ccc Lou Thr Ala Ala Met Pro 890 895 csa gtg ctc aat-ggt gtg Gin Val Lou Asn Gly Val 910 tct tea ggt cca tct agc Sor Ser Gly Pro Ser Ser 925 gac sac tta tct ggg agt Asp Asn Lou Ser Gly Ser 940 agt gga aca gag ggt gct Ser Gly Thr Glu Gly Ala 955 gta gat ttt agc ata act Val Asp Phe Ser Ile Thr 970 975 cta atg gat ata ttt gag Leu Met Asp Ile Phe Giu 990 gag atqgg99 cac aag gag Giu Met Gly His Lys Glu 1005 cat agg cac aaa cta. att z His Arg His Lys Lou Ile I 1020 ga t Asp 800 gca Ala gca Ala gca Ala gga Gly t ta Lou 880 cca. Pro aga Arg cca Pro ttt Phe tcc Ser 96 0 caa Gln ga krg :tg jOu iaa .ys 2353 2401 2449 2497 2545 2593 2641 2689 2737 2785 2833 2881 2929 2977 3025 3073 3121 gga gtc gag Gly Val Glu 1025 aga ctt atc tcc gga Arg Lou Ile Ser Gly 1030 caa caa ggt ctt aac cca tat tta Gin Gin Gly Lou Asn Pro Tyr Lou 1035 1040 -68- act ttg aac acc tct ggt agt gga aca att ctt ata gat ctg tct cct 3169 Thr Leu Asn Thr Ser Gly Ser Gly Thr Ile Leu Ile Asp Leu Ser Pro C11045 1050 1055 gat gat aaa gag ttt cag tct gtg gag gaa gag aig caa agt aca gtt 3217 Asp Asp Lys Giu Phe Gin Ser Val Giu Giu Glu Met Gin Ser Thr Val 1060 1065 1070 cga gag cac aga gat gga ggt cat gca ggt gga atc ttc aac aga tac 3265 Arg Giu His Arg Asp Gly Gly His Ala Gly Gly Ile Phe Asn Arg Tyr 1075 1080 18 *aat att ctc aag att cag aag gtt tgt aac aag aaa cta tgg gaa aga 3313 Asn Ile Leu Lys Ile Gin Lys Val Cys Asn Lys Lys Leu Trp Giu Arg 1090 1095 1100 tac act cac cgg aga aaa gaa. gtt tct gaa gaa aac cac aac cat gcc 3361 Tyr Thr His Arg Arg Lys Giu Val Ser Glu Giu Asn His Asn His Ala 1105 1110 1115 1120 KIaat gaa. cga atg cta ttt cat ggg tct cct ttt gtg aat gca att atc 3409 Asn Giu Arg Met Leu Phe His Gly Ser Pro Phe Val Asn Ala Ile Ile 1125 1130 1235 cac aaa ggc ttt gat gaa agg cat gcg tac ata ggt ggt atg ttt 99a 3457 His Lys Gly Phe Asp Giu Arg His Ala Tyr Ile Gly Gly.Met Phe Gly 1140 1145 1150 gct ggc att tat ttt gct gaa, aac tct tcc aaa agc aat caa. tat gta 3505 Ala Gly Ile Tyr Phe Ala Giu Asn Ser Ser Lys Ser Asn Gin Tyr Val 1155 1160 1165 tat gga att gga gga ggt act ggg tgt cca gtt cac aaa gac aga. tct 3553 Tyr Gly Ile Gly Gly Gly Thr Gly Cys Pro Val His Lys Asp Arg Ser 1170 1175 1180 tgt tac att tgc cac agg cag ctg ctc ttt tgc cgg gta acc ttg gga 3601 Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val Thr Leu Gly 1185 1190 1195 1200 aag tct ttc ctg cag ttc agt gca atg aaa atg gca cat tct cct cca 3649 Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His Ser Pro Pro 1205 1210 1215 gt cat cac tca gtc act ggt agg ccc agt gta aat ggc cta gca tta 3697 Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly Leu Ala Leu 1220 1225 1230 gct gaa tat gtt att tac aga. gga gaa cag gct tat cct gag tat tta 3745 Ala Giu Tyr Val Ile Tyr Arg Gly Glu Gin Ala Tyr Pro Glu Tyr Leu 1235 1240 1245 att act tac cag att atg agg cct gaa ggt atg gtc gat gga 3787 Ile Thr Tyr Gin Ile met Arg Pro Glu Gly Met Val Asp Gly 1250 1255 1260 taaatagtta ttttaagaaa ctaattccac tgaacctaaa atcatcaaag cagcagtggc 3847 ctctacgttt tactcctttg ctgaaaaaaa. atcatcttgc ccacaggcct gtggcaaaag 3907 gataaaaatg tgaacgaagt ttaacattct gacttgataa agctttaata atgtacagtg 3967 ttttctaaat atttcctgtt ttttcagcac tttaacagat gccattccag gttaaactgg 4027 gttgtctgta ctaaattata aacagagtta acttgaacct tttatatgtt atgcattgat 4087 tctaacaaac tgtaatgccc tcaacagaac taattttact aatacaatac tgtgttcttt 4147 aaaacacagc atttacactg aatacaattt catttgtaaa actgtaaata agagcttttg 4207 -69- tactagccca gtatttattt acattgcttt gtaatataaa tctgttttag aactgcagcg 4267 gtttacaaaa ttttttcata tgtattgttc atctatactt catcttacat cgtcatgatt 4327 gagtgatctt tacatttgat tccagaggct atgttcagtt gttagttggg aaagattgag 4387 ttatcagatt taatttgce 4406 <210> 107 <211> 1262 <212> PRT <213> Homro sapiens <400> 107 Glu Leu Ala Gly Gly Ala Leu Pro Ala Ser Ala Ala Ala Ser Phe Gin 10 Asp Pro Asp Gly Gly Phe Ala Leu Pro Pro Pro Pro Arg Gly Ser Arg 25 Gly Ala Gly Ser Pro Ala Arg Gly Ala Arg Gly Arg Gly His Gly Thr 40 Ala Pro Asp Pro Val Thr Ala Gly Ser Gin Ala Ala Arg Ala Leu Ser ou Ala Ser Ser Pro Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu 75 Leu Leu Arg Leu Leu Ala Leu Leu Leu Ala Val Ala Met Ala Arg Val 145 Ala Gly Asn His His 225 Gin Ser Ala Asn 130 Asn Ala Ala Ala Gly 210 Gi u His Gly Arg 100 GlU Ala 115 Gly., Asp Ser Arg Gly Phe Asn Val 180 Cys Ser 195 Ala Asp Ala Ala Gly Ala Arg Val Val Asp Gly Gln Phe Pro Ile Cys Ala Gly Glu Glu Thr 150 Arg Ala Gly Asn Lys 230 Pro Arg 135 Ala Lys Arg His Ala. 215 Gly Thr Ala 120 Val Gly Asp Asp Ala 200 Arg Lys I le PG1) 105 Ala Lys Arg Val Asp 185 Glu Asp Ile Arg Lys 265 90 Gly Ala Ala Arg Glu Leu Arg Leu Val 140 Lys Ser Thr 155 Val Glu Tyr 170 Gly Gly Leu Val Val Asn Asn Trp Asn 220 Asp Val Cys 235 Asn Thr Asp 250 Ala Val Leu Ala Ala Cys'Ala 110 Phe Glu 125 Thr Pro Pro Leu Leu Leu Ile Pro 190 Leu Leu 205 Tyr Thr Ile Val Gly Arg Arg Ser Ala Glu His Gln 175 Leu Leo Pro Leu Thr 255 Ile Ala Cys Lys Phe 160 Asn His Arg Leu Leu 240 Ala Giu Pro 245 Leu Asp Leu Ala Asp Pro Ser Ala 260 rhr Gly Glu Tyr 270 Lys Lys Asp Glu Leu 275 Leu Glu Ser Ala Arg 280 Scr Gly Asn Glu Glu Lys 285 Met Met 290 Gly Arg 305 Lys lie Asp Lys Tyr Glu Met Asp 370 Arg Val 385 Leu Leu Gin Leu Gin Ala 4 Leu Glu I 450 His Cys A 465 Leu Leu L Leu Thr P Glu Val V Gly Gin T 530 Cys Arg L4 545 Gin Gly PI Leu Gin G] Leu Glu Al Thr Val G1 610 Pro Leu Hi 625 Leu Leu GI Ala Leu Leu Lys Ser Thr Val Gin Leu 325 Gly Asp Leu 340 Val Thr Glu 355 Leu Trp Gin Glu Val Cys Asn Cys His 405 Lys Glu Arg 420 Ala Arg Glu 435 let Val Asn P la Ala Ala S 4 *eu Arg Lys G 485 ro Leu His V 500 al Val Lys H 15 hr Ser Leu H: eu Leu Leu Si 5i he Thr Ala LE 565 Lu Gly Ile SE 580 .a Ala Lys Al >5 n Ser Val As s Phe Ala Al 63 n His Gly Al 645 Thr P: 2; Pro L( 310 Leu Le Val Pr Leu Le Phe Th 37 Ser Le 390 Asn Ly Leu Ali la As Phe Lys 455 er Pro 70 ly Ala al Ala is Glu is Arg 535 er Tyr 50 eu Gin r Leu .a Gly ;n Cys 615 a Gly 0 a Asp ro Leu Asn 95 eu His Leu u Gin His o Leu His 345 u Val Lys 360 r Pro Leu 5 u Leu Leu s Ser Ala a Tyr Glu 425 p Val Thr J 440 SHis Pro C Tyr Pro L Asn Ile A 4 Ser Glu L 505 Ala Lys V 520 Ala Ala T Gly Cys A! Met Gly A! 5. Gly Asn SE 585 Asp Val G3 600 Arg Asp Il Tyr Asn Ar Val His Al 65 Vi A] G1 33 As Hi Hi Se 11 41 Ph Arg lnr rys fsn 90 ys al yr sp sn 70 er .u .e .9 a 0 al Asn Cys His Ala Ser Asp 300 La Ala Gly Tyr Asn Arg Val 315 320 ly Ala Asp Val His Ala Lys 10 335 n Ala Cys Ser Tyr Gly His 350 s Gly Ala Cys Val Asn Ala 365 s Glu Ala Ala Ser Lys Asn 380 r Tyr Gly Ala Asp Pro Thr 395 400 e Asp Leu Ala Pro Thr Pro 0 415 e Lys Gly His.Ser Leu Leu 430 Ile Lys Lys His Leu Ser 445 Thr His Glu Thr Ala Leu 460 Arg Lys Gin Ile Cys Glu 475 480 Glu Lys Thr Lys Glu Phe 495 Ala His Asn Asp Val Val 510 Asn Ala Leu Asp Asn Leu 525 Cys Gly His Leu Gin Thr 540 Pro Asn Ile Ile Ser Leu 555 560 Glu Asn Val Gin Gin Leu 575 Glu Ala Asp Arg Gin Leu 590 Thr Val Lys Lys Leu Cys 605 Glu Gly Arg Gin Ser Thr 620 Val Ser Val Val Glu Tyr 635 640 Lys Asp Lys Gly Gly Leu 655 Val Pro Leu Leu Phe Thr 690 Lys Leu 705 Gly Asn Asp Leu Cys Leu Arg Asp 770 Tyr Asn 785 Val Asn Ser Tyr Cys Val E Ala Gin I 850 Ala Asp P 865 Val Ser A Ser Ala L Ser Pro G 9 Ser Ser L 930 Ser Glu L 945 Ser Leu G: Phe Val A Glu Gin I] 9i Lys Glu I] 1010 Le Va 67 Pr Lei Th Lei Ale 755 Thr Asn Ala ;ly Asn 835 Lys 'ro la .eu ly 15 eu eu lu rg Le 95 le u Hi 66 1 Ly 5 o Le u Le r Pr u Ar 74 SArl Gl1 Lei SGni His 820 Ala Gly Thr Asp Pro 900 Ala Ser Ser Lys Asn 980 Thr Gly -71- .s Asn Ala Cys Ser Tyr Gly His Tyr Glu 0 665 's His Gly Ala Val Val Asn Val Ala Asp 680. 685 u His Glu Ala Ala Ala Lys Gly Lys Tyr 695 700 u Gin His Gly Ala Asp Pro Thr Lys Lys. 710 715 o Leu Asp Leu Val Lys Asp Gly Asp Thr 725 730 3 Gly Asp Ala Ala Leu Leu Asp Ala Ala 0 745 g Val Lys Lys Leu Ser Ser Pro Asp Asn 760 765 i Gly Arg His Ser Thr Pro Leu His Leu 775 780 Glu Val Ala Glu Tyr Leu Leu Gin His 790 795 Asp Lys Gly Gly Leu Ile Pro Leu His 805 810 Val Asp Val Ala Ala Leu Leu Ile Lys 825 a Thr Asp Lys Trp Ala Phe Thr Pro Leu.H 840 845 Arg Thr Gin Leu Cys Ala Leu Leu Leu A 855 860 Leu Lys Asn Gin Glu Gly Gin Thr Pro L 870 875 Asp.Val Ser Ala Leu Leu Thr Ala Ala M 885 890 Ser Cys Tyr Lys Pro Gin Val Leu Asn G 905 9 Thr Ala Asp Ala Leu Ser Ser Gly Pro S 920 925 Ala Ala Ser Ser Leu Asp Asn Leu Ser G 935 940 Ser Val Val Ser Ser Ser Gly Thr Glu G 950 955 Lys Glu Val Pro Gly Val Asp Phe Ser I] 965 970 Leu Gly Leu Glu His Leu Met Asp Ile Pt 985 95 Leu Asp Val Leu Val Glu Met Gly His Ll 1000 1005 Ile Asn Ala Tyr Gly His Arg His Lys Le 1015 1020 Va 67 Le Gl As As Ly 75( Va Al Gly Asnr ryr 830 Iis la eu et ly er ly ly Le he 's u l Ala Glu !u Trp Lys u Ile Cys n Arg Asp 720 p IleGln 735 s Lys Gly 0 1 Asn Cys a Ala Gly SAla Asp 800 SAla Ala 815 Asn.Ala Glu Ala His Gly Asp Leu 880 Pro Pro 895 Val Arg Ser Pro Ser Phe Ala Ser 960 Thr Gin 975 Glu Arg Glu Leu Ile Lys -72- Giy Val Giu Arg Leu Ile Ser Gly Gin Gin Gly Leu. Asn Pro Tyr Leu 1025 1030 1035 1040 Thr Leu Asn Thr Ser Giy Ser Gly Thr Ile Leu Ile Asp Leu Ser Pro 1045 1050 1055 Asp Asp Lys Giu Phe Gin Ser Val Glu Giu Giu Met Gin Ser Thr Val 1060 1065 1070 Arg Giu His Arg Asp Gly Gly His Ala Giy Giy Ile Phe Asn Arg Tyr 1075 1080 1085 Asn Ile Leu Lys Ile Gin Lys Val Cys Asn Lys Lys Leu Trp Giu Arg 1090 1095 1100 Tyr Thr His Arg Arg Lys Giu Val Ser Glu Giu Asn His Asn His Ala 1105 1110 1115 1120 Asn Giu Arg Met Leu Phe His Gly Ser Pro Phe Val Asn Ala Ile Ile 1125 1130 1135 His Lys Gly Phe Asp Giu Arg His Ala Tyr Ile Giy Gly Met Phe Gly 1140 1145 1150 Ala Gly Ile Tyr Phe Ala Giu Asn Ser Ser Lys Ser Asn Gin Tyr Val 1155 1160 1165 Tyr Giy Ile Giy Giy Gly Thr Gly Cys Pro Val His Lys Asp Arg Ser 1170 1175 1280 Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val Thr Leu Gly 1185 1190 1195 1200 Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His Ser Pro Pro 1205 1210 1215. Giy His His Ser Val Thr Gly Arg Pro Ser Val Asn Gly Leu Ala Leu 1220 1225 1230 Ala Glu Tyr~Val Ile Tyr Arg Gly Giu Gin Ala Tyr Pro Giu Tyr Leu. 1235 1240 1245' Ile Thr Tyr Gin Ile Met Arg Pro Giu Gly Met Val Asp Gly 1250 1255 1260 c210> 108 c211> 436 c212> DNA <213> Homo sapiens <400> 108 ttttttttgc agttctaaaa cagatttata ttacaaagca atgtaaataa atactgggct agtacaaaag ctcttattta cagttttaca aatgaaattg tattcagtgt aaatgctgtg 120 ttttaaagaa cacagtattg tattagtaaa attagttctg ttgagggcat tacagtttgt 180 tagaatcaat gcataacata taaaaggttc aagttaactc tgtttataat ttagtacaga 240 caacccagtt taacctggga tgggcatctg ttaaagtgct ggaaaaaaca gggaaatatt 300 taggaaaaca ctggtacatt atttaaaggc tttntccaag gtcaggantg tttaaacttc 360 gtttcacatt tttatccntt tggccacggc ctgtggggcn aggatggatt ttttttccgg 420 ccaagggtgt taaacg 436 -c210> 109 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer -73- c400> 109 cgcctgagaa ggtgaacagc c 21 <210> 110 <211> c212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 110 acgcctcgaa cagctctcgg c-K1<210> Ill tn<211> 23 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> Ill gcgtgggcgc ggccatggga ctg 23 <210> 112 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 112 cagcgcgaat ccgccgtccg <210> 113 <211> 620 <212> DNA <213> Homo sapiens <220> <221> CDS <222> <400> 113 tt aaa, aca aca aca aca aaa aac aca ata tgc agg atc gtt cgg ctt 47 Lys Thr Thr Thr Thr Lys Asn Thr Ile Cys Arg Ile Val Arg Leu 1 5 10 cag cag aac cca ccg caa aga tgg cgg tgg gac gaa, gcc cct tct ccc Gin Gln Asn Pro Pro Gin Arg Trp Arg Trp Asp Glu Ala Pro Ser Pro 25 gcc gcc gaa gcc tct cgc ctc aca ttt ccc aca aac cct tcg cgc cgc 143 Ala Ala Glu Ala Ser Arg Leu Thr Phe Pro Thr Asn Pro Ser Arg Arg 40 ctc gct agc cga aac ctg ccc agc cgg tgc ccg gcc act gcg cac gcg 191 Leu Ala Ser Arg Asn Leu Pro Ser Arg Cys Pro Ala Thr Ala His Ala s0 55 cgg gac gac gtc acg tgc gct ccc ggg 9cr gga cgg agc tgg cag gag 239 Arg Asp Asp Val Thr Cys Ala Pro Gly Ala Gly Arg Ser Trp Gin Glu 70 ctg Leu cCS Pro gca Ala cc9 Pro tct Ser ctC Leu 160 tc9 Ser gcc Ala gca gga Ala Gly gac 99c Asp Gly ggg agc Gly Ser gat ccg Asp Pro 130 tct ccg Ser Pro 145 cgg ttg Arg Leu ggt cgc Gly Arg gag gc Glu Ala 999 9cc Gly Ala gga ttc Gly Phe 100 cca 9cg Pro Ala 115 gtg aca Val Thr ggg ggc Gly Gly ctg gcg Leu Ala cgc tgc Arg Cys 180 gtg gag Val Glu 195 t tg Leu 85 9cg Ala agg Arg gca Ala ctc Leu ctg Leu 165 cc Ala :cg Pro cca Pro ctg Leu ggC Gly ggg Gly 9CC Ala 150 t tg Leu ggc Gly gcc Ala gct tcc Ala Ser cct ccg Pro Pro gcg cgt Ala Arg 120 agc caa. Ser Gln 135 Ctc ct9 Leu Leu Ct9 gct. Leu Ala ggg gga. Gly Gly gcc cga Ala Arg 200 -74- gcc 9CC Ala Ala 90 ccg ccg Pro Pro 105 ggg cgc Gly Arg gcg gc Ala Ala Ctc gcg Leu Ala gtq gcg Val Ala 170 gcg gcc kla Ala LBS ;ag ctg1 flu Leu 'ys Arg I 10 .sp Glu A hr Asn P ro Ala T ly Arg S 75 la Ala S 90 ro Arg G: rg Gly H: la Arg A: 14 .a Gly P3 155 gcg tC9 Ala Ser cgg ggc Arg Gly ggc cat Gly His cgg gcc Arg Ala 140 999 ccg Gly Pro 155 9cg gcc Ala Ala tgc gcg Cys Ala ttC gag ?he Glu ttt Phe agc Ser 999 Gl y 125 Ct9 Leu 999 Gly agg Arg agc Ser 3cg kla cag Gln C99 Arg 110 act Thr agc Ser ctc Leu atc I le 9CC Ala 190 tgc Cys gac Asp 999 Gly 9C9 Ala gcg Ala C tg Leu aig Met 175 gc9 Ala 287 335 383 431 479 527 575 <210> 114 <211> 206 <212> PRT <213> Homo sapiens <400> 114 Lys Thr Thr .Thr Thr Lys 1 5 Gin Asn Pro Pro Gln Arg Ala Glu Ala Ser Arg Leu Ala Ser Arg Asn Leu Pro Asp Asp Val Thr Cys Ala 70 Ala Gly Gly Ala Leu Pro Asp Gly Gly Phe Ala Leu 100 Gly Ser Pro Ala Arg Gly 115 Asp Pro Val Thr Ala Gly 130 Ser Pro Gly Gly Leu Ala 145 150 Asn Trp Thr Ser 55 Pro Ala Pro Al a Ser 135 Lieu Thr Ile Arg Trp 25 Phe Pro 40 Arg Cys Gly Ala Ser Ala Pro Pro 105 Arg Gly 120 Gln Ala Leu Leu le Val Arg la Pro Ser ro Ser Arg hr Ala His er Trp Gln er Phe Glri ly Ser Arg .110 is Gly Thr 125 la Leu Ser I0 0o Gly Leu Leu Gln Pro Ala Arg Leu Ala Arg Glu Leu Asp Pro Gly Ala Ala Pro Ala Ser Leu Leu 160 Arg Leu Leu Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile Met Ser 165 170 175 Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala Ala Ala 180 185 190 Glu Ala Val Giu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys 195 200 205 <210> 115 c211> 1039 <212>. DNA :213> Homo sapiens c220> <221> CDS <222> (287)..(1039) <400> 115 gtacaatatt qatttacaaa a agttcctct aateaatcet aaagagtaat tgatcagagc catcceteca attggagtca ttCctttatt ttgggggcag ttcatceaaa cttctattaa gagaagtggt ttacaagaaa caacaacaac aacaacaaag gagaeaaagt aaaaaaaacg gaaaagaaat ctceaggag ctg aaa aca cgg aca att. tcc aca gta aga ett Leu L~ys Thr Arg Thr Ile Ser Thr Val Arg Leu 10 gagctaataa actttcatga acggcaaeta cagttgcgga aaaggg atg Met 1 eca aaa gaa Pro Lys Glu ettaetgtg etgttcggal gttcacttta ggaaagaaai tgg aag Trp Lys tgt gca 0)75 Ala aga tee Arg Ser aga aag Arg Lys aac aca Asn Thr tgg egg Trp Arg aca ttt Thr Phe agc cgg Ser Arg 100 Ccc ggg Pro Gly get tee Ala Ser gag caa aac ttt caa Glu t te Phe ata Ile tgg Trp ccc Pro tgc Cys get Ala gce A.la Gin age Scr tgc Cys gac Asp aca Thr ceg Pro 9ga Gly gee Ala 135 Asn etg Leu agg Ary gaa Glu aae Asri gcc Ala egg Arg 120 geg Phe 25 gaa Glu ate Ile gc Ala ect. Pro act Thr 105 age Ser tcg Ser Gin age Ser gtt Val ect Pro teg Ser 90 gcg Ala tg Trp, ttt Phe ggg etc Gly Leu ces ggg Pro Gly egg ett Arg Leu 60 tet ccc Ser Pro 75 ege ege Akg Arg eac gcg His Ala eag gag Gin Giu eag gac Gin Asp 140 ttt Phe ett Leu 45 eag Gin gee Ala etc Leu egg Arg ctg Leu 125 :eg Pro tte Phe 30 aaa Lys cag Gin gee Ala get Ala gac Asp 110 gea Ala gae Asp agt gta 5cr Val aca aea Thr Thr aae eca Asn Pro gaa gee Glu Ala age ega Ser Arg gac gte Asp Val gga ggg Gly Gly gge gga Gly Gly atg Met aca Thr eeg Pro tet Ser aa c Asn aeg Thr gee Ala tte Phe 145 gta Val aea Thr eaa Gin ege Arg etg Leu tge Cys t tg Leu 130 ;Cg gtg Val aaa Lys aga Arg etc Leu ccc Pro get Ala 115 cca Pro ctg Leu t 120 t180 240 295 343 391 439 487 535 583 631 679 727 cct ccg ccg ccg cgg ggc agc cg Pro Pro Pro Pro Arg Gly Ser Ar 150 15 gcg cgt 999 cgc 99C cat 999 ac Ala Arg Gly Arg Gly His Gly Th 165 170 agc caa gcg gcc cgg gcc ctg ag Ser Gin Ala Ala Arg Ala Leu Se: 180 185 ctc ctg ctc qcg 999 cc9 ggg Ct( Leu Leu Leu Ala Gly Pro Gly Lei 200 ctg gct gtg 9C9 gcg gee agg atc Leu Ala Val Ala Ala Ala Arg Ile 215 ggg gga gcg 9CC tgc gcg agc 9CC Gly Gly Ala Ala Cys Ala Ser Ala 230 235 9cc cga gag ctg ttc gag gcg tgc Ala Arg Glu Leu Phe Glu Ala Cys 245 250 <210> 116 <c211> 251 <212> PRT <213> Homo sapiens <400> 116 Met Trp Lys Leu Lys Thr Arg Thr 1 5 Glu Cys Ala Arg Ser Glu Gin Asn Met Val Val AXg Lys Phe Ser Leu .40 Thr Thr Lys Asn Thr Ile Cys Arg 55 Pro Gin Arg Trp Arg Trp Asp Glu 70 Ser Arg Leu Thr Phe Pro Thr Asn Asn Leu Pro Ser Arg Cys Pro Ala 100 Thr Cys Ala Pro Gly Ala Gly Arg 115 120 Ala Leu Pro Ala Ser Ala Ala Ala 130 135 Phe Ala Leu Pro Pro Pro Pro Arg 145 150 Ala Arg Gly Ala Arg Gly Arg Gly 165 Thr Ala Gly Ser Gin Ala Ala Arg 180 9 .9 5 t r c r I -76- 999 gca 999 Gly Ala Gly geg ccg gat Ala Pro Asp gcg ict tct Ala Ser Ser 190 ctg ctc cgg Leu Leu Arg 205 atg tc9 ggt Met Scr Gly 220 9cg 9CC gag Ala Ala Glu agc cca gc Scr Pro Al 160 C9 gtg ac Pro Val Th 175 cC9 999 9g9 Pro Gly GI ttg ctg gcs Leu Leu Ali Cgc C9c tgC Arg Arg Cys 225 9CC gtg gag Ala Val Glu 240 g agg ggc a Arg Gly a gca ggg r Ala Gly *ctc 9CC rLeu Ala 195 ct9 ttg Leu Leu 210 9CC 99C Ala Gly CCg gcc Pro Ala Pro Lys Ser Val Thr Thr Asn Pro Glu Ala Ser Arg Asp Val Giy Gly 31Y Gly 3er Pro 160 ~ro, Val 'ro Gly 775 823 871 919 967 1015 1039 Ile Sei Phe Glr 25 Glu Sez Ile Val Ala Pro Pro Ser 90 Thr Ala 105 6cr Trp, Scr Phe Gly Ser ~is Gly 170 lia Leu .85 rThr Val IGly Leu 7Pro Gly Arg Leu 60 Ser Pro 75 Arg Arg His Ala Gin Glu Gin Asp 140 Arg Gly 155 Thr Ala Ser Ala Arg Leu i Phe Phe *Leu Lys Gin Gin Ala Ala Leu Ala Arg Asp 110 Leu Ala 125 Pro Asp Ala Gly Pro Asp I 1 Ser 5cr P 190 Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu Leu Leu Arg Leu Leu 195 200 205 Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile Met Ser Gly Arg Arg 210 215 220 Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala Ala Ala Glu Ala Val 225 230 235 240 Glu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys 245 250 CK< 210> 117 <211> 473 .212> DNA <c213> Homo sapiens <220>. c221> CDS <400>. 117 ct agc cga aac ctg ccc agc cgg tgc ccg gcc act gcg cac gcg c9q 47 Ser Arg Asn Leu Pro Ser Arg Cys Pro Ala Thr Ala His Ala Arg 1 5 10 gac gac gtc acg tgc gct ccc ggg gct 9ga cgg agc tgg cag gag ctg Asp Asp Val Thr Cys Ala Pro Gly Ala Gly Arg Ser Trp Gin Glu Leu 25 gca gga ggg 9CC ttg cca gct tcc gCC gcc gcg tcg tit cag gac ccg 143 Ala Gly Gly Ala Leu Pro Ala Ser Ala Ala Ala Ser Phe Gin Asp Pro 40 gac ggc gga ttc gcg ctg cct ccg ccq ccg cgg ggc agc cgg ggg gca 191 Asp Gly Gly Phe Ala Leu Pro Pro Pro Pro Arg Gly Ser Arg Gly Ala 55 999 agc cca geg agg ggc gcg cgt ggg cgc 99c cat ggg act gcg ccg 239 Gly Ser Pro Ala Arg Gly Ala Arg Gly Arg Gly His Gly Thr Ala Pro 70 gat ccg gtg aca gca 999 agc caa gcg gcc cgg gcc ctg agc gcq tct 287 Asp Pro Val Thr Ala Gly Ser Gin Ala Ala Arg Ala Leu Ser Ala Ser 85 90 tct ccg ggg ggc ctc 9cc ctc ctg ctc gcg ggg ccg ggg ctc ctg ctc 335 Ser Pro Gly Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu Leu Leu 100 105 110 cgg ttg ctg gcg ctg ttg ctg gct gtg gcg gcg gcc agg atc atg tcg 383 Arg Leu Leu Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile Met Ser 115 120 125 ggt egc cgc tgc gcc ggc ggg gga gcg gcc tgc gcg agc 9cc gcqg9CC 431 Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala Ala Ala 130 135 140 gag gcc gtg gag ccg gcc gcc cga gag ctg ttc gag gcg tgc 473 Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys 145 150 155 <210> 118 <211> 157 <212> PRT <213> Homo sapiens <400> 118 Ser Arg A 1 Asp Val T] Gly Gly A: Gly Gly P1 so Ser Pro Al Pro Val Th Pro Gly Gi Leu Leu Al 11 Arg Arg Cy 130 Ala Val Gi 145 sn la ye a 5 S U Leu Cys Leu Ala Arg Ala Leu 100 Leu Ala Pro Pro Ala Pro Leu Gly Gly 85 Ala Leu ;ly Ula Ser Arg Cys *Pro Gly Ala *Ala Ser Ala 40 Pro Pro Pro 55 Ala Arg Gly 70 Ser Gln Ala Leu Leu Leu Leu Ala Val 120 Gly Gly Ala 135 Ala Arg Glu 150 Pro Ala Thr 10 Gly Arg Ser 25 Ala Ala Scr Pro Arg Gly Arg Gly His 75 Ala Arg Ala 90 Ala Gly Pro 105 Ala Ala Ala Ala Cys Ala Leu Phe Glu 155 Ala His Trp Gln Phe Gln Ser Arg Gly Thr Leu Ser Gly Leu krg Ile 125 'er Ala 140 Qa Cys Al a Glu Asp Gly Ala Ala Leu 110 Met Ala Arg Leu Pro Ala Pro Ser Leu Ser A~la Asp Ala Asp Gly Asp s0 Ser Arg Gly Glu <c210> 119 <c211> 22 <212> DNA <213> Artificial Sequence <220> <223>. Description of Artificial Sequence: Primer <400> 119 gttcctctaa tcaatcctga gc <210> 120 <211> 26 <212> DNA <213> Artificial Sequence <220.; <223> Description of Artificial Sequence:Primer <400> 120 ggaaagagta attgatcaga gccatc <210>. 121 <211> 27 <212> DNA <213>. Artificial Sequence <c220> <223>. Description of Artificial Sequence:Primer <400> 121 cgccgaagcc tctcgcctca catttcc <210> 122 <211> 27 <212> DNA 4213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400, 122 ggaaatgtga ggcgagaggc ttcggcg <210> 123 <211> 659 <212> DNA <213> Homo sapiens -c400> 123 ggaaagagta atttccttta ttgagaagtg aagagacaaa aaaacacgga tttcaagggc ct taaaacaa ccgcaaagat tttcccacaa actgcgcacg gggccttgcc at tgatcaga ttttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga acccttcgcg- cgcgggacga agcttccgcc gccatccctc agttcatcca aacaacaaca c9gaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct ccgcctcgct cgtcacgtgc gccgcgtcgt caattggagt aacttctatt acaacaacaa at ctcccagg ccaaaagaat gtgagaaagt tgcaggatcg tctcccgccg agccgaaacc 9ctcccgggg ttcaggaccc caacttccat aaacggcaac agcagt tgcg agaaagggat gtgcaagatc tcagcctgga ttcggcttca ccgaagcctc tgcccagccg ctggacggag ggacggcgga gactgt tcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca tcgcctcaca gtgcccggcc ctggcaggag ttcgcgctg <210> 124 <211> 669 <212> DNA <213> Homo sapiens <400> 124 ggaaagagta attgatcaga gccatccctc atttccttta ttttgggggc agttcatcca ttgagaagtg gtttacaaga aacaacaaca aagagacaaa _9taaaaaaaa cggaaaagaa aaaacacgga caatttccac agtaagactt tttcaagggc tctttttcag tgtaatggta cttaaaacaa caacaacaaa aaacacaata ccgcaaagat ggcggtggga cgaagcccct tttcccacaa acccttcgcg ccgcctcgct actgcgcacg cgcgggacga cgtcacqtgc gggccaggag gggccttgcc agcttccgcc ttcgcgctg caat tggagt aacttctatt acaacaacaa atctcccagg ccaaaagaat gtgagaaagt tgcaggatcg tctcccgccg agccgaaacc gctcccgggg gccgcgtcgt caact t tcat aaacggcaac agcagt tgcg agaaagggat gtgcaagatc tcagcctgga ttcggcttca ccgaagcctc tgcccagccg ctggacggag t tcaggaccc gactgttcgg tagttcactt 120 gaggaaagaa 180 gtggaagctg 240 cgagcaaaac 300 aagcccaggg 360 gcagaaccca 420 tcgcctcaca 480 gtgCCCggcc 540 ctggcaggag 600 ggacggcgga 660 669 <210> 125 <211> 659 <212> DNA <213) Homo sapiens <400> 125 ggaaagagta atttccttta ttgagaagtg aagagacaaa aaaacacgga t ttcaagggc ct taaaacaa ccgcaaagat tttcccacaa actgcgcacg gggccttgcc <210> 126 attgatcaga ttttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga accct tcgcg cgcgggacga agcttccgcc gccatccctc agttcatcca aacaacaaca cggaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct ccgcctcgct cgtcacgtgc gccgcgtcgt caattggagt aacttctatt acaacaacaa atctcccagg ccaaaagaat gtgagaaagt tgcaggatcg tctcccgccg agccgaaacc gctcccgggg ttcaggaccc caact tccat aaacggcaac agcagttgcg agaaagggat gtgcaagatc tcagcctgga ttcggcttca ccgaagcct c tgcccagccg ctggacggag g9acggcgga gactgttcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca tcgCctcaca gtgcccggcc ctggcaggag ttcgcgctg 120 180 240 300 360 420 480 540 600 659 <211> 659 <212> DNA <213> Homo sapiens <400> 126 ggaaagagta atttccttta t tgagaagtg aagagacaaa aaaacacgga tttcaagggc cttaaaacaa ccgeaaagat tttcccacaa a ctgcg cacg gggccttgcc attgatcaga ttttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga acccttcgcg cgcgggacga agct tccgcc gccatccctc agttcatcca aacaacaaca cggaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct cCgcct CgCt cgtcacgtgc gCcgcgtcgt caattggagt aacttctatt acaacaacaa atctcccagg ccaaaagaat gtgagaaagt tgcaggatcg tCtCccgccg agccgaaacc gctcccgggg ttcaggaccc caact tccat aaacggcaac agcagttgcq agaaagggat gtgcaagatc tcagcctgga t tcggcttca ccgaagcctc tgcccagccg ctggacggag ggacggcgga gactgttcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca tcgcctcaca gtgcccggcc ctggcaggag ttcgcgctg <210> 127 <211> 659 <212> DNA <213> H~omo sapiens <400> 127 ggaaagagta atttccttta ttgagaagtg aagagacaaa aaaacacgga tttcaagggc cttaaaacaa CCgcaaagat tttcccacaa actgcgcacg gggccttgcc attgatcaga ttttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga acccttcgcg cgcgggacga agcttccgcc gccatccctc a t t catcca aacaacaaca cggaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct ccgcctcgct cgtcacqtgc gccgcgtcgt caattggagt aacttctatt acaacaacaa atctcccagg ccaaaagaat gtgagaaagt tgcaggatcg tctcccgccg agccgaaacc gctcccgggg t tcaggaccc caact tccat aaacggcaac agcagttgcg agaaagggat gtgcaagatc tcagcctgga ttcggct ica ccgaagcctc tgcccagccg ctggacggag ggacggcgga gactgttcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca t cg cctcaca gtgcccggcc ctggcaggag ttcgcgctg <210> 128 <211> 669 <212> DNA <c213> Homo sapiens <400> 128 ggaaagagta atttccttta t tgagaagtg aagagacaaa aaaacacgga t ttcaagggc cttaaaacaa ccgcaaaga t tttcccacaa actgcgcatg ctggcaggag t tcgcgctg attgatcaga ttttgggggc gtttacaaga 9taaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga acccttcgcg cgcgggacga gggccttgcc gccatccctc agttcatcca aacaacaaca cggaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct CCgcctcgct cgtcacgtgc agct tccgcc caat tggagt aacttctatt acaacaacaa atctcccagg ccaaaagaa t gtgagaaagt tgcagga tcq tctcccgccg agccgaaacc gctcccgggg gccgcgtcgt caactttcat aaacggcaac agcagttgcg agaaaggga t gtgcaagatc tcagcctgga ttcggCttca ccgaagcctc tgcccagccg ctggacggag ttcaggaccc gactgttcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca tcgcctcaca gtgcccggcc ctggcaggag ggacggcgga <210> 129 <211> 597 <212> DNA <213> Homo sapien's <400> 129 ggaaagagta atttccttta ttgagaagtg aagagacaaa aaaacacgga tttcaagggc cttaaaaCaa attgatcaga ttttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa gccatccctc agttcatcca aacaacaaca cggaaaagaa a~taagactt tgtaatggta aaacacaata caattggagt aacttctatt acaacaacaa atctcccagg ccaaaagaat gtgagaaagt tgcaggatcg caactttcat aaacggcaac agcagttgcg agaaagggat gtgcaagatc tcagcctgga ttcgcttca gactgttcgg tagttcactt gaggaaagaa gtggaagctg cgagcaaaac aagcccaggg gcagaaccca -81- ccgcaaagat ggcggtggga cgaagcccct tCtCCCgccg ccgaagcctc tcgcctcaca 480 tttcccacaa acccttcgcg CCgcctcgct agccgaaacc tgcccagccg gtgcccggcc 540 actgcgcacg cgcgggacga cgtcacgtgc gctcccgggg ctggacggag ctggcag 597 <210> 130 <211> <212> DNA <213> Homno sapiens <400> 130 gagctggcag <210> 131 <211> <212> DNA <213> Homo sapiens <400> 131 gggctggacg gagctggcag <210> 132 <211> 5002 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (229)..(4383) <400> 132 ggaaagagta attgatcaga gaggggcctt gccatccctc caattggagt caactttcat gactgttcgg atttccttta ttttgggggc agttcatcca aacttctatt aaacggcaac tagttcactt 120 ttgagaagtq gtttacaaga aacaacaaca acaacaacaa agcagttgcg gaggaaagaa 180 aagagacaaa etaaaaaaaa cggaaaagaa atctcccagg agaaaggg atq tgg aag Met Trp Lys ctg aaa Leu Lys aca cgg aca ati Thr Arg Thr Ile aca gta aga ctt cca aaa gaa tgt gca Thr Val Arg Leu Pro Lys Glu Cys Ala tcc gag caa aac Ser Giu Gin Asn caa ggg ctc ttt Gin Gly Leu Phe agt gta atg 9ta Ser Val Met Val aga aag ttc age ctg gaa age cca ggg ctt Arg Lys Phe Ser Leu Giu Ser Pro Gly Leu 45 aaa aca aca aca Lys Thr Thr Thr aca aaa Thr Lys so aac aca ata Asn Thr Ile tgg egg tgg Trp Arg Trp agg atc gtt cgg Arg Ile Val Arg cag cag aac eca Gin Gin Asn Pro ccg caa aga Pro Gin Arg tet cgc ctc Ser Arg Leu gac gaa 9cc cct Asp Giu Ala Pro CCC 9CC 9CC gaa Pro Ala Ala Glu aca ttt ccc aca aac cct Thr Phe Pro Thr Asn Pro tcg cgc cgc cte Ser Arg Arg Leu 90 get age Ala Ser cga aac ctg ccc Arg Asn Leu Pro C9g tgc Ceg 9CC Arg Cys Pro Ala gcg cac geg Ala His Ala egg gac Arg Asp 110 gac gtc acg tgc Asp Val Thr Cys ccc Pro get Ala ect Pro geg Al a age Ser 180 etc Leu ctg Leu ggg Gly C 9cC C Ala aag a Lys 260 agg a ArgL gta g Val V gat g Asp G gaa g Giu V~ 3: gat a~ Asp A~ 340 att g4 Ile As ega aa Arg As GI tc Se cc Pr eg Ar 16 ca~ 3et ga :ga Lrg rg aa ,ys tt al 99 ly ta 25 It it n ig g y A :e 9 r A: 9 CC o P2 t gc 5 q *i Al 3 cL as Le -gt, Va ge Al 23i *ga~ Gli cts Let t cc Se2 gaa Glu 9gC Gly 310 gte Val tgg Trp, gtt Val aca Thr Ct gga egg la Gly Arg 120 ce gc gcg la Ala Ala 135 :g ceg egg :o Pro Arg .y Arg Gly 9 gee egg a Ala Arg C gcg ggg u Ala Gly 200 9 geg geg 1 Ala Ala*~ 215 9 gee tge a Ala Cys 0 9 etg ttc 5 a1 Leu Phe C gtg acg c iVal Thr 1 ace ceg c Thr Pro L 280 Itat ttg c ITyr Leu L 295 ctt att c Leu Ile P aat etc c Asn Leu L aat tat a Asn Tyr T] tge att 9g Cys Ile V~ 360 gat gga ac Asp Gly A2 375 age tgg eag Ser Trp Gin Leg ttt eag Ser Phe Gin gge age egg Giy Ser Arg 155 cat ggg act His Gly Thr 170 gee etg age Ala Leu Ser 185 Ceg ggg etc Pro Gly Leu gcc agg ate.s Ala Arg Ile gcg age gc kla Ser Ala 235 3ag gcq tgc c flu Ala Cys 250 :ct gag aag g ~ro Giu Lys V ~65 :tg eac ttc g .eu His Phe A 'tt cag aat g eu Gin Asn G 3, et ctt cat a ro Leu His Al 315 tt ttg ega c~ eu Leu Arg H: 330 ct ect etc ca hir Pro Leu Hi 45 tg ctg tta ca 11 Leu Leu Gl ~g aca gea tt 7g Thr Ala Le 38 95 G] 98 As 14 gg GI ge Al gel Al Le~ Itc 4et ;cg :ge Lrg rtg 'al cc la qt ly 00 at sn is It Ls '9 0 -82- 19 Ctg gca gga ggg gee ttg eca *u Leu Ala Gly Gly Ala Leu Pro 125 130 be cc9 gae gge gga ttc geg ctg ;p Pro Asp Gly Gly Phe Ala Leu 0 145 9 gca ggg age eca geg agg gge y Ala Gly Ser Pro Ala Arg Gly 160 g ceg gat eeg gtg aea. gea ggg a Pro Asp Pro Val Thr Ala Gly 175 g tet tet ceg ggg ggc etc gee a Ser Ser Pro Gly Gly Leu Ala 190 195 9 etc egg ttg ctg geg etg ttg .s Leu Arg Leu Leu Ala Leu Leu 205 210 ;teg ggt ege ege tge gee gge Ser Gly Arg Arg Cys Ala Gly 225 gee gag gee gtg gag ceg gee Al1a Giu Ala Val Giu Pro Ala 240 aac ggg gac gtg gaa ega gte IAsn Giy Asp Val Giu Arg Val 255 aac age ege gac acg gcg gge Asn Ser Arg Asp Thr Ala Gly 270 275 gca ggt. ttt ggg egg aaa gac Ala Gly Phe Gly Arg Lys Asp 285 290 gca. aat gte eaa gea egt gat Ala, Asn Val Gln Ala Arg Asp 305 gca tgc tet ttt ggt eat get Ala Cys Ser Phe Gly His Ala 320 ggt. gea gac ccc aat get ega Gly Ala Asp Pro Asn Ala Arg 335 gaa get gea att aaa gga aag Giu Ala Ala Ile Lys Gly Lys 350 355 cat gga get gag eca ace ate His Giy Ala Glu Pro Thr Ile 365 370 gat tta gea gat eca tet gee Asp Leu Ala Asp Pro Ser Ala 385 621 669 717 765 813 861 909 957 1005 1053 1101 1149 1197 1245 1293 1341 1389 -83- aaa gat Lys Asp aaa gca gtg Lys Ala Val 390 ctt act ggt gaa tat aag Leu Thr Gly Glu Tyr Lys 395 958 ctc tta gaa agt Glu Leu Leu Glu Ser 400 1437 9CC Ala aat Asn 420 t tg Leu cat His cac His aag Lys Ctt Leu 500 t ta Leu gCt Ala gaa Glu act Thr Cct4 Pro 580 ccc Pro atc Ile gag Giu agg Arg 405 gtC Val gca Ala gga Gly sat Asn cat His 485 cat His agt Ser ata I le ttt Phe Cga Arg 565 caa Gln ~aaa Lys iat k-sn iaa ys agt Ser aac Asn gca Al a gct Ala 9CC Al a 470 ggt Gly gag Glu tat Tyr gac Asp aa Lys 550 atc Ile aca Thr 595 Arg gas Glu gct Ala 1 630 ggc G1y tgc Cys gga Gi y gat Asp 455 tgt Cys 9CC Ala gcs Ala ggt Gly ttg Leu 535 9gc Gly ~a Lys cat His aag Lays lag -,ys 615 :a t 4is sat Asr cac His tat Tyr 440 gtc Val tct Ser tgt Cys gct Ala gca Ala 520 gct Ala cac His aaa Lys gaa Glu caa Gin 600 act Thr aat Asn gas ga Giu Glu 410 gca agt Ala Ser 425 aac aga Asn Arg cat gct His Ala tat ggt Tyr Gly gta sat Val Asn 490 tct sag Ser Lys 505 gac cca Asp Pro ccc aca Pro Thr tcg ttg Ser Leu cat ctc His Leu 570 aca gca Thr Ala 585 ata tgt 5 Ile Cys C ass gaa t Lys Giu I gat gtt g Asp Val V a55 atg atg gcl Lys met Met Al~ tcta ctc aca eca tta gat As; gta Val asa Lys cat His 475 gca Ala aac Asn aca Thr cca Pro :tg Leu 555 t 3cr :tg .jCu ;aa 31u :tc ~he itt ;35 gg9c Gly aa55 Lys ga9t Asp 460 tat Tyr atg Met agg Arg ctg Leu cag Gin 540 aa Gin Ctg Leu cat His ctg Leu ttg Leu 620 gas Glu aga aa Ar at t Ile 445 ass Lys gas Glu gac Asp gtt Val ctc Leu 525 tta Leu gct Als gaa Glu tgt :ys t tg Lieu 605 Ict rhr ;ta 7l Lyi 430 gta Val ggt Gly gta Val ttg Leu ga Giu 510 aat Asn ass Lys gca Ala atg Met gct Ala 590 cta Leu cct Pro gtg Val lLeu Leu Thr 415 ;tca act cca Ser Thr Pro cag ctg tta *Gin Leu Leu gat ctg gts Asp Leu Val 465 *act gas ctt Thr Glu Leu 480 tgg cas ttc Trp Gin Phe 495 gts tgt tct Val Cys Ser tgt cac aat Cys His Asn gaa ags tts Glu Arg Leu 545 cga gsa gct Arg Giu Ala 560 gtg ast ttc Val Asn Phe 575 gct gca tct c Ala Ala Ser I ags ass gga g Arg Lys Gly 6 ctg cac gtg g Leu His Val P5 625 gtg ass cat 9 Val Lys His G 640 Pr( tti Let Ctc Leu 450 cc Pro ttg Leu act Thr ctt Leu aaa Lys 530 qca Ala 35 t ksp lag .Iys ~ca ~ro ica la 'ca las 'as ;lu Leu Scat iHis 435 cas Gin Itta 4Leu gtc Val cct Pro ctc Leu 515 agt Ser tat Tyr 9t t Val cat His tat Tyr 595 sac Asn tct. Ser gca Ala 1485 1533 1581 1629 1677 1725 1773 1821 1869 1917 1965 2013 2061 2109 2157 sag gtt Lys Val 645 sat gct ctg gat sat ctt ggt cag Asn Ala Leu Asp Asn Leu Gly Gin 650 act tct. cta cac aga gct Thr Ser Leu His Arg Ala 655 2205 gea tat tgt Ala Tyr Cys 660 tgL-gaL cct Cys Asp Pro gga aat gaa Gly Asn Giu aat tca gag Asn Ser Giu 710 gte gaa act Val Giu Thr 725 gac att gaa Asp Ile Giu 740 aac aga gtg Asn Arg Val cat'get aaa His Ala Lys tat gga cat Tyr Gly His 790 gtt aat gta Val Asn Val 805 gca aaa gga Ala Lys Gly 820 gac cct aca Asp Pro Thr aaa gat gga Lys Asp Gly ttg eta gat Leu Leu Asp 870 tet tet ect Ser Ser Pro 885 aca ect tta Thr Pro Leu 1 900 991 GI~ aac Asx aat Asr 6 95 gca Ala gta Val ggg Gly tee Ser gat Asp 775 tat Tyr get Ala aaa Lys aaa Lys gat Asp 855 3ct 3at k.sp :at jis tcat y His :att i Ile 680 -gta. Val gac Asp *aaa Lys egt Arg gtg Val 760 aaa Lys gaa Glu7 gat Asp tat Tyr aaa Lys 840 aca Thr 9CC i Ala aat S Asn N tta 9 Leu 9 ace tgc Thr Cys ett cag Leu Gin etc etc Leu Leu -84- ege eta Arg Leu 670 ggc ttt Gly Phe 685 caa gag Gin Giu etq Leu get Ala ate Ile age tat Ser Tyr tta cag Leu Gin 690 tea tta Ser Leu aga caa ttg etc Arg aaa Lys cag Gin 745 gtg Val gga Gly gtt Val t ta Leu gaa- Glu 825 sac Asn ;at hasp hag '.YS ;ta l ica la 05 Gin Ct 9 Leu 730 tet Ser gaa Glu 9gC Gly gca Ala tgg Trp 810 at Ile agg Arg att Ile aag Lys aat Asn 890 get Ala Leu 715 tgt Cys aca Thr tat Tyr ett Leu gaa Giu 795 aaa Lys tgc Cys gat Asp caa Gln ~gt fly 875 :gc :ys ;gt1 ;iy Let act Thi eca Prc ctg Leu gta. Val 780 ett Leu t tt Phe aaa Lys gga Gly gat A~sp 860 Lgt :ys :ge krg tat ryr 3 gaa .a Glu gtt Val Ictt Leu eta Leu 765 ect Pro ctt Leu aca. Thr ett Leu aat Asn 845 ctg Leu tta Leu2 gat a Asp ~I aat a Asn get Al a cac Gir eat His 750 eag Gin ttg Leu gt t Val cet Pro etg Leu 830 act rhr :t t Leu ?cc Icc hr hat ~sn Al agi Se~ 73! tt Phe eat Hisa cac His aaa Lys tta Leu 815 etc Leu ct Pro agg Arg aga Arg eaa Gin 895 tta Leu aag get Lys Ala 720 tgte aac cVal Asn 5 gea get Ala Ala gga get Gly Ala aat gea Asn Ala 785 cat gga His Gly eat gaa His Giu cag cat Gin His ttg gat Leu Asp gga gat Gly Asp 865 gtg aag Val Lys 880 ggc aga Gly Arg gaa gtt Giu Val 99' Gl~ tgC Cyg 999 Giy gat Asp 770 tgt Cys gca Ala gea Ala ggt Gly ett 1.eu 850 gea Alia aag Lys cat ~ii5 Ica kla i gat rAsp -aga ~Arg tat Tyr 755 *gtg Vai tct Ser gta Val gca Ala gca Al a 835 gtt Val get Ala ttg Leu tea Ser gag Giu 915 2253 2301 2349 2397 2445 2493 2541 2589 2637 2685 2733 2781 2829 2877 2925 2973 tat ttg tta eaa Tyr Leu Leu Gin cac gga get gat gtg His Gly Ala Asp Val aat. gee eaa gac aaa gga gga Asn Ala Gin Asp Lys Gly Gly 925 930 3021 ett att cct tta eat aat gca gca Leu Ile Pro Leu His Asn Ala Ala 935 tet tac ggg cat 9ta Ser Tyr Gly His Val 940 gat gta gca Asp Val Ala 945 gct Ala gct Ala tgt Cys 980 gaa Glu ett Leu Ct' Le~ Pht 965 get Ala gga Giy ctg Leu cct caa Pro Gin etc tct Leu Ser 1045 ett gac Leu Asp 1060 tea agt Ser Ser gga gta Gly Val cac eta His Leu gtt gag Val Giu 1125 gga eat Gly His 1140 e ta ata aag tat aat gea tgt gte aat gec aeg gac aaa tgg Leu Ile Lys Tyr Asn Ala Cys Val Asn Ala Thr Asp Lys Trp 950 955 960 aca cet ttg eac gaa gca gee caa aag gga ega aca cag ett Thr Pro Leu His Glu Ala Ala Gin Lys Gly Arg Thr Gin Leu 970 975 ttg ttg eta gee eat gga get gae ceg act ett aaa aat cag Lou Leu Leu Ala His Gly Ala Asp Pro Thr Leu Lys Asn Gin 985 990 995 eaa aea ect tta gat tta gtt tea gca gat gat gte age get Gin Thr Pro 1.eu Asp Leu Vai Ser Ala Asp Asp Vai Ser Ala 1000 1005 1010 aea gea gee atg eec eca tet get etg ccc tet tgt tae aag Thr Ala Ala Met Pro Pro Ser Ala Leu Pro Ser Cys Tyr Lys 1015 1020 1025 gtg etc aat ggt gtg aga age eca gga gee act gea gat get Val Leu Asn'Gly Val Arg Ser Pro Gly Ala Thr Ala Asp Ala 1030 1035 1040 tea ggt cea tet age eca tea age ett tet gca gee age agt Ser Gly Pro Ser Ser Pro Ser Ser Lou Ser Ala Ala Ser Ser 1050 1055 aac tta tet ggg agt ttt tea gaa etg tet tea gta gtt agt Asn Leu Sor Giy Ser Phe Ser Giu Leu Ser Ser Val Val Ser 1065 1070 1075 gga aca gag ggt get tee agt ttg gag aaa aag gag gtt eca Gly Thr Giu Gly Ala Ser Ser Leu Glu Lys Lys Glu Val Pro 1080 1085 1090 gat ttt age ata act eaa tte gta agg aat ctt gga ett gag Asp Phe Ser Ile Thr Gin Phe Val Arg Asn Leu Gly Leu Glu 1095 1100 1105 atg gat ata ttt gag aga gaa eag ate act ttg gat gta tta Met Asp Ile Phe Giu Arg Glu Gin Ile Thr Leu Asp Val Leu 1110 1115 1120 atg ggg eae aag gag etg aag gag att gga ate aat get tat Met Giy His Lys Glu Leu Lys Giu Ile Gly Ile Asn Ala Tyr 1130 1135 agg eac aaa eta att aaa gga gte gag aga ett ate tee gga Arg His Lys Leu Ile Lys Gly Val Giu Arg Leu Ile Ser Gly 1145 1150 1155 ggt ett. aac eca tat tta act ttg aac ace tet ggt agt gga Gly Lou Asn Pro Tyr Lou Thr Leu Asn Thr Ser Gly Ser Gly 1160 1165 1170 ett ata gat etg tet cet gat gat aaa gag ttt eag tet gtg Lou Ile Asp Leu Ser Pro Asp Asp Lys Glu Phe Gin Ser Vai 1175 1180 1185 3069 3117 3165 3213 3261 3309 3357 3405 3453 3501 3549 3597 3645 3693 3741 3789 eaa Gin aca Thr gag gaa gag atg caa agt aca gtt cga gag Giu Giu Giu Met Gin Ser Thr Val Arg Giu 1190 1195 cac aga gat gga ggt cat His Arg Asp Gly Gly His 1200 3837 gca ggt gga arc ttc aac aga tac aat art crc sag art cag aag gtt Ala Giy Gly Ile Phe Asn Arg Tyr Asn Ile Leu Lys Ile Gin Lys Val 1205 1210 1215 tgt aac aag aaa cra tgg gas aga tac act cac cgg aga aaa gaa gtt Cys Asn Lys Lys Leu Trp Glu Arg Tyr Thr His Arg Arg Lys Giu Vai 1220 1225 1230 1235 tct gaa gaa aac cac aac cat gcc aat gaa cga. atg cra trt cat ggg Ser Glu Glu Asn His Asn His Ala Asn Glu Arg Met Leu Phe His Gly 1240 1245 1250 rcr ccr, rtt gtg Ser Pro Phe Val 1255 gcg tac ata ggt Ala Tyr Ile Gly 11270 tct tcc aaa agc Ser Ser Lys 5cr 1285 aat gca. at Aen Ala Ile arc cac Ile His 1260 aaa ggc ttt gar gas agg cat Lys Gly Phe Asp Giu Arg His 1265 ggt atg rtt gga gct Gly Met Phe Gly Ala 1275 aat caa rat gra tat Asn Gin Tyr Val Tyr 1290 ggc art tat ttt Gly Ile Tyr Phe 1280 gga att gga gga Gly Ile Gly Gly .1295 gct gaa aac Ala Glu Asn ggt act ggg Gly Thr Gly 3885 3933 3981 4029 4077 4125 4173 4221 4269 .4317 4365 4413 tgr cca gtt cac a gac aga tct Cys Pro Val His Lys Asp-Arg Ser 1300 1305 ctc ttt tgc cgg gta acc ttg gga Leu Phe Cys Arg Val Thr Leu Gly 1320 atg aas atg gca cat tct cct cca Met Lys Met Ala His Ser Pro Pro 1335 ccc agt gta sat ggc cta gca. tts Pro Ser Val Asn Gly Leu Ala Leu 1350 1355 tgt tac at Cys Tyr Ile 1310 aag tct ttc Lys Ser Phe 1325 tgc cac agg Cys His Arg ctg cag ttc Leu Gin Phe cag ctg Gin Leu 1315 agt gca Ser Ala 1330 ggr. Gly .340 9cr. Ala cat cac rca gtc act ggt agg His His Ser Val Thr Gly Arg 1345 gas tar gtr att. tac aga gga Giu Tyr Val Ile Tyr Arg Gly 1360 gsa cag 9cr tat Glu Gin Ala Tyr 1365 gaa ggt stg gtc Glu Gly Met Val 1380 cct gag tat tta att act tac cag art atg sgg cct Pro Glu Tyr Leu Ile Thr Tyr Gin le Met Arg Pro 1370 1375 gat g taastagtta ttttaagaas ctaarrccac Asp Gly 1385 tgaaccraaa atcatcsaag atcatcttgc ccscaggccr gactrgataa agctrraata tttaacagat gccarrccag scttgaaccr tttstatgtr tasrtttact satacaatac catttgtasa actgtaaata gtasaasaa tcrgrrttag atctarsctt catcttacat srgtrcagtt gttagrrggg csgcagtggc gtggcaaaag atgracagrg gttaaactgg atgcarrgsr tgtgttcttt agagcttttg sactgcagcg cgtcatgsrr aaagattgag ctcrscgttr gataaaaatg ttttctaaat gttgtctgta tctaacasac aaaacacagc tactagccca gtttacaa gagtgarct ttatcagatt tactcctrrg tgaacgaagr stttcctgrr crasattata tgtaatgccc atttacactg gtatttattt ttttttcara tacatrrgat taatttgcc ctgasaaaasa 4473 ttaacattcr 4533 ttttcagcac 4593 aacsgagtta 4653 rcaacagaaC 4713 aataCaattt 4773 acatrgcrrr 4833 tgtsttgttc 4893 tccagaggcr 4953 5002 <210> 133 <211> 1385 <212> PRT <213> Homo sapiens <400> 133 Met Trp Lys Leu Lys Thr Arg Thr Ile Ser Thr Val Arg Leu Pro Lys 1 5 10 Glu Cys Ala Arg Ser Glu Gin Asn Phe Gin Gly Leu Phe Phe Ser Val 25 Met Val Val Arg Lys Phe Ser Leu Giu Ser Pro Gly Leu Lys Thr Thr 40 Thr Thr Lys Asn Thr Ile Cys Arg Ilie Val Arg Leu Gin Gin Asn Pro 55 Pro Gin Arg Trp Arg Trp Asp Glu Ala Pro Ser Pro Ala Ala Giu Ala 70 75 Ser Arg Leu Thr Phe Pro Thr Asn Pro Ser Arg Arg Leu Ala Ser Arg 90 Asn Leu Pro Ser Arg Cys Pro Ala Thr Ala His Ala Arg Asp Asp Val 100 105 110 Thr Cys Ala Pro Gly Ala Gly Arg Ser Trp Gin Giu Leu Ala Gly Gly 115 120 125 Ala Leu Pro Ala Ser Ala Ala Ala Scr Phe Gln Asp Pro Asp Gly Gly 130 135 140 Phe Ala Leu Pro Pro Pro Pro Arg Gly Ser Arg Gly Ala Gly Ser Pro 145 150 155 160 Ala Arg Gly Ala Arg Gly Arg Gly His Gly Thr Ala Pro Asp Pro Val 165 170 175 Thr Ala Gly,8cr Gin Ala Ala Arg Ala Leu Ser Ala Ser Ser Pro Gly 180 185 190 Gly Leu Ala Leu Leu Leu Ala Gly Pro Gly Leu Leu Leu Arg Leu Leu 195 200 205 Ala Leu Leu Leu Ala Val Ala Ala Ala Arg Ile Met Ser Gly Arg Arg 210 215 220 Cys Ala Gly Gly Gly Ala Ala Cys Ala Ser Ala Ala Ala Glu Ala Val 225 230 235 240 Glu Pro Ala Ala Arg Glu Leu Phe Glu Ala Cys Arg Asn Gly Asp Val 245 250 255 Glu Arg Val Lys Arg Leu Val Thr Pro Glu Lys Val Asn Ser Arg Asp 260 265 270 Thr Ala Gly Arg Lys Ser Thr Pro iLeu His Phe Ala Ala Gly Phe Gly 275 280 285 Arg Lys Asp Val Val Glu Tyr Leu Leu Gin Asn Gly Ala Asn Val Gin 290 295 300 Ala Arg Asp Asp Gly Gly Leu Ile Pro Leu His Asn Ala Cys 5cr Phe 305 310 315 320 Gly His Ala Glu Val Val Asn Leu Leu Leu Arg His Gly Ala Asp Pro 325 330 335 Asn Lys Pro Pro 385 Leu Arg Asp 340 Lys Ile 355 Ile Arg Ala Lys Ser Ala 88- Asn Tyr Thr Pro Leu 345 Cys Ile Val Leu Leu 360 Asp Gly Arg Thr Ala 375 Leu Thr Gly Giu Tyr 395 GJly Asn Giu Giu Lys 410 Giu His 365 Asp Lys Met Ala 350 Giy Leu Asp Ala Ala Ala Ala Giu Leu Thr Pro Leu Asn Val Asn Cys His 420 Ala Ser Asp Gly A9gLys Ser Thr 425 430 Pro Leu Val 465 Leu Phe Ser Asn Leu 545 Ala, Phe Ser Gly2 Leu Leu 450 Pro Leu Thr Leu Lys 530 Ala Asp Lys Pro kla *His 435 Gin Leu Val Pro Leu 515 Ser Tyr Val His Tyr 595 Asn Let. HisE His Lys Leu 500 Leu Ala Giu Thr Pro 580 Pro Ile aAla *Gly *Asn His 485 His Ser Ile Phe Arg 565 Gin Lys Asn Gly Asp 455 Cl's Ala Arg Ala Gly Asn 490 Ile 445 Lys Giu Asp Gin Asp Thr Trp 495 Giu Ala Ala Ser Lys Asn Arg Val Giu Val Cys Tyr Giy Ala Asp Pro Asp Lys 550 Ile Thr Arg Glu Leu 535 Gly Lys His Lys Lys 615 520 Ala His Lys Glu Gin 600 Thr Pro Ser His Thr 585 Ile Lys Asp Thr Leu Leu 570 Al a Cys Giu Val Thr Pro Leu 555 Ser Leu Giu Phe Vai 635 Leu Gin 540 Gin Leu His Leu Leu 620 Glu Leu 525 Leu Ala Giu Cys Leu 605 Thr Val1 Asn Lys Ala Met Ala 590 Leu Pro Val Cys Giu Arg Vai 575 Ala Arg Leu Val His Arg Glu 560 Asn Ala Lys His Lys 640 Val Ala Ser Giu Lys Ala His Asn 625 .630 Leu Asp Asn 650 Leu Gly Gin Thr Ser Leu 655 His Leu Gin Thr Cys Arg Leu Leu Leu 665 670 Ser Tyr Gly 675 Cys Asp Pro Asn Ile Ile Ser Leu Gin 680 Phe Thr Ala Giu Gly Ile Leu Gin Met Gly Asn Giu Asn 690 695 Vai Gin Gin Leu Leu Gin 700 Ser 705 Ala Asn Leu Gly Asn Gly Asp Val Cys Arg Asp 740 Ser Glu Ala 710 Giu Thr Val 725 Ile Glu Gly Asp Arg Lys Lys Arg Gin -89- Gin Leu 715 Leu Cys 730 Leu Glu Ala Ala Lys 720 Thr Val Gin Ser Val 735 Pro Leu His Phe Ala 750 745 Ala Ala Al a 785 Gly Glu His Asp Asp 865 Lys Arg Val Lys Aspi 94S Asp Thr C Lys Gil Asj 770 Cys Ala Ala Gly Leu 850 Ala Lys His Ala Gly 930 Lal .4's ISn Tyr 755 )Val Ser Val Ala Ala 835 Val Ala Leu Ser Glu, 915 Gly Ala Trp LeuC 9 Gin G 995 Asn Arg Val Ser Val Val Glu Tyr Leu Leu Gin His Gly 760 765 Hii Ty2 Val Ala 820 Asp Lys Leu Ser rhr 900 ryr .,eu lia lia .ys '80 flu sAla r Gly *Asn 805 Lys Pro Asp Leu Ser Pro Leu Ile Leu Phe 965 Ala Gly c 79 Va Gl GI As 87 Pr Lei Pr L~e 95( rhi In rs Asp Lys Gly Gly Leu Val Pro Leu His Asn 775 780 *s Tyr Glu 1i Ala Asp .y Lys Tyr .r Lys Lys 840 y Asp Thr 855 p Ala Ala 0 o Asp Asn u His Leu ua Gin His 920 o Leu His 935 j Ile Lys 7Pro Leu Leu Leu Thr Pro 1000 *Ala Ala 1015 Leu AsnC VaJ Let Glu 825 Asn Asp Lys Val Ala 9505 Gly Asn Tyr His kila 985 LeOu 4et LAla Glu Leu Leu 795 Trp Lys Phe Thr 810 Ile Cys Lys Lou IArg Asp Giy Asn 845 Ile Gin Asp Leu 860 Lys Gly Cys Leu 875 Asn Cys Arg Asp 890 Ala Gly Tyr Asn Ala Asp Vai Asn 925 Ala Ala Ser Tyr 940 Asn Ala Cys Val 955 Giu Ala Ala Gin 970 His Gly Ala Asp Asp Leu Val Ser I 1005 Pro Pro Ser Ala I 1020 Val Arg Ser Pro G 1035 Val Pro Leu 830 Thr Leu Al a Thr Asn 910 Ala Gly kisn Lays ?ro 990 fly *Lys His 800 Leu His 815 *Leu Gin Pro Leu Arg Gly Arg Val 880 Gin Gly 895 Leu Glu Gin Asp His Val Ala Thr 960 Gly Arg 975 Thr Leu Asp Asp Pro Ser Ala Thr 1040 Val Ser Ala Leu Leu Thr 1010 Cys Tyr 1025 Ala Asp Gin Val 1030 Leu Ser Ser Gly Pro Ser Ser Pro Ser 5cr 1045 1050 Leu Ser Ala 1055 Ala Ser Ser Leu Asp Asn Leu 1060 Ser Gly Ser Phe 1065 Ser Giu Leu Ser Ser 1070 If Val Val Ser Ser Ser Gly Thr Glu Gly Ala Ser Ser Leu Glu Lys Lys C 1075 1080 1085 Glu Val Pro Gly Val Asp Phe Ser Ile Thr Gln Phe Val Arg Asn Leu 1090 1095 1100 Gly Leu Glu His Leu Met Asp Ile Phe Glu Arg Glu Gln Ile Thr Leu 1105 1110 1115 1120 Asp Val Leu Val Glu Met Gly His Lys Glu Leu Lys Glu Ile Gly Ile 1125 1130 1135 Asn Ala Tyr Gly His Arg His Lys Leu Ile Lys Gly Val Glu Arg Leu C1140 1145 1150 Ile Ser Gly Gin Gin Gly Leu Asn Pro Tyr Leu Thr Leu Asn Thr Ser 1155 1160 1165 SGly Ser Gly Thr Ile Leu Ile Asp leu Ser Pro Asp Asp Lys Glu Phe 1170 1175 1180 Gin Ser Val Glu Glu Glu Met Gin Ser Thr Val Arg Glu His Arg Asp 1185 1190 1195 1200 Gly Gly His Ala Gly Gly Ile Phe Asn Arg Tyr Asn Ile Leu Lys Ile 1205 1210 1215 Gin Lys Val Cys Asn Lys Lys Leu Trp Glu Arg Tyr Thr His Arg Arg 1220 1225 1230 Lys Glu Val Ser Glu Glu Asn His Asn His Ala Asn Glu Arg Met Leu 1235 1240 1245 Phe His Gly Ser Pro Phe Val Asn Ala Ile Ile His Lys Gly Phe Asp 1250 1255 1260 Glu Arg His Ala Tyr Ile Gly Gly Met Phe Gly Ala Gly Ile Tyr Phe 1265 1270 1275 1280 Ala Glu Asn Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile Gly Gly 1285 1290 1295 Gly Thr Gly Cys Pro Val His Lys Asp Arg Ser Cys Tyr Ile Cys His 1300 1305 1310 Arg Gln Leu Leu Phe Cys Arg Val Thr Leu Gly Lys Ser Phe Leu Gin 1315 1320 1325 Phe Ser Ala Met Lys Met Ala His Ser Pro Pro Gly His His Ser Val 1330 1335 1340 Thr Gly Arg Pro Ser Val Asn Gly Leu Ala Leu Ala Glu Tyr Val Ile 1345 1350 1355 1360 Tyr Arg Gly Glu Gin Ala Tyr Pro Glu Tyr Leu Ile Thr Tyr Gin Ile 1365 1370 1375 Met Arg Pro Glu Gly Met Val Asp Gly 1380 1385 <210> 134 <211> 4992 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (876)..(4373) -91- <400> 134 ggaaagagta atttcttta ttgagaagtg aagagacaaa aaaacacgga tttcaagggc cttaaaacaa ccgcaaagat tttcccacaa actgcgcacg gggcct tgc ctccgeegce gccatgggac cgtettctcc tggcgctgtt attgatcaga gccateectc caattggagt caacttccat gaetgttcgg tt ttgggggc gtttacaaga gtaaaaaaaa caatttccac tctttttcag caacaacaaa ggcggtggga acccttcgcg cgcgggacga agcttccgcc, gcggggcagc tgcgccggat ggggggcctc gctggCtgtg agttcatcca aaettetatt aacaacaaca cggaaaagaa agtaagactt tgtaatggta aaacacaata cgaagcccct Ccgcctcgct cgtcacgtgc gccgcgtcgt cggggggcag ccggtgacag gccctcctgc acaacaacaa atcteeeagg ccaaaagaat gtgagaaagt tgcagga tcg tctcccgceg agccgaaacc gctcecgggg ttcaggaccc ggagcccage cagggagcca tcgcggggc aaacggcaac agcagttgcg agaaaggga t gtgeaagatc t cagcctgga ttcggcttca ccgaagcctc tgcccagccg ctggacggag ggacggcgga gaggggcgcg agcggcccgg ggggctcetg :tagttcactt 120 1gaggaaagaa 180 gtggaagctg 240 cgagcaaaac 300 aagcccaggg 360 gcagaaccca 420 tcgcctcaca 480 gtgCCCggcc 540 ciggcaggag 600 ttcgegctgc 660 CgtgggCgeg 720 gccctgagcg 780 ctCeggttgc 840 ege tgc 893 Arg Cys gcggcggcca ggate atg teg ggt egc Met Ser Gly .Arg 1 9cc ggc ggg gga geg gcc tgc Ala Gly Gly Gly Ala Ala Cys ccg gcc 9CC cga Pro Ala Ala Arg cga gtc aag agg Arg Val Lys Arg gag ctg ttc Glu Leu Phe ctg gtg acg Leu Val Thr tcc ace ceg Ser Thr Pro gcg agc 9CC gcg gec gag gec gtg gag Ala Ser Ala Ala Ala Giu Ala Val Glu gag gcg tge cgc aac 999 gac gtg gaa Glu Ala Cys Arg Asn Gly Asp Val Glu 30 ect gag aag gtg aac age ege gae acg Pro Giu Lys Val Asn Ser Arg Asp* Thr gcg ggc Ala Gly agg aaa, Arg Lys Ctg cac tte Leu His Phe gca ggt ttt Ala Gly Phe gea aat gte Ala Asn Val gac gta gtt Asp Vai Val ttg ett cag Leu Leu Gln 999 C99 Gly Arg caa gea Gin Ala tit ggt Phe Gly 941 989 1037 1085 1133 1181 1229 1277 1325 egt gat gat Arg Asp Asp cat get gaa His Ala Glu 105 get cga gat Ala Arg Asp ett att ect Le Ile Pro cat aat gea His Asn Ala tge tet Cys Ser 100 gte aat etc Val Asn 1,eu ttg cga cat ggt Leu Arg His Gly gac ccc aat Asp Pro Asn gea. att ass Ala Ile Lys ast tgg aat Asn Trp Asn 120 995 aag Gly Lys 135 tat act Tyr Thr 125 att gtg Ile Val cct etc eat Pro Leu His etg tta cag Leu Leu Gin 145 att gat gtt Ile Asp Val eat gga get gag His Gly Ala Giu eca Pro ISO acc atc cga Thr Ile Arg tct gcc aaa Ser Ala Lys gaa agt gcc Glu Ser Ala 185 cca tta aat Pro Leu Asn 200 tta cat ttg Leu His Leu 215 ctg caa cat Leu Gin His cca tta cac Prol1eu His ttg gtc aag Leu Val Lys 265 aa t Asn gca Ala 170 agg Arg gtc Val gca Al a gga Gly aat Asn 250 cat His a c Th 9ts Val ag t Ser ac Asn gca Ala gct Ala 235 C Ala ggt Gly *gat Asp ;ctt Leu ggc Gly tgc Cys gga Gly 220 gat Asp tgt Cys gcc Ala gga Gly act Thr aat Asn cac His 205 tat Tyr gtc Val tct 3er :gt :ys agg Arg ggt Gly gaa Glu 190 gca Ala sac Asn cat His tat Tyr gta Val a ca Thr gsa Giu 175 gaa Giu agt Ser aga Arg gct Ala 9gt Gly 255 iat -92- gca ttg Ala Leu 160 tat aag Tyr Lys ass atg Lys Met gat ggc Asp Gly gta sag Val Lys 225 aas gat Lys Asp 240 cat tat His Tyr gca atg Ala Met gat tta Asp Leu aaa gat Lys Asp atg gct Met Ala 195 aga aag Arg Lys 210 stt gta Ile Val ass ggt Lys Gly gaa gta Glu Val gac ttg ksp Leu 275 gca Ala gas Giu 180 cts Leu tca Ser cag Gin gat Asp act Thr 260 tgg rrp, *gat cca Asp Pro 165 ctc tta Leu Leu ctc aca Leu Thr act cca Thr Pro ctg tta Leu Leu 230 ctg gta Leu Val 245 gsa ctt Glu Leu caa ttc Gin Pixe 270 1373 1421 1469 1517 1565 1613 1661 1709 1757 1805 1853 1901 1949 1997 2045 2093 act cct ctt cat Thr ctt Leu 295 aaa Lys gca Ala gat Asp sag Lys cca Pro 375 gca Ala Pro 280 ctc Leu agt Ser tat Tyr gtt Val cat His 360 tat Tyr sac Leu tta Leu gct Ala gas Glu act Thr 345 cct Pro ccc Pro atc His agt Ser ata Ile ttt Phe 330 cga Arg caa Gin ass Lys at gag gca gct Giu Ala Ala 285 tct sag sac agg gtt gas gta tgt tct Ser Lys Asn Arg Va]. Glu Val Cys- Ser 290 tat Tyr gac Asp 315 ass Lys atc Ile aca Thr aga Arg gaa Giu 395 ggt Gly 300 t tg Leu ggc Gly ass Lys cat His sag Lys 380 sag Lys gca Ala gct Ala cac His aas Lys gas Giu 365 caa Gin act Thr gac Asp ccc Pro tcg Ser cat His 350 aca Thr. ata Ile aas Lys cca Pro aca Thr t tg Leu 335 ctc Leu gca Ala tgt Cys gaa Glu a ca Thr cca Pro 320 ctg Leu tct Ser t tg Leu ga Glu ttc Phe 400 ctg Leu 305 cag Gin caa Gin ctg Leu cat His ctg Leu 385 t tg CLeu ctc Leu t ta Leu gct Ala gas Glu tgt Cys 370 t tg Leu act Thr aat IAsn ass Lys gca Ala atg Met 355 gct Ala cta Leu cct Pro tgt cac sat Cys His Asn 310 gas aga tta Glu Arg Leu 325 cga gas gct Arg Glu Ala 340 gtg sat ttc Val Asn Phe gct gca tct Ala Ala Ser 595 ass gga Arg Lys Gly 390 ctg cac gtg Leu His Val 405 Asn Ile Asn gcs tct gag Ala Ser Glu gct cat sat gat gtt gtt gsa gta Ala His Asn Asp Val Val Giu Val 415 gtg gtg ass cat Val Val Lys His 420 2141 gaa gca aag gtt aat gct ctg Giu Ala Lys Val Asn Ala Leu 425 -93- aat ctt ggt Asn Leu Gly cag act tct cta cac Gin Thr Ser Leu His 435 aga Ary tat Tyr 455 cag Gin tta Leu gga Gly tgc Cys gyg Gly 535 gat Asp tgt Cys gca Ala gca Ala ggt Gly. 615 ctt ILeu gca Ala aag Lys gct Ala 440 gyg Gly aig Met gy t Gly gat Asp aga Arg 520 tat Tyr gtg Val tct Ser gta Val gca Ala 600 gca Ala gtt Val gct Ala ttg LJCu gca *Ala tyt *Cys gga Gly aat Asn gtc Val 505 gac Asp aac Asn cat His tat Tyr gtt Val 585 gca Ala gac Asp aaa Lys ttg Leu tct 5cr 665 tat Tyr gat Asp aat Asn tca Ser 490 gaa Giu at t Ile aga Arg gct Ala gga Gly 570 aat Asn aaa Lys cct Pro gat S Asp C cta 9 Leu 1 650 tct c Ser P tyt cys cct Pro gaa Glu 475 gag Giu act Thr gaa Giu gtg Val aaa Lys 555 cat His gta Val jga ica [hr ;ga fly Jat L5p .ct ~ro, gyt Gly aac Asn 460 aat Asn gca Ala gta Val ggg Gly tcc Ser 540 gat Asp tat Tyr gct Ala aaa Lys aaa Lys 620 gat Asp gct 5 Ala,; gat a Asp cat cta caa acc His 445 att Ile gta Val gac Asp aaa Lys cgt Arg 525 gtg Val aaa Lys gaa Glu gat Asp tat ryr 605 iaa 4's ica rhr ;cc la iat snf iLeu ata Ile cag Gin aga Arg aaa Lys 510 cag Gin gtg Val gga Gly gtt Val ttaI Leu 590 gaa Glu aac i Asn gat a AspI aag a Lys 1 6 gta a Vail~ 670 tc( Se~ cai Glr caa Gir 495 ctg Leu tct Ser gaa Giu cfly gca Ala 575 tgg rrp Itt Ie krg Itt :le Lag Jys 55 Lat Lsn ni Thr :ctt r Leu ctc Leu 480 Ittg Leu tgt Cys aca Thr tat Tyr ctt Leu 560 gaa Giu aaa Lys tgc Cys gat 5 Asp C caa g 640 ggt t Gly C tgc c Cys tyc Cys cag Gin 465 ctc Leu ctg Leu act Thr cca Pro ctg Leu 545 9ta Val :tt Lieu ttt Phe iaa 4's ;ga 25 jat Isp :gt :ys 9gc S xrg cg Arc 451 Gil cae Glr gaa Gl. gtt Val ctt Leu 530 Cta Leu cct Pro ctt Leu aca Thr ct t Leu 510 aat k.sn :tg eu :ta ,eu jat ~sp ccta ctc 9 Leu Leu 0 ttt act ~Phe Thr Igag ggt 1Giu Gly gct gca Ala Ala 500 cay agt Gin .Ser 515 cat. ttt His .Phe cay -cat Gin His ttg cac Leu His gtt aaa Val Lys 580 cct tta Pro Leu 595 ctg ctc LeU Leu act cctI Thr Pro ctt agg Leu Arg gcc aga S Ala Arg A 660 acc caa g Thr Gin C 675 c tg Leu gct Ala atc Ile 485 aag Lys gtc Val gca Ala gga Gly aa t Asn 565 cat His cat His cay Gln :tg eu Iga ;iY ;tg ~al agc Ser *tta Leu 470 *tca Ser gct Ala aac Asn gct Ala gct Ala 550 gca Ala gga Gly gaa Glu cat His gat Asp 630 gat Asp aag Lys aga Arg 2189 2237 2285 2333 2381 2429 2477 2525 2 573 2621 2669 2717- 2765 2813 2861 2909 2957 cat tca His Ser 680 aca cct tta cat Thr Pro Leu His gca yct gyt tat Ala Ala Gly Tyr aat aat tta gaa gtt Asn Asn Leu Glu Vai 690 gca Al a 695 gga Gi y gta Val aaa Lys cag Gin aat Asn 775 age Ser gag Glu 99a Gly gca Ala tgg Trp ctt Leu 760 cag Gin gCt Ala tat Tyr ctt Leu get Ala get Ala 745 tgt Cys gaa Glu Ct t Leu t tg Leu att Ile eta Leu 730 tte Phe get Ala gga Gly Ctg Leu t ta Leu ect Pro 715 eta Leu aca Thr t tg Leu caa Gin aca Thr caa eac Gin His 700 tta eat Leu His ata aag Ile Lys cet ttg Pro Leu ttg eta Leu Leu 765 aca cet Thr Pro 780 gca gee Ala Ala gga Gly aa t Asn tat Tyr eac His 750 gee Ala tta Leu atg get Ala gea Ala aat Asn 735 gaa Glu cat His gat Asp -94- gat gtg Asp Val 705 gea tet Ala Ser 720 gea tgt Ala Cys gea gee Ala Ala gga get Gly Ala tta gtt Leu Val 785 aat Asn tac Tyr gte Val eaa Gin gac Asp 770 tea Ser get gee eaa Ala Gin ggg eat Gly His aat gee Asn Ala 740 aag gga Lys Gly 755 eeg act Pro Thr gea gat Ala Asp. etg c Leu Pro gac Asp gta Val 725 aeg Thr ega Arg Ct t Leu gat Asp tet Ser 805 aaa Lys 710 ga t Asp gac Asp aca Thr aaa Lys gte Val 790 tgt Cys M1et Pro Pro Ser 795 800 tac aag ect Tyr Lys Pro gat get etc Asp Ala Leu 825 ggt gtg aga age eca gga gee act gca Gly Val Arg Ser Pro Gly Ala Thr Ala 815 820 3005 3053 3101 3149 3197 3245 3293 3341 3389 3437 3485 3533 3581 3629 3677 3725 tet age eea tea age agt Ser Ser 840 gtt agt Val Ser 855 gtt eca Val Pro ett gag Leu Glu gta tta Val Leu get tat Ala Tyr 920 tee gga Ser Gly 935 ett gac aac tta tct Leu Asp tea agt Ser Ser gga gta Gly Val cac eta His Leu 890 gtt gag Vai Giu 905 gga eat Gly His caa caa Gin Gin Leu aea Thr 860 ttt Phe gat Asp ggg Gly eac His et t Leu 940 Ser 830 ggg Gly ggt Gly ata Ile ttt Plie aag Lys 910 eta Leu cca Pro Ser Pro Ser age ett tet gca gee Scr Leu Ser Ala Ala agt Ser get Ala act Thr gag Giu 895 gag Glu att Ile tat Tyr ttt Phe tee Ser caa Gin 880 aga Arg etg Leu aaa Lys t ta Leu tea Ser agt Ser 865 tte Phe gaa Glu aag Lys gga Gly act Thr 945 gaa Glu 850 ttg Leu gta Val eag Gin gag Giu gte Val 930 ttg Leu etg tet tea Leu Ser Ser gag aaa aag Glu Lys Lys agg aat ett Arg Asn Leu 885 ate act ttg Ile Thr Leu 900 att gga ate Ile Giy Ile 915 gag aga ett Giu Arg Leu aac ace tet Asn Thr Ser gta Val gag Glu 870 gga Gly gat Asp aat Asn ate Ile ggt Gly 950 agt gga aea att ett Ser Gly Thr Ile Leu 955 ata gat ctg tet Ile Asp Leu Ser cet gat gat aaa gag ttt eag Pro Asp Asp Lys Giu Phe Gin 960 965 3773 tct gtg gag gaa gag atg caa agt aca gtt cga gag cac aga gat 99a Ser Val Giu Giu Giu Met Gin Ser Thr Vai Arg Giu His Arg Asp Gly 970 97S 980 ggt cat gca Gly His Ala 985 aag gtt Lys Val 1000 gaa gtt Giu Val 1015 cat ggg His Gly tgt Cys tct Ser ggt gga atc ttc Gly Gly Ile Phe aac aag aaa cta Asn Lys Lys Leu 1005 gaa gaa aac cac Giu Glu Asn His aga tac aat att ctc aag att cag Arg Tyr Asn Ile Leu Lys Ile Gin gaa aga tac act Giu Arg Tyr Thr 1010 cat gcc aat gaa His Ala Asn Giu aac Asn tct cct ttt Ser Pro Phe 1035 1020 gtg Val aat gca att Asn Ala Ile atc Ile 1040 gga Gly 1025 cac His cac cgg aga aaa His Arg Arg Lys cga atg cta ttt Arg Met Leu Phe 1030 ggc ttt gat gaa Gly Phe Asp Giu 1045 att tat ttt gct aaa Lys agg cat gcg tac ata ggt Arg His Ala Tyr Ile Gly 1050 gaa aac tct tcc aaa agc Giu Asn Ser Ser Lys Set~ 1065 act ggg tgt cca gtt cac Thr Gly Cys Pro Val His 10801 cag ctg ctc ttt tgc cgg Gin Leu Leu Phe Cys Arg 1095 1100 agt gca atg aaa atg gca Ser Ala Met Lys Met Ala ggt atg Gly Met ttt Phe .055 gct ggc Ala Gly aat caa tat Asn Gin Tyr 1070 gta Val 1060 tat gga att .gga gga ggt Tyr Gly Ile Gly Gly Gly 1075 aaa gac aga Lys Asp Arg .085 tct tgt tac Ser Cys Tyr 1090 att tgc cac agg Ile Cys His Arg gta Val cat His acc ttg gga aag Thr Leu Gly Lys 1105 tct cct cca ggt Ser Pro Pro Gly 1120 tct ttc ctg cag Ser Phe Leu Gin cat cac-tca gtc His His Ser Val 1125 ttc Phe .110 act Thr 3821 3869 3917 3965 4013 4061 4109

4157. 4205 4253 4301 4349 4403 4463 4523 4583 4643 4703 4763 4823 4883 4943 1115 ggt agg ccc Gly Arg Pro agt Ser 1130 *gta -Val aat ggc Asn Gly cta Leu aga gga gaa cag gct tat cct gag Arg Gly Glu Gin Ala Tyr Pro Giu 1145 1150 agg cct gaa ggt atg gtc gat gga Arg Pro Giu Gly Met Val Asp Gly 1160 1165 gca tta gct gaa tat gtt att tac Ala Leu Ala Giu Tyr Val Ile Tyr 1135 1140 tat tta att act tac cag att atg Tyr Leu Ile Thr Tyr Gin Ile Met 1155 taaatagtta ttttaagaaa ctaattccac tgaacctaaa atcatcttgc gacttgataa tttaacagat acttgaacct taattttact catttgtaaa gtaatataaa atctatactt atcatcaaag ccacaggcct agctttaata gccat tccag tttatatgtt aatacaatac actgtaaata tctgttttag catcttacat cagcagtggc gtggcaaaag atgtacagtg gttaaactgg atgcattgat tgtgttcttt agagcttttg aactgcagcg cgtcatgatt ctctacgttt gataaaaatg ttttctaaat gttgtctgta tctaacaaac aaaacacagc tactagccca gtttacaaaa gagtgatctt tactcctttg tgaacgaagt atttcctgtt ctaaattata tgtaatgccc atttacactg gtatttattt ttttttcata tacatttgat ctgaaaaaaa ttaacattct ttttcagcac aacagagtta tcaacagaac aatacaattt acattgcttt tgtattgt tc tccagaggct -96- atgttcagrt gttagttggg aaagattgag ttatcagatt taatttgcc <210> 135 <211> 1166 c212> PRT c213, Homo sapiens c400, 135 Met Ser Gly Arg Arg Cys Ala Gly Gly Gly Ala Ala Cys Al 1 5 10 Ala Ala Glu Ala Val Glu Pro Ala Ala Arg Glu Leu Phe Gl 25 3 Arg Asn Gly Asp Val Glu Arg Val Lys Arg Leu Val Thr Pr 40 Val Asn Ser Arg Asp Thr Ala Gly Arg Lys Ser Thr Pro Le 55 4992 aa uu .0 u Ala Ala Gly Phe G) Gly Asn His His Gln 145 Leu Lys Met Gly Lys 225 Asp Tyr I Met Ala Ala Gly Glu 130 His Asp Lys Met Arg 210 Ile Lys Glu ksp Asn Cys Ala 115 Ala Gly Leij Asp Ala 195 Lys Val Gly. Val Leu 275 Val Ser 100 Asp Ala Ala Ala Glu 180 Leu Ser Gin Asp Thr 260 rrp, Gln Phe Pro Ile Glu Asp 165 Leu Leu Thr Leu Leu 245 Glu Gin Arg Lys Asp 70 Ala Arg Asp Gly His Ala Asn Ala Arg 120 Lys Gly Lys 135 Pro Thr Ile 150 Pro Ser Ala Leu Glu Ser Thr Pro Leu 200 Pro Leu His 215 Leu Leu Gin i 230 Val Pro Leu I Leu Leu Val Phe Thr Pro I 280 Val Val Glu Tyr Leu Ile Asp Val Arg Lys Ala 185 Asn Lieu His iis ys 165 Asn Ala 170 Arg Val Ala Gly Asn 250 His Thr 155 Val Ser Asn Ala Ala 235 Ala Gly Leu Asn Asn Cys 140 Asp Leu Gly Cys Gly 220 Asp Cys Ala Ile Val Leu Leu Gly Thr Asn His 205 Tyr Val 3er -ys Arg Gly Glu 190 Ala Asn His Tyr Val 270 Thr Glu 175 Glu Ser Arg Ala Gly 255 Asn Ala 160 Tyr Lys Asp Val Lys 240 His Ala Leu Pro Leu 110 Thr Ser Ala Glu His Gln Leu Leu Pro Ala Cys Lys Phe Asn His Arg Leu .eu His Glu Ala Ala Ser Lys Asn 285 Arg Val 290 Glu Val Cys Ser Leu Leu Leu Ser 295 Tyr Gly Ala Asp Pro Thr 300 Leu Asn Cys His Asn Lys 310 Ser Ala Ile Asp Leu 315 Ala Pro Thr Gin Gin Leu His Leu 385 Leu Glu Gly Cys Gin 465 Leu Leu Thr Pro I Leu L 545 Val P Leu L Phe T Lys L 6 Gly A 625 Asp L Cys L( Arg A! Le Al Gl Cy 37 Le Th Va G1l Ar 313 Glr 31rn 3lu Val jeu -eu 'ro eu hr eu 10 sn eu eu sp eu Ly .a Al .u Me 's Al 0 u Le r Pr 1 Va n Th 435 g Lei 0 y Phe 1 Glu SAla Gin 515 His Gin Leu Val Pro 595 Leu Thr Leu Ala Thr 675 's Glu Arg Leu 325 a Arg Glu Ala 340 t Val Asn Phe 5 a Ala Ala Ser u Arg Lys Gly 390 o Leu His Val 405 I Val Lys His 420 r Ser Leu His 5 SLeu Leu Ser SThr Ala Leu 470 SGly Ile Ser I 485 Ala Lys Ala C 500 Ser Val Asn C ,Phe Ala Ala G 5 His Gly Ala A 550 His Asn Ala C 565 Lys His Gly A 580 Leu His Glu A Leu Gin His G 6: Pro Leu Asp L 630 Arg Gly Asp A] 645 Arg Val Lys L) 660 Gin Gly Arg Hi A: A! L Pr 37 Al Al Gl Ar ry 45 jel 3 ys ily 35 spF ys la la ly 15 eu La ys .S la Tyr G1 sp Val Th 34 ys His Pr 360 o Tyr Pr 5 .a Asn Il a Ser GlI u Ala Lys 42 g Ala Ala 440 r Gly Cys 5 n Met Gly u Gly Asn y Asp Val 505 s Arg Asp 520 STyr Asn Val His Ser Tyr Val Val 585 Ala Ala 600 Ala Asp Val Lys Ala Leu Leu Ser 665 Ser Thr 680 -97- u Phe Lys Gly His Ser Leu Leu 330 335 r Arg Ile Lys Lys His Leu Ser 5 350 o Gin Thr His Glu Thr Ala Leu 365 o Lys Arg Lys Gin Ile Cys Glu 380 e Asn Glu Lys Thr Lys Glu Phe 395 400 U Lys Ala His Asn Asp Val Val 410 415 s Val Asn Ala Leu Asp Asn Leu 5 430 STyr Cys Gly His Leu Gin Thr 445 SAsp Pro Asn Ile Ile Ser Leu 460 Asn Glu Asn Val Gin Gln Leu 475 480 Ser Glu Ala Asp Arg. Gin Leu 490 495 Glu Thr Val Lys Lys Leu Cys 510 Ile Glu Gly Arg Gin Ser Thr 525 Arg Val Ser Val Val Glu Tyr 540 Ala Lys Asp Lys Gly Gly Leu 555 560 Gly His Tyr Glu Val Ala Glu 570 575 Asn Val Ala Asp Leu Trp Lys 590 Lys Gly Lys Tyr Glu Ile Cys 605 Pro Thr Lys Lys Asn Arg Asp 620 Asp Gly Asp Thr Asp Ile Gin 635 640 Leu Asp Ala Ala Lys Lys Gly 650 655 Ser Pro Asp Asn Val Asn Cys 670 Pro Leu His Leu Ala Ala Gly 685 -98- Tyr Asn Asn Leu Giu Val Ala Glu Tyr Leu 690 Leu Gin His Gly Ala Asp 700 695 Vai Asn Ala Gin Asp Lys Gly Gly Leu Ile Pro Leu His 705 Ser Tyr Cys Val Ala Gin Ala Asp 770 Val Ser 785 Ser Ala Ser Pro Ser Ser Ser Giu 850 Ser Leu 865 Phe Val Giu Gin Lys Glu Gly Val 930 Thr Leu 945 Asp Asp Arg Glu Asn Ile 1 Tyr Thr I 1010 715 Asn Ala Ala 720 Gi As2 Lys 755 Pro Ala Leu Gly Leu 835 Leu Giu Arg Ile, Ile 915 Glu ksn .sys fis .eu 'is His Ala 740 Gly Thr Asp Pro Ala 820 Ser Ser Lys Asn Thr 900 Gly Arg Thr Giu Arg 980 Lays Arg3 Val Asp Val Ala Ala Leu Leu Ile Lys Tyr Asn Ala 72! Th2 Ar5 Let Asp Ser 805 Thr Ala Ser Lys Leu 885 Leu Ile Leu Ser Phe 965 ksp Ile I-rg 7Asp Thr Lys Val 790 Cys Ala Ala Val Giu 870 Gly Asp Asn Ile Gly 950 Gin Gly Gin Lys Lys Trp Aia 745 Gin Leu Cys 760 Asn Gin Giu 775 Ser Ala Leti Tyr Lys Pro Asp Ala Leu 825 Ser 5cr Leu 840 Val Scr Ser 855 Val Pro Gly Leu Giu His Val Leu Val 905 Ala Tyr Gly 920 Scr Gly Gin 935 Ser Gly Thr *Ser Val Glu 3'. 735 Phe TI Ala LI Gly Leu Gin 8i0 Scr Asp Ser Val Leu 890 Glu His Gin Ile G1u 970 Gly C ksn .7lu G T1 7! Va Se Gi As 87 Me Me ;ii hr Pro Leu eu Leu Leu 765 Ln Thr Pro 780 ~r Ala Ala 1 Leu Ass *r Gly Pro Leu Ser 845 y Thr Glu 860 p Phe Ser 5 t Asp Ile t Gly His SHis Lys 925 y Leu Asn 940 u Ile Asp I 5 u1 Met Gin S 'le Phe A 9 iLys Leu 'T 1005 Asn His A 1020 Val Asn A Hi, Ala Met Gly Ser 830 Gly Gly Ile Phe Lays 910 'ro eu er ~sn rp .sn 3G1i IHi! Asl *Prc *Val 815 *Ser Ser Ala Thr Giu 895 Giu Ile Tyr Ser Thr 975 Arg Giu His *1 Ala *Gly ,Leu Pro 800 *Arg *Pro *Phe Ser Gin 880 Arg Leu Lys Leu Pro 960 Val Tyr Arg Ala Gly His Lys Val i1000 Giu Val 2 C 1015 Ass Giu Arg 1025 His Lys Gly Met Leu Phe His Gly Ser Pro Phe 1030 Phe Asp Glu Arg His 1045 1035 1040 Ala Tyr Ile Gly Giy Met Phe Gly 1050 1055 Ala Gly Ile Tyr Phe Ala Glu Asn Ser Ser Lys Ser Asn Gin Tyr Val 1060 1065 1070 Tyr Gly Ile Gly Gly Gly Thr Gly Cys Pro Val His Lys Asp Arg Ser 1075 1080 1085 Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg Val Thr Leu Giy 1090 1095 1100 Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala His.Ser Pro Pro 1105 1110 1115 1120 Gly His His Ser Val Thr Gly Arg Pro Ser Vai Asn Gly Leu Ala Leu 1125 1130 1135 Ala Giu Tyr Val Ile Tyr Arg Gly Giu Gin Ala Tyr Pro Glu Tyr Leu rl1140 1145 1150 Ile Thr Tyr Gin Ile Met Arg Pro Glu Gly Met Vai Asp Gly 1155 1160 1165 <210> 136 c211> 3045 c212> DNA <213> Homo sapiens <220> <221> CDS <400> 136 atg gcg gag tct tcg gat aag cic tat cga gtc gag tac 9CC aag agc 48 Met Ala Glu Ser Ser Asp Lys Leu Tyr Arg Val Glu Tyr Ala Lys Scr 1 5 10 ggg C9C 9CC tct tgc aag aaa tgc agc gag agc atc ccc aag gac tcg 96 Gly Arg Ala 5cr Cys Lys Lys Cys Ser Giu Ser Ile Pro Lys Asp 25 ctc cgg atg gcc atc atg gtg cag tcg ccc atg ttt gat gga aaa gtC 144 Leu Arg Met Aia Ile Met Val Gin Ser Pro Met Phe Asp Gly Lys Val 40 cca cac tgg tac cac ttc tcc tgc ttc tgg aag gtg ggc cac tcc atc 192 Pro His Trp Tyr His Phe Ser Cys Phe Trp Lys Vai Gly His Ser Ile 55 cgg cac cct gac gtt gag gtg gat ggg ttc tct gag ctt cgg tgg gat 240 Arg His Pro Asp Val Glu Val Asp Gly Phie 5cr Glu Leu Arg Trp Asp 70 75 gac cag cag aaa gtc aag aag aca gcg gaa gct gga gga gtg aca ggc 288 Asp Gin Gin Lys Val Lys Lys Thr Aia Giu Ala Gly Giy Val Thr Gly 90 aaa gyc cag gat gga att ggt agc aag gca gag aag act ctg ggt gac 336 Lys Gly Gin Asp Gly Ile Gly Ser Lys Ala Glu Lys Thr Leu Gly Asp 100 105 110 ttt gCa gca gag tat 9CC aag tCC aac aga agt acg tgc aag ggg tgt 384 Phe Ala Ala Giu Tyr Ala Lye Ser Asn Arg Ser Thr Cys Lys Gly Cys 115 120 125 atg gag aag ata gaa aag ggc cag gtg cgc Ctg tcc aag aag atg gtg 432 Met Glu Lys Ile Giu Lys Gly Gin Val Arg Leu Ser Lye Lys Met Val 130 135 140 gac Asp 145 ggC Gly ag t Ser ccg Pro tgC Cys gcg Ala gag aag Giu Lys ttt gtc Phe Val agt cag Ser Gin cag cta Gin Leu 150 aac agg Asn Arg aag ggc Lys Gly ggc atg Gly Met gag gag Glu Glu ttc agc Phe Ser -100- att gac Ile Asp 155 ctg 99t Leu Giy 170 Ctc ctt Leu Leu tac cat Tyr H i CCC gag Pro Gil 175 gag gat Giu Asp 190 181 gaa gcc ctg aa( Giu Ala Leu Lyi 195 aaa ggc gat gac Lys Gly Asp Gi 210 aaa aaa gaa aaa Lys Lys Giu LyE 225 cag aac gac ctS Gin Asn Asp Leu tca act aat gac Ser Thr Asn Asp 260 185 ect Pro ttC Phe aag Lys 305 tgt Cys aag Lys cag Gin cct Pro tca Ser 385 tct Ser ggt Gly 290 agc Ser a tg Met. gaa Glu gac Asp ccg Pro 370 gca Ala ggg Gly 275 gcc Ala gat Asp gte Val t tc Phe cgt Arg 355 ccc Pro gat Asp gag Glu ctc Leu gcc Ala aag Lys cga Arg 340 a ta Ile tcc Ser aag Lys 3aag cag ctc 3Lys Gin Leu ;gtg gat gga iVal Asp Gly 215 igac aag gat Asp Lys Asp 230 1atc tgg aac le Trp Asn 245 ctg aag gag Leu Lys Glu tcg gcg atc 5cr Ala Ile ctt ccc tgc Leu Pro Cys 295 tat tac tgc Tyr Tyr Cys 310 aca cag aca Thr Gin Thr 325 gaa atc tctt Glu Ile 5cr ttc ccc cca Phe Pro Pro C aca gee tcg g Thr Ala 5cr A 375 cca tta tcc a Pro Leu Ser A cca gga Pro Gly 200 gtg gat Val Asp agt aag Ser Lys atc aag Ile Lys cta etc Leu Leu 265 ttg gac Leu Asp gtc Val gaa Glu ct t Leu gac Asp 250 atc Ile cga Arg aag Lys gtg Val gaa Giu 235 gag Glu ttc Phe gta Val agi Se~ gcS Alz 220 aaa Lys cta Leu aac Asn gct Ala 280 gag Glu act rhr ce Pro :ac [yr ;aa ;lu 60 pct lia .ac sn gaa Glu ggg Gly aac Asn ctc Leu 345 acc Thr cct Pro a tg Met *tgc Cys gac Asp cgg Arg 330 aag Lys agc 5cr gct Ala aag Lys gcc Ala 410 tcg ggt Ser Gly 300 gtc act Val Thr 315 aag gag Lys Glu aaa ttg Lys Leu gcc tcc Ala 5cr gct gtg Ala Val 380 atc ctg Ile Leu tgaa r Glu 205 aag Lys gcc Ala aag Lys aag Lys gat Asp 285 cag Gin gcc Ala tgg Trp aag Lys gtg S Val 365 aac t Asn S act c gga Gi y aag Lys cta Leu aaa Lys cag Gin 270 ggc Gly aag Lys aaa Lys aag Lys gtg Val 255 caa Gin atg Met *cca Pro 160 tac Tyr aaa Lys aga Arg t ct Scr gct Ala 240 tgt Cys gtg Val gtg Val 480 528 576 624 672 720 768 816 864 912 960 1008 1056 1104 1152 1200 1248 ctg Leu Lgg rrp gta Jal It t lal ;cg l1a cc ;er tc gtc Val acc Thr acc Thr 335 aaa Lys gcc Al a tct 5cr ggg Gly ttc Phe aag Lys 320 cca Pro aag Lys acg Thr gct Aia aag Lys 400 395 ctg tcc cgg aac Leu 5cr Arg Asn gat gaa gtg aag Asp Glu Val Lys atg att gag aaa Met Ile Giu Lys ctc ggg Leu Gly 415 ggg aag ttg acg ggg acg gec aac Gly Lys Leu Thr Gly Thr Ala Asn 420 -101- aag get tee ctg tgc atc age ace Lys Ala Ser Leu Cys Ile Ser Thr 425 430 aae aag Lys Lys gee aac Ala Asri 450 tee ace Ser Thr 465 tgg ggg Trp Gly ggg aag Gly Lys gag gaa Glu Glu gga gga Gly Gly 530 gte etg Val Leu 545 gac ate Asp Ile gae gae Asp Asp ggt aeg Gly Thr gat gee Asp Ala 610 gct tgg Ala Trp 625 etg gag Leu Glu gta aat Val Asn gas Gli 43! atc II( aa Lys gca Ala tea Ser 9gt Gly 515 gea Ala gag Giu gtt Val aag Lys gtg Val 595 at t Ile eae His ct Ile cet Pro g i Val ega Arg age Ser gag Glu gg *Gly 500 ate Sle get Ala aa Lys ace Lys gaa Giu 580 ate Ile gag Glu tee Ser gae Asp ggC Gly 660 gaa Glu git Val cit Leu gig Val 485 get Ala ac Asn gtg Val ggt Gly gga Gly 565 aae Asn ggt Gly cag G3n ace Lys tat T'yr 645 acc rhr aag atg act Lys gtg Val eag Gln 470 aag Lys geg Ala aae Lys gat Asp 9gg Gly 550 ace Thr agg Arg age Ser te Phe aat Asn 630 ggc Gly aag Lys Met tet *Sez 455 gag gea Ala etc Leu tet Ser cct Pro 535 aag Lys aac Asn tat Tyr ac Asn atg Met 615 tie Phe cag Gin tee 5cr Asn 440 gag Giu pttg Leu gag Gi u tee Ser gac Giu 520 get Asp gte Val ice Ser tgg Trp aaa Lys 600 ac1 Lys aeg Thr get s AspC aag c Lys 1 aac Lys gac Asp tie Phe cet Pro aaa Lys 505 ag Lys tct Ser tie Phe tee Tyr ata Ile 585 Leu Leu mag .4's 3aa ;iu eu ~65 Sag Lys tic Phe te Leu git Val 490 aa Lys age Arg gga Gly agt Ser tac Tyr 570 tc Phe gee Glu tat Tyr tatc Tyr 1 gag g Glu 650 ccc a Pro a ig Met etc Leu geg Ala 475 ga Giu age 5cr atsg Met etg Leu qee Ala 555 aag L~ys agg krg; cag 31n ;aa flu cc ~ro ~35 cea lia ~ag lys gag Gil cag Gln 460 eac His gti Val aag Lys aaa Lys gee Giu 540 aee Thr cig Leu tee 5cr atg; Met gae Giu 620 ea Lys gtg Val eca Pro gaa Glu 445 Igae Asp ate Ile gtg Val Gly tic Leu 525 eac His ct Leu cag Gin tgg Trp ceg Pro 605 aaa Lys aag Lys aag a LysI gtt C Val C 6 gta ValI gtc Val t ig Leu gee Ala eag Gin 510 act Thr tct Ser 9gc Gly ct t Leu 9gc fly 590 tcc Scr Ice ['hr :tt ?he ieg :ag aag Lys tee 5cr tee 5cr cca Pro 495 gte Val ett Leu geg Ala cig Leu cig; Leu 575 egt Arg ag Lys ggg Gly tac Tyr etc Leu 655 gac c AspI gea Gl u gee Al a cci Pro 480 aga Arg aag Lys ace Lys cat His gig Val 560 gag Glu gig Val gag flu aac iksn ccc Pro ;4 0 ca ['hr ~te .Deu 1296 1344 1392 1440 1488 1536 1584 1632 1680 1728 1776 1824 1872 1920 1968 2016 2064 ate aag cig Ile Lys Met 675 ate itt gai gig Ile Phe Asp Vai agt atg ceg ac Ser Met Lys Lys etg gig gag Met Val Glu -102- tat gag atc gac ett cag aag atg coc ttg ggg aag ctg agc aaa agg 2112 Tyr Giu Ile Asp Leu Gin Lys Met Pro Leu Giy Lys Leu Ser Lys Arg 690 695 700 cag ate eag gee ge: tac tce ate etc agt gag gte eag eag geg gtg 2160 705 710 715 720 tet cag ggc age age gac tet eag ate ctg gat etc tea aat egc ttt 2208 Ser Gin Giy Ser Ser Asp Ser Gin Ile Leu Asp Leu Ser Asn Arg Phe 725 730 735 tac acc etg ate ec cac gac ttt ggg atg aag aag ect ccg etc ctg 2256 Tyr Thr Leu Ile Pro His Asp Phe Giy Met Lys Lys Pro Pro Leu Leu 740 745 750 aae aat gea gac agt gtg eag gee aag gtg gaa atg ctt gac aae etg 2304 Asn Asn Ala Asp Ser Val Gin Aia Lys Vai Giu Met Leu Asp Asn Leu 755 760 765 C1 tg gac ate gag gtg gee tac agt etg etc agg gga ggg tet gat gat 2352 Leu Asp Ile Giu Val Aia Tyr Ser Leu Leu Arg Gly Gly Ser Asp Asp 770 775 780 age age aag gat cee ate gat gte aae tat gag aag etc aaa aet gac 2400 Ser Ser Lys Asp Pro Ile Asp Vai Asn Tyr Giu Lys Leu Lys Thr Asp 785 790 795 800 att aag gtg gtt gae aga gat tet gaa gaa gee gag ate ate agg aag 2448 Ile Lys Val Val Asp Arg Asp Ser Giu Giu Ala Gu Ile Ile Arg Lys 805 810i 815 tat gtt aag aae act eat gca ace aea cae agt geg tat gac ttg gaa 2496 Tyr Vai Lys Asn Thr His Ala Thr Thr His Ser Ala Tyr Asp Leu Glu 820 825 830 gte ate gat ate ttt aag ata gag cgt gaa gge gaa tge eag cgt tae 2544 Val Ile Asp Ile Phe Lys Ile Glu Arg Giu Gly Giu Cys Gin Arg Tyr 835 840 845 aag ccc ttt aag eag ett eat aac ega aga ttg ctg tgg cac ggg tee 2592 Lys Pro Phe Lys Gin Leu His Asn Arg Arg Leu Leu Trp His Gly Ser 850 855 860 agg ace ace aac ttt get ggg ate etg tee eag ggt ett egg ata gee 2640 Arg Thr Thr Asn Phe Ala Gly Ile Leu Ser Gin Gly Leu Arg Ile Ala 865 870 875 880 ceg cet gaa gcg ccc gtg aea ggc tac atg ttt ggt aaa ggg ate tat 2688 Pro Pro Giu Ala Pro Vai Thr Gly Tyr Met Phe Gly Lys Gly Ile Tyr 885 890 895 tte get gac atg gte tee aag agt gee aae tac tae cat aeg tet eag 2736 Phe Ala Asp Met Val Ser Lys Ser Ala Asn Tyr Tyr His Thr Ser Gin 900 905 910 gga gac eca ata ggc tta ate etg ttg gga gaa gtt gee ett gga aae 2784 Gly Asp Pro Ile Gly Leu Ile Leu Leu Gly Glu Val Ala Leu Gly Asn 915 920 925 atg tat gaa ctg aag cac gct. tea eat ate age agg tta eec aag ggc 2832 Met Tyr Giu Leu Lys His Ala Ser His Ile Ser Arg Leu Pro Lye Gly 930 935 940 aag eac agt gtc aaa ggt ttg gge aaa act ace cet gat ect tea get 2880 Lys His Ser Val Lys Gly Leu Giy Lys Thr Thr Pro Asp Pro Ser Ala 945 950 955 960 aac att agt ctg Asn Ile Ser Leu tot ggt gtg ata Ser Gly Val Ile 980 gat att got cag Asp Ile Ala Gin 995 ttt aag acc tcc Phe Lys Thr Ser 1010 <210> 137 <211> 1014 <212> PRT <213> Homo sapie <400> 137 Met Ala Giu Ser 1 Gly Arg Ala Ser Leu Arg Met Ala -103- gat ggt gta gao gtt cot ott ggg ace ggg att tea Asp Gly Val Asp Val Pro Leu Gly Thr Gly Ile Ser 965 970 975 gac acc tot ota ota tat aac gag tac att gtc tat Asp Thr Ser Leu Leu Tyr Asn Giu Tyr Ile Val Tyr 985 990 gta aat otg aag tat ctg otg aaa ctg aaa tto aat Val Asn Leu Lys Tyr Leu Leu Lys Leu Lys Phe Asn 1000 1005 ctg tgg taa Leu Trp 2928 2976 3024 3045 rs Ser 5 Cys lie Asp Lys Leu Tyr Arg 10 Lys Lys Cys Ser Glu 25 Met Val Gin Ser Pro 40 Pro Arg 65 Asp Lys Phe Met Asp 145 Gly Ser Glu Lys Lys 225 His His Gin Gly Ala Glu 130 Pro ys Ala Ala Gly 210 Trp Tyr His Phe Ser Cys Phe Trp 55 Pro Gin Gin Ala 115 Lys Glu Phe Ser Leu 195 Asp Asp Lys Asp 100 Glu Ile Lys Val Gin 180 Lys Glu Val Val Gly Tyr Glu Pro Lys 165 Leu Lys Val Glu Val Asp Gly Phe 70 Lys Lys Ile Gly Ala Lys Lys Gly 135 Gin Leu 150 Asn Arg Lys Gly Gln Leu Asp Gly 215 Lys Asp 230 Thr Ala Glu Ser Ser 120 Gin Gly Glu Phe Pro 200 Val 90 Ala Arg Arg Ile Leu 170 Leu Val Glu Val Glu I Ser Ile Met Phe Lys Val Ser Glu 75 Ala Gly Glu Lys Ser Thr Leu Ser 140 Asp Arg 155 Gly Phe Leu Ala Lys Ser Val Ala 220 Glu Lys 235 Tyr Ala Pro Lys Asp Gly Gly His Leu Arg Gly Val Thr Leu 110 Cys Lys 125 Lys Lys Trp Tyr Arg Pro Thr Glu 190 Glu Gly 205 Lys Lys Ala Leu I LyE 1! Asr Lye Ser Trp Thr Gly Gly Met His Glu 175 Asp Lys Lys -ys Ser Ser Val Ile Asp Gly Asp ys Val Pro 160 Tyr Lys Arg Ser Ala 240 Lys Giu Lys Asp Ser Lys Leu Gin Asn Asp Leu Trp Asn Ile Lys Glu Leu Lys Lys Val Cys 255 Ser Thr Asn Asp Leu Lys Glu Leu 260 -104- Leu Ile Phe 265 Asn Lys Gin Gin Vai 270 Pro Ser Giy Giu Ser Ala Ile Leu Asp Arg Val Ala 275 280 Asp Gly Met Val Phe Gly Ai 290 Lys Ser As1 305 Cys Met Val Lys Giu Phe Gin Asp Arg 355 Pro Pro Pro 370 Ser Ala Asp 385 iLeu Ser Arg Gly Lys Leu Lys Lys Giu 435 Ala Asn Ile 450 Ser Thr Lys 465 Trp Gly Ala Gly Lys Ser Giu Giu Gly 515 Gly Gly Ala 530 Val Leu Giu 545 Asp Ile Val Asp Asp Lys Giy Thr Val 595 iLeu Ala LDys Arg 340 Ile Ser Lys Asn Thr 420 Val Arg Ser Glu Gly 500 Ile Ala I Lys c Lys G Glu A 580 Ile G Leu Pro Cys Giu Giu Cys Ser Giy Gin Leu Val Phe 295 300 Tyr Tyr Cys Thr Gly Asp Val Thr 310 315 Thr Gin Thr Pro Asn Arg Lys Glu 325 330 Giu Ile Ser Tyr Leu Lys Lys Leu 345 Phe Pro Pro Giu Thr Ser Ala Ser 360 Thr Ala Ser Ala Pro Ala Ala Val 375 380 Pro Leu Ser Asn Met Lys Ile Leu 390 395 Lys Asp Giu Val Lys Ala Met Ile 405 410 Gly Thr Ala Asn Lys Ala Ser Leu 425 Giu Lys Met Asn Lys Lys Met Giu 440 Val Val Ser Giu Asp Phe Leu Gin 455 460 Leu Gin Glu Leu Phe Leu Ala His 470 475 Val Lys Ala Glu Pro Val Giu Val 485 490 klia Ala Leu Ser Lys Lys Ser Lys 505 .sn Lys Ser Giu Lys Arg Met Lys 520 lal Asp Pro Asp Ser Gly Leu Glu 1 535 540 ;iy Gly Lys Val Phe Ser Ala Thr I 550 555 ;iy Thr Asn Ser Tyr Tyr Lys Leu C 65 570 Lsf Arg Tyr Trp Ile Phe Arg Ser T1 585 Ala Trp Th Trj Lys Val 365 Asn Thr Gi u Cys Giu 445 Asp Ile V'al Gly -'Cu 525 i s ~rp Val Val 350 *Ala Ser *Leu Lys Ile 430 Vai Val Leu Ala Gin 510 Thr Ser Gly I Leu L 5 Gly A 590 Th, 33! Lyf Ala Ser Gly Leu 415 Ser Lys Ser Ser Pro 495 lal 4 eu ~eu 475 Lrg r Lys 320 c, Pro Lys Thr Ala Lys 400 Gly Thr Glu Ala Pro 480 Arg Lys Lys His Val 560 Glu Val1 'ly Ser Asn Lys Leu Glu Gin met Pro Ser Lys Giu 600 605 Asp Ala Ile 610 Giu Gin Phe Met Lys Leu Tyr Glu Giu 615 620 Lys Thr Gly Asn Ala 625 Leu Val Trp Glu Asn Asn Phe 630 Giy Gin Lys Ser Thr Lys Asp Glu Lys Leu 665 -105- Tyr Pro Lys 635 Giu Ala Val 650 Pro Lys Pro Lys Phe Tyr Pro 640 Lys Lys Leu Thr 655 Val Gin Asp Leu 670 Ile Lys met Ile Phe Asp Val Glu Ser Met Lys Lys Ala Met Val DID Tyr Giu Ile Asp Leu Gin Gin 705 Ser Tyr Asn Leu Ser 785 Ile Tyr Val Lys Arg 865 Pro Phe 690 Ile Gin Thr Asn Asp 770 Ser Lys Val Ile Pro 850 rhr Pro kla Gin Gly Leu Ala 755 Ile Lys Val Lys Asp. 835 Phe Thr. Giu Asp Ala Ile 740 Asp Giu Asp Val Asn 820 Ile Lys Asn Ala M4et 900 IAla 8cr 725 Pro Ser Val Pro Asp 805 Thr Phe Gin Phe Pro 885 Val Tyr 710 Asp His Val Ala Ile 790 Arg His Lys Leu Ala 870 Val SerI Lys 695 Ser Ser Asp Gin Tyr 775 Asp Asp Ala Ile His 855 Met Pro Leu Ile Leu Ser Gin Ile Leu 730 Phe Gly met 745 Ala Lys Val 760 Ser Leu Leu Val Asn Tyr Ser Giu Glu 810 Thr Thr His 825 Giu Arg Glu 840 Asn Arg Arg 685 Gly Lys Leu 700 Giu Val Gin 715 Asp Leu 5cr Lys-Lys Pro Giu Met Leu 765 Arg Gly Gly 780 Giu Lys Leu 795 Ala Glu Ile Ser Ala Tyr Gly Giu Cys 845 Leu Leu Trp 860 Gln Giy Leu B75 Phe Gly Lys C Tyr Tyr His T1 9 flu Val Ala L 925 ger Arg Leu P 940 rhr Pro Asp P Se, Gir Asr Pro 750 Asp Ser Lys Ile Asp 83 0 'In fis Lrg ;iy hr 'Cu ro ro r* Lys iAla 1Arg 735 Leu Asn Asp Thr Arg 815 Leu Arg Gi y Ile Ile 895 Ser Gly Lys Ser IGiu Arg Val 720 IPhe Leu Leu Asp Asp 800 Giu Tyr Ser Ala 880 Tyr Gin Asn Gly Ala 960 Gly Ile Leu Ser Gly Asp Pro Ile Gly Leu Ile Leu Leu GlyC 915 920 Met Tyr Giu Leu Lys 930 Lys His 5cr Val Lys 945 Asn Ile Ser Leu Asp 965 Gly Val Asp Val Pro Leu Gly Thr Gly Ile Ser 970 975 Thr Ser Leu Leu Tyr Asn Glu Tyr Ile Val Tyr 985 990 Ser Gly Val Ile Asp 980 -106- Asp Ile Ala Gin Val Asn Leu Lys Tyr Leu Leu Lys Leu Lys Phe Asn 995 1000 1005 Phe Lys Thr Ser Leu Trp 1010 <210> 138 <211> 5482 <212> DNA <213> Drosophila melariogaster .c220> <221> CDS <222> (474)..(4016) <c400> 138 aaaeaatgca atatttegcg gagcagtgaa- ttaatcegga aataatcgtc cgtgcceaga gctttggagg ccaagtaeea gggagetagt cccagagttg gtcgcagtct gaatcgtagc attttgggtc gccagtggca aagccagcga agaactggac gcctattttt caaccgcgat tgcaattgtg aattgttgct cggacaacgg tgggagtgga t teggggegt ccttgcaacc cattaaatat cctgcggcat cgaggcttgt aaadccgaaa gtgtgtgcca gtgctgtgte taagcaaaaa aggcaggaea gtaggacggg gcccactgaa aagcgtagca gaaccaaaga cgagggctgg cctggataca cagagcaact tattgcgct t aacaagcaca cagtaaaaac aatectattg tcgcgtggca ggatgcgggc gctggaggag gtt t tttgt t aea atg Met 1 9CC aac agc agc cga agt egg 9CC att Ala Asn Ser Ser Arg Ser Arg Ala Ile 10 gte atg gcc aac gat ccg ctg agg gag Val Met Ala Asn Asp Pro Leu Arg Glu 25 ttg agc gtt aat etc gat geg Leu Ser Val Asn Leu Asp Ala etc tcc gag gec tgc aaa acg Leu Ser Giu Ala Cys Lys Thr ggc gag Gly Giu 9CC agg Ala Arg atc gee aag gtg Ile Ala Lys Val aag cta ata acq cet. cag aec gtg aac Lys Leu Ile Thr Pro Gin Thr Val Asn gat acg gcg Asp Thr Ala aaa tee aca Lys Ser Thr cea ttg cat Pro Leu His ttc gca Phe Ala ggt tat gga ege egg gaa Gly Tyr Giy Arg Arg Giu tce ata eag geg tgt gac Ser Ile Gin Ala Cys Asp gtg gtt gaa Val Val Glu ctg Leu eae His gag 9gt, 9gg ctg Giu Gly Gly Leu 90 ctg aae age gge gee Leu Asn Ser Gly Ala Ceg etg eac aac tgt Pro Leu His Asn Cys ttg etg aag gea ggt Leu Leu Lys Ala Giy 620 668 716 764 81.2 860 tge tce ttt Cys Ser Phe 100 9CC agt eca Ala Ser Pro 115 gge eae Gly His aae ace Asn Thr gee gag gta Ala Glu Val 105 ace gac aae Thr Asp Asn 120 gtt ega ttg Val Arg Leu tgg aae tac Trp, Asn Tyr 110 aeg cea Thr Pro 125 ttg eac gag Leu His Glu gc Al 13 gg9 GI Ct' Lei gal As 1 C Ali~ cgc Arg 210 gtg Val1 ggc Gly gtg Val ctg Leu gag Glu 290 aac Asn aga Arg tgt Cys. att Ile gcc Ala 370 acc Thr 9 gc a Al 0 C gc. y Al. u Al~ tgac SGli cta Leu 1 95 tca Ser gaa Glu ggt Gly acc Thr tgg Trp 275 gtc Val tgC Cys gag Glu cga Arg git Val 355 gtt Val aga Arg agc aag Ser Lys a aac cat a Asn Hius gac gag iAsp Glu 165 cig ctt 1Leu Leu 180 ctc acg Leu Thr acg ccg Thr Pro att Ctg Ile Leu ctg gtg Leu Val 245 aag ctg Lys Leu 260 9CC tt 1 Ala Phe tgc agc c Cys Ser I cac agc a His Ser 3 cgg att 9 Arg Ile A 325 aag tgt 9 Lys Cys A 340 aac ttC g Asn Phe v gtC agt c Val Scr P aag gga ti Lys Gly Si ggc aag gig gat gtg Gly Lys Val Asp Val 135 acg atc cgc aac tcg Thr Ile Arg Asn 5cr 150 gcg acg cgt CCC gta Ala Thr Arg Pro Val 170 gaa 9CC gca cgc tcg Glu Ala Ala Arg Ser 185 cca ctc aat gtc aac Pro Leu Asn Val Asn 200 CtC cat ctg gca 9Cg Leu His Leu Ala Ala 215 Ctg 9CC aac gga 9Cg Leu Ala Asn Gly Ala 230 ccq Ctg Cac aat 9CCt Pro Leu His Asn Al1a 250 Ctt atc cag gCg ggc g L.eu Ile Gln Ala Gly 265 1Cg CC9 CtC cac gag g r'hr Pro Leu His Glu A 280 ~tg Ctg ctC agt cgt g ~eu Leu Leu Ser Arg G 295 lag tcg 9CC atC gat g ,ys Ser Ala Ile Asp A 10 3 CC ttt gaa taC aag g' ~la Phe Glu Tyr Lys G 330 at gtg tCC Cgt 9CC a~ .sp Val Ser Arg Ala L' 345 tg cat CCa tat aca g al His Pro Tyr Thr G~ 360 C9 gat 999 aag c9C ai ro, Asp Gly Lys Arg L3 375 CC ttg Ctg aaC gag aa er Leu Leu Asn Glu Ly 4 -107- tgC Cig gc Cys Leu Al 140 gag Cag aa Glu Gin Ly 155 ttg aCC 99 Leu Thr GI 999 9CC gai Gly Ala Gli tgt cat gc4 Cys His Ali g9C taC aat Gly Tyr Asx 220 gat gta cat Osp Val HiE 235 9CgciC tac 'ys Ser Tyr ~cc aai gtc Lla Asn Val cc 9CC tCC la Ala Ser 285 'ga gCg gat ly Ala Asp 300 Cg 9C9 CC la Ala Pro 15 gt CaC igc ly His Cys ag aag ctg ys Lys Leu 3a gac act Ly Asp Thr 365 g9 cag ctg ~s Gin Leu 380 ~a aac aag ~s Asn Lys '5 :t Ctg ttg a Leu Leu g aca cca 's Thr Pro c gaa tat y Glu Tyr 175 9 gat cgc u Asp Arg 190 :agc gat a 5cr Asp C99 *atc I Arg Ile 9ct.aag Ala Lys ggacac Gly His 255 aac .9CC Asn Ala3 270 aaa agt c Lys Ser CCC acc c Pro Thr L acc agg g Thr Arg G 3 ctg Ctg 9 Leu Leu A 335 gta tgc g Val Cys A 350 CCg CtC C Pro Leu H. atg gaa ci Met Glu Li gCt ttc Cl Ala Phe LE ca cl Ct Le 16 Cg Arl Ct! Lei 99 G1~ 9gC Glj gac 240 ttc Phe iac ksn :gC :tc ~eu rag iu ac sp ca la ac is eu 9 cat n His 145 9 gag u Glu 0 a aag SLys 9 Ctg a Leu I cga e Arg -atc Ile 225 *aag Lys *gat Asp gat Asp gtc Val cta Leu 305 Ctg Leu 9CC Ala gag Glu Ct9 Leu Ctg Leu 385 acg Thr 908 956 1004 1052 1100 1148 1196 1244 1292 1340 1388 1436 1484 1532 1580 1628 1676 CCC Pro ctg Leu acg Thr ctc Leu 450 9C Ala ccg Pro gac Asp cgg Arg ttt Phe 530 gtt Val tett Ser aat 9 Asn V~ 9CC g Ala A~ get g Ala A 610 gtt a Val L get C Ala L ttg 9' Leu V. L( Ct Le cc Pr 43 tc Se 9c Al ga As ac' Tb: gai A~s 51~ ~aa ksl tat :at ;ta ral la 95 rat ,sp ag YB tg eu tt al :9 ca *u Hi *a aa *u Ly 42' *a et ~o Lei 5 'g tac r Ty~ t caa a Gir agt p Ser t gtg r Val 500 ttg SLeu -aga )Arg *gcg *Ala *999 *Gly aat Asn 580 aag Lys cca Pro gaa Glu cta Leu a ca Thr 660 t ttg 9ct s Leu Ala 405 9 cag gge s Gin Gly 0 g cat egg u His Arg :gca gcg rAla Ala Ittg gee LeU Ala 470 gag aca Glu Thr 485 ege egt Arg Arg gac gga Asp Gly gtg eca Val Pro get gac a Ala Asp 550 cac tat 9 His Tyr G 565 gta teg g Val Ser A gga aag t Gly LysT atg aag a Met Lys L 6 tct gat c Ser Asp H 630 gac gca gi Asp Al a A 645 ccg gaa ti Pro Glu Si 9 c Al geC Al t 9 Cy g a Asj 45I t C S e eat Hisc ata I le cga krg ;tg lal ~35 iag 'YS ~ag Ilu a t 'sp a t yr a g i s L a c ga a GI C as a Ly C ge Al 44 ac p Th 3 ga r Asj ttj Le~ Val cat His 520C gtt Val gge Gly gta Val t tg Leu gat Asp 600 aat Asn ga t Asp aag Lys att Ile 19 Ctg ett .u Leu Leu 410 g gtt aat '5 Val Asn 425 C cgt gat a Arg Asp 0 9 aat ate r Asn Ile c age gtg p Ser Val a Ctg gag .a Leu Glu 490 c tc aac Leu Asn 505 tee aca Ser Thr cag ttt c Gin Phe I gga ctg g Gly Leu V, 5 ace gaa c Thr Giu L 570 tgg aag t Trp Lys P 585 att tge a Ile Cys L egg gat g Arg Asp G. gtt gca g~ Val Ala G: 6: aaa gga a 1 Lys Gly A~ 650 aat tgc cS Asn Cys Al 665 -108- cac tae His Tyr gca ttg Ala Leu gag caa Giu Gin gtt tee Val Ser. 460 ctg aag Leu Lys 475 gca gee Ala Ala aat ceg k.sn Pro :et ttg ?ro Leu ~tt ttg 9 .eu Leu C 540 ~tg ccc c al1 Pro L 55 :tg etg g .eu Leu V tt act c be Thr P ag ctg c ys Leu L 6 gc geg a Ily Ala TI 620 a9 ct9 cI L u Leu L 35 Ie ttg gC sn Leu Al g9 gac gc ~Asp Al 9, A: 91 gC Al 44 Ct Le Ct Le aa Ly at 1ij :tc Jei 'tc Ct ro te Cu 05 Ca La at gc sp Al Ic ag sp Se 43 9g gt .a Va :t ga ~u G1i 9 etc u Lea 9 geS s Ala t tec e, Ser ttt Phe i cac a His ;cac His aag Lys Ct t Leu 590 ttg Leu cca Pro aga Arg egg Arg eag Gin 670 *c atg gag a Met Glu 415 t Ctt gga r Leu Gly 0 9 ega ctg 1 Arg Leu g gga ctt u Gly Leu c aag aat .a Lys Asn 480 gga gat Gly Asp 495 gtc aat *Val Asn get get Ala Ala ggC gee Gly Ala aat gce Asn Ala C 560 eac gga g His Gly eat gaa g His Glu A aaa eat g Lys His G geg gat t Ala Asp L 6 gga ceg t~ Gly Pro S 640 gta eag c( Val Gin A 655 ggc agg a~ Gly Arg A~ gtg Val1 caa Gin etg Leu aeg Thr 465 ect Pro ets Leu tge Cys 9gg 31 y ;ag 3iu 54 :gc :ys Ll a ret la ge ly tg Cu cc Cr rg I t 1724 1772 1820 1868 1916 1964 2012 2060 2108 2156 2204 2252 2300 2348 2396 2444 2492 -109- gga tat aac Gly Tyr Asn tee aea cca ctt cac ctg 9CC gee Ser Thr Pro Leu His Leu Ala Ala 675 680 aac ttt gag tgt gcc Asn Phe Glu Cys Ala 685 2540 gag tac ctt ctg gag aat Glu Tyr Leu Leu Glu Asn gga gcc gat gtt aa Gly Al. gga Gly 9gg Ala tgq Trp ttg Leu cag 770 tgc Cys agt Ser act Thr Cta Leu att Ile B 50 agt gat Asp eta Leu caa a GlnI Cta Let Sica Ala gga Gly t-gc Cys 755 gag Giu t tg Leu gct Ala get Ala tcg Ser 835 ctg Leu ce Pro gat %sp Ige 3cr ~tc lie ata Ile ctg Leu ttc Phe 740 tcg Ser 999 Gly Ctc Leu tcc Ser gc~t Ala 820 CCC Pro agt Ser 9CC Ala eta Leu agc Ser 900 acct Thr cc Prc Cta Let 725 aca Thr C te Leu qag Gin cag Gin acg Thr 805 geg Ala ace Thr gtt Val caa G1n :tg 1.eu 885 :ag ;In :tg Aeu *ctg cac aat )Leu His Asn 710 att aag cac Ile Lys His ccg etc eac *Pro Leu His ttg ttg gCC *Leu Leu Ala 760 acg ccc att Thr Pro Ile 775 gac gcg atg Asp Ala Met 790 caa teg ctg Gln Ser Leu get ceg gge Ala Pro Gly acg gsa aeg Thr Giu Thr 840 CCt gtt cca Pro Val Pro 855 gga gca gag Gly Ala Giu2 870 ccg gat geg 5 Pro Asp Ala cag ctg cat c Gin Leu His H 9 gac att eta g Asp Ile Leu A 920 gel Al. aa Lyn ga~ Glt 741 cac His gag Glu 9CC Ala aca Thr a Thr B25 gtg Val :tt Leu kla ;at ~sp :at Iis 105 Icc .la a Asp Val As c agc agc ta a Ser Ser Ty 715 3 acg gtt gt( s Thr Val va 730 3 gt gea cac Ala Ala G1i 99t 9CC gat Gly Ala AsI Fttg 9cc acc Leu Ala Thr 780 ace tcg ttg Thr Ser Leu 795 agc agt tce Ser 5cr Ser 810 tct tea teg Ser Ser Ser ttg ctg ccc Leu Leu Pro eca ctg tee Pro Leu Ser 860 sat g99 gCt Asn Gly Ala 875 acc ata sa Thr Ilie Thr 890 eta atc gaa Leu Ile Glu gag atg ggc Giu Met Gly t 9c~ n Al~ 0 t ggs G13 aat 1. Asr aa i Lys 9CC Ala 765 gea Ala agt Scr Ceg Pro tee Ser ace Thr 845 agt Ser gag Giu aat Asn acag a Gin c at SHis geg Ala I999 Gly 750 tat Tyr gat Asp caa Gin ges Ala 5cr 830 ggt Gly2 age a Ser I ge t Gly S gtg .t ga Asj t t Let ace Thi 731 cC Arc atg Met gat Asp eag Gin cca Pro 815 tee Scr )CC ~C9 Lhr cc er cc c aag 999 p Lys Gly 705 3 gat att a Asp Ile 720 gat aaa rAsp Lys act eaa Thr Gin aaa aae Lys Asn gtt aag Val Lys 785 gCg ttg Ala Leu 800 gat gca Asp Ala gea ate Ala Ile tee atg Ser Met egc atc Arg Ile 865 tet teg Ser 880 9 ttc 2588 2636- 2684 2732 2780. 2828 2876 2924 2972 3020 3068. 32116 3164 3212 3260 895 etg ttC gag cge gas Leu Phe Giu Arg Giu 910 eac gac gat cte aag His Asp Asp Leu Lys 925 cag Gin 930 gtg ggc gte tc Val Gly Val 5cr 9CC tac ggc ttc cgc Ala Tyr Gly Phe Arg 935 eae aag ata cte aag His Lys Ile Leu Lys 3308 ate gec cag etg agg tcc acc aca gg c att ggt aac aac gtg aat cta 3356 Ile Ala Gin Leu Arg Ser Thr Thr Gly Ile Gly Asn Asn Val Asn Leu C1950 955 960 tgc aca ttg ttg gtg gac ttg ctg ccg gac gat aag gag ttt gtg gcc 3404 Cys Thr Leu Leu Val Asp Leu Leu Pro Asp Asp Lys Giu. Phe Val Ala 965 970 975 gtc gag gag gag atg cag gcc acg att cgt gaa cat cgt gat aat gga 3452 Val Glu Giu Giu Met Gin Ala Thr Ile Arg Glu His Arg Asp Asn Gly 980 9B5 990 cag gct gga ggt tat ttc act cga tat aac atc att cgg gtg caa aag 3500 Gin Ala Gly Gly Tyr Phe Thr Arg Tyr Asn Ile Ile Arg Vai Gin Lys 995 1000 1005 gta caa aat cga aag ctg tgg gag cgt tat gct. cat cga egg caa gag 3548 Val Gin Asn Arg Lys Leu Trp Glu Arg Tyr Ala His Arg Arg Gin Giu 1010 1015 1020 1025 rN ~atc gcc gag gag aat ttc ctg cag tcc aac gag ogt atg ctc ttc cac 3596 Ile Ala Giu Giu Asn Phe Leu Gin Ser Asn Giu Arg met Leu Phe His 1030 1035 1040 ggt agt ccc tte ate aac gca att gtg caa ege gga tte gac gag cgc 3644 Gly Ser Pro Phe Ile Asn Ala Ile Val Gin Arg Gly Phe Asp Glu Arg 1045 1050 1055 eac gee tac att ggc ggc atg ttt ggg get ggc att tat tte gec gag 3692 His Ala Tyr Ile Gly Gly Met Phe Gly Aia Gly Ile Tyr Phe Ala Giu 1060 1065 1070 cat age teg aaa age aae cag tat gtg tac ggra att ggc ggc ggc att 3740 His Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile Giy Gly Giy le 1075 .1080 1085 gge tgt ccc teg eac aag gat aag tee tge tac gtg tgt ect aga eaa 3788 Gly Cys Pro Ser His Lys Asp Lys Ser Cys Tyr Val Cys Pro Arg Gin 1090 1095 1100 1105 ttg ctg ctg tgc ega gtg gcg tta ggc aaa tee tte ttg caa tac agt 3836 Leu Leu Leu Cys Arg Val Ala Leu Gly Lys Ser Phe Leu Gin Tyr Ser 1110 1115 1120 gca atg aag atg gee cat gea. eeg ecg gga cac eac teg gtg gtg ggc 3884 Ala Met Lys Met Ala His Ala Pro Pro Gly His His Ser Val Val Gly 1125 1130 1135 aga ccc teg geg ggt ggc ttg cat tte gee gaa tac gtt gte tat egg 3932 Arg Pro Ser Ala Gly Gly Leu His Phe Ala Ghi Tyr Val Val Tyr Arg 1140 1145 1150 gge gaa cag tet tat ceg gag tac ttg ata ace tac caa ate gte aag 3980 Gly Glu Gin Ser Tyr ProGlu Tyr Leu Ile Thr Tyr Gin Ile Val Lys 1155 1160 1165 ccc gat gac age agt agt gga aeg gag gat aca aga tgatggatgc 4026 Pro Asp Asp Ser Scr Ser Gly Thr Giu Asp Thr Arg 1170 1175 1180 cctctgtcgg gtccacgece acaaccacgt e~gecggt geaecagceg eaaaegcaac 4086 aacaaccgca geagcaacag eagcagcagc egeaaecaca aeaacageag aaggeaccae 4146 tgccgttgcc accgecacaa eageagacet eagctccagt tgccaagagg eggcegaaae 4206 atgceaaace ategctgcag ttgeagtate agcetatca gcecageac eaeccggttg 4266 ttgcaacegc egetgctgtg aecaceacee aaeettcgec egetggegtt tttgegcaca 4326 -1III- gcaataacaa caataatacg agcagcggaa atgtgaataa taacaacaat gacatgtCgC 4386 cggtgtcgaa tggccaacca aggcgaatcS atcgcgact t acaatggcaa gccacagcag gccagcattt acgccttcac 999ccggggg taagacgctg aggcgcgcaa acatgctggt tactagctat tctataatat tggattggat gaaatacgga tacattacat caataattaa aaaaaaaaaa kcagcaatagc igcagcgcaac icagccaaaag cgagtacgag tctgtt tcga cgatagcagc gctatcgaaa Ctcgtcgtgg agccgggcac t tcg tcgt ac gacgcgcgac ggttattgat agatgtcgtg atcacgtaag tcgattgggt aaatgcgatt tacattacgc tactcctcqq tggacaccaa ccagacgctg catcgacagc tatagtcaat tcgcatttgg ct tggat tgc agtttccgct ggtggtaatg cgctggtgca gggaatgctc aatgcggaga cacatgaata ctctatgtct tcctgtgtgt ggcgagctag taatcaaaag cgattatacg tcgcgcgttt cacagaa tca ttatgatcat actt tgagga ggcggagtga cgaattacaa gtggtggcgg gtcttctgtg cgtacagcag atgcctacga acatcaccta ccgt tggcct CtCtctctct cgagatggat tgaagcacag aggttacaag atttaagtgt tcatcatcag cacacccgcc tttcgccaat tagcagcagc tccctacttg cggtgctagt cgccgccatg ctcgctgcaa gcactttgcg cgagttgtga cccgtctatt Ctcgttgttt tcgttcggtt tttttgagtg ttctttgccg ttaagcttag ctcaactCgC 4446 cagcagcagC 4506 gtttccatag 4566 gCggcccaca 4626 gacgacagCg 4686 catcaCagtC 4746 cgtcacttct 4806 CgCtgCtttg 4866 catcatcgaC 4926 gCCCccttca 4986 cggtggtacg 5046 ttattacaat 5106 attatattac 5166 tggatcgaat 5226 attttaattc 5286 atgaatgcat 5346 ttaatttaaa 5406 aactccaatt aaaaaa aaatttaaat atacaaatac atatacatca atcgaaaaaa 5466 5482 c2lO> 139 <211> 1181 c2l2> PRT c2l3> Drosophila melanogasti <400> 139 Met Ala Asn Ser Ser Arg Ser Arg Ala Ile Leu Ser Val Asn Glu Leu Leu Asp Ala Val Met Ala Asn Asp Pro Leu Arg 25 Thr Gly Glu Ile Ala Lys Val Lys Lys 40 Asn Ala Arg Asp Thr Ala Gly Arg Lvs Ser Leu Ile Thr so Ala Gly Tyr Gly Arg Ser Thr Proi- Val Val Glu Phe Leu 75 Glu Gly Gly Leu His 90 Glu Ala Cys Lys Pro Gln Thr Val Leu His Phe Ala Leu Asn Ser Gly Pro Leu His Asn Ala Ser Ile Gln Ala Cys Cys Ser Phe Gly 100 Gly Ala Ser Pro Asri 115 Asp His Ala Glu Val Val Arg Leu Leu Leu Lys Ala 105 110 Thr Thr Asp Asri Trp Asn Tyr Thr Pro Leu His 120 125 -112- Val Cys Leu Ala Leu 140 Ser Giu Gin Lys Thr 155 Leu Gin Pro Leu 160 Tyr Arg 175 Glu Leu Ala Asp Giu Ala Thr Arg Pro Val Leu Thr Giy Glu 165 170 Lys Asp Giu Leu Leu Giu Ala Al Leu Arg Ile 225 Lys Asp Asp Val Leu 305 Leu Ala Glu Leu Leu 385 Thr Val Gin Leu Ala Arg 210 Val Gly Val Leu Glu 290 Asn Arg Cys Ile Ala 370 Thr Pro Leu rhr Leu 450 Leu 195 Ser Glu Gly Thr Trp 275 Val Cys Glu Arg Val 355 Val Arg Leu Leu Pro 435 Ser 180 Leu Thr Ile Leu Lys 260 Ala Cys His Arg Lys 340 Asn Val Lys His I Lys C 420 Leu I Tyr Thr Prc Leu Val 245 Leu Phe Ser Ser lle 325 Cys Phe Ser Gly eu 105 ;in 'is rla Pro Leu Leu His 215 Leu Ala 230 Pro Leu Leu Ile Thr Pro Leu Leu 295 Lys Ser 310 Ala Phe Asp Val Val His I Pro Asp 375 Ser Leu I 390 Ala Ala C Gly Ala I Arg Cys A 4 Ala Asp T 455 As 20( Lei Asr His Gin Leu 280 Leu Ala Glu Ser Pro 360 ;ly .eu lu ,ys 4la 40 s Ar! 18! i Va: Al G1 lAsr Ala 265 His Ser Ile Tyr Arg 345 Tyr Lys Asn Leu Val 425 Arg 3 e; Ser Gly Ala GlI I2 1 Asn i Ala r Ala Ala 250 Gly Glu Arg Asp. Lys 4 330 Ala Thr Arg I Glu I 3 Leu 1 410 Asn A Asp G Cy GI1 As 1 235 Cys Ala Ala Gly Ala 315 G 1 y Lys 3 iy -ys .ys 195 is la hlu s His Ala 205 I Tyr Asn 220 Val His Ser Tyr Asn Val. Ala Ser 285 Ala Asp 300 Ala Pro His Cys Lys Leu Asp Thr 365 Gin Leu t 380 Asn Lys I Tyr Asp I Leu Asp S 4 Gin Ala 445 Ser Leu G 460 Lys Leu L Asp 190 Ser Arg Ala Gly Asn 270 Lys Pro Thr Leu Val 350 Pro let C Qa I lia t' 4 er L :30 'al A Iiu G eu L Ar As Ii Ly: His Al Set Thi Ar Lieu 335 :ys -eu ;lu 'he let 'eu .rg 'ly ys g Leu p Gly e Gly s Asp 240 s Phe i Asn 7 Arg Leu Glu 320 Asp Ala His Leu Leu 400 Glu Gly Leu Leu Asn 480 'hr Asn Ile Val Thr Ala Ala Gin Leu Ala Ser Asp Ser 465 470 Val Leu 475 Glu Ala 490 Pro Pro Asp Ser Giu Thr 485 His Leu Leu Ala Lys Ala Gly Asp 495 Leu Asp Thr Cys Arg Asp 515 Ile Arg Val Leu 505 His Ser 520 -113- Asn Asn Thr Pro Pro Ile Ser 510 Leu His Phe 525 Asn Ala Ala Ala 560 Gly Glu 545 Cys Ala Ala Gly Leu 625 Ser Arg Asn Ala 4 Gly 4 705 Ile Lys Gin I Asn C Lys C 785 Leu S Ala 1 lie L Phe 530 Val Ser Asn Ala Ala 610 Val Ala Leu Ser Glu 590 Gly kla rrp .eu fIn 770 ys ier 'hr *eu i Asn Arg Val Pro Val Val Gin Phe Leu Leu Glu His Tyr Tyr Val Ala 595 Asp Lys Leu Val Thr 675 Tyr Leu Ala Gly Cys 755 Glu Leu Ala Ala Ser 835 Ala Gly Asn 580 Lys Pro Glu Leu Thr 660 Pro Leu ,Iie Leu Phe 740 Ser Gly C Leu C Ser I 8 Ala A 820 Pro T Ala His 565 Vai Gly Met Ser Asp 645 Pro Leu Leu Pro Leu 725 [hr Reu i fIn in I 'hr C 05 la I 'hr I Asi 55C Tyi Ser Lys Lys Asp 630 Ala Glu His Glu Leu 710 Ile Pro Leu rhr ksp 790 ;In 4la hr 535 Lys Glu Asp Tyr Lys 615 His Ala Ser Leu Asn 695 His Lys Leu Leu Pro 775 Ala Ser I Pro C Glu 1 8 540 Gly Gly Leu Val Pro Leu His Val Thr Giu Leu Leu Val Lys His Gly Let As; 600 Asn Asp Lys Ile Ala 680 Gly As His His kla 760 Ile 4et .eu fly 'hr 140 Trp 585 Ile I Arg I Val Lys Asn 665 Ala Ala Ala Lys Glu 745 His 4 Glu Ala Thr I Thr S 825 Val I 57 Lyi Cys Asp Ala Gly 650 Cys Gly Asp Ser Thr 730 Ala 3 iy Leu rhr 3er 310 er Phe Lys Gly Glu 635 Asn Arg Tyr Val Ser 715 Val Ala 4 Ala Ala Ser I 795 Ser S Ser S Thr Leu Ala 620 Leu Leu Asp Asn Asn 700 Tyr Val Gln ksp rhr 780 jeu er ;er Pro Leu 605 Thr Leu Ala Ala Asn 685 Ala Gly Asn Lys Ala 765 Ala I Ser C Pro A Ser S 8 Lei 591 Let Prc Arg Arg Gin 670 Phe Sin His Ala ;ly 750 yr rsp in la er 575 i His Lys Ala Gly F Val 655 Gly Glu Asp Leu Thr 735 Arg Met Asp Gin I Pro I 815 Ser I Glu His Asp Pro 640 Gin Arg Cys Lys Asp 720 Asp rhr Lys al kia 300 ~sp la -eu Leu Pro Thr Gly Ala Ser 845 Met Ile 850 Leu Ser Val Pro Val 855 Pro Leu Pro Leu Ser Ser Ser Thr Arg 860 -114- Ile Ser Pro Ala Gin Gly Ala Giu Ala Asn Gly Ala Giu Gly Ser Ser 865 870 875 880 Ser Asp Asp Leu Leu Pro Asp Ala Asp Thr Ile Thr Asn Val Ser Gly 885 890 895 Phe Leu. Ser Ser Gin Gln Leu His His Leu Ile Glu Leu Phe Glu Arg 900 905 910 Glu Gin Ile Thr Leu Asp Ile Leu Ala Giu Met Gly His Asp Asp Leu 915 920 925 Lys Gin Val Gly Val Ser Ala Tyr Gly Phe Arg His Lys Ile Lou Lys 930 935 940 Gly Ile Ala Gin Leu Arg Ser Thr Thr Gly Ile Gly Asn Asn Val Asn C1945 950 955 960 Leu Cys Thr Leu Leu Val Asp Leu Leu Pro Asp Asp Lys Giu Phe Val 965 970 975 Ala Val Giu Glu Giu Met Gin Ala Thr Ile Arg Giu His Arg Asp Asn 980 985 990 Gly Gin Ala Gly Giy Tyr Phe Thr Arg Tyr Asn Ile Ile Arg Val Gin *995 1000 1005 Lys Val Gin Asn Arg Lys Leu Trp Giu Arg Tyr Ala His Arg Arg'Gin 1010 1015 1020 Giu Ile Ala Giu Glu Asn Phe Leu Gin Ser Asn Glu Arg Met Leu Phe 1025 1030 1035 1040 His Gly 8cr Pro Phe Ile Asn Ala Ile Val Gin Arg Gly Phe Asp Glu 1045 1050 1055 Arg His Ala Tyr Ile Gly Gly Met Phe Gly Ala Gly Ile Tyr Phe Ala 1060 1065 1070 Giu His Ser Ser Lys Ser Asn Gin Tyr Val Tyr Gly Ile Gly Gly Gly 1075 1080 1085 Ile Gly Cys Pro Ser His Lys Asp Lys Ser Cys Tyr Val Cys Pro Arg 1090 1095 1100 Gin Leu Leu Leu Cys Arg Val Ala Leu Gly Lys Ser Phe Leu Gin Tyr 1105 1110 1115 1120 Ser Ala Met Lys Met Ala His Ala Pro Pro Gly His His Ser Val Val 1125 1130 1135 Gly Arg Pro Ser Ala Gly Gly Leu His Phe Ala Giu Tyr Val Val Tyr 1140 1145 1150 Arg Gly Glu Gin Ser Tyr Pro Giu Tyr Lou Ile Thr Tyr Gin Ile Val 1155 1160 1165 Lys Pro Asp Asp Ser Ser Ser Gly Thr Giu Asp Thr Arg 1170 1175 1180 <210> 140 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer -115- <400> 140 ggcctgaagg tatggtcgat <210> 141 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 141 tgagggcatt acagtttgtt <210> 142 <211> 346 <212> DNA <213> Homo sapiens <400> 142 ggcctgaagg aaaatcatca tgcccacagg taaagct tta gatgccattc ccttttatat tatggtcgat aagcagcagt cctgtggcaa ataatgtaca caggttaaac gttatgcatt ggataaatag ggcctctacg aaggataaaa gtgttttcta. tgggttgtct gattctaaca ttattttaag ttttactcct atgtgaacga. aatatt tcct gtactaaatt aactgtaatg aaactaattc cactgaacct ttgctgaaaa aaaatcatct agtttaacat tctgacttga gttittttcag cactttaaca ataaacagag ttaacttgaa ccctca <210> 143 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 143 gccgaattcg gcctgaaggt atggtcgat <210> 144 <211> 33 <212> DNA- <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 144 gccgaattct agatgagggc attacagttt gtt <210> 145 <211> 362 <212> DNA <213> Homo sapiens <400> 145 gaattcggcc gaacctaaaa tcatcttgcc acttgataaa ttaacagatg cttgaacctt tc <210> 146 tgaaggtatg tcatcaaagc cacaggcctg gctttaataa ccattccagg ttatatgtta gtcgatggat agcagtggcc tggcaaaagg tgtacagtgt t taaactggg tgcattgatt aaatagttat tctacgtttt ataaaaatgt tttctaaata ttgtctgtac ctaacaaact tttaagaaac actcct ttgc gaacgaagt t tttcctgttt taaattataa gtaatgccct taattccact tgaaaaaaaa taacattctg t ttcagcact acagagttaa catctagaat -116- c2ll> 5616 c212> DNA 'c213> Homo sapiens <c400>. 146 tgaatgcctc gtttctaatz tcttctatai ctactgttcc tttcattgca aataagaaaa tgcatgpcgt gccagacatc tactttgaaa atcattagee tttttttatt aaacatcaag caccaacctq Ctctttccaa cacgggcttg ggagggtgag ccaaaaaata ttagctgcct ccacttgatt cacacaaatg cttcaaatag agtgtgttta tgaaggtgag acatttacca gcccttttca tgcatctact tgtgacacaa gattaagctg tctagaaata tggaactagg at taaatcga gtgtttgtgt tgatattcat gt tgaagaaa cccccagacg aatatgatat tgtggttgta tggtccttac tctcatgctc gtcctataat gct taagaga gaaaaccaaa ttttcatctg ctgaagtctt caatatggcc gaacgtctcc ttccagttta ggtcccgaac aattaaaatt ttaaaaaagg cctcatgcgc agttttgatt ct tggagtt t ttcatgaaat Ctttgctctc caaataatgt atatgccgga tctcccaatg cactatctgg tttcccccat gtgttttctq tat tcaaaac aaatttgttt tttgagctat agaacatgag Ictggtgaags kacaacatcai iagcattgct2 :ctttgagga2 kattatccatt Lccaatgcttt gtctataaca Icatcattggc atgagccaga Igtgcaaccca ttgctctgta i ttttagtacc iacttaggaac cacaagcctg agttccaagg gagcgtgtgg catgcttccc tatttcaaaa gtt tctt tag caaggacttt t tcataaaga gacaaggaga aaagaaatac agtgccattg ccttaactga ctgctttgaa acttgccatt tgacctcctt cactcttaaa catccagact gaattagcct cttggctact taagagggct ttgccatctg .tagtttaaaa agatatggaa tgttgtttec acttgagaag tgtgtgccag gattcaagta gtgggttaat ggtcatcatg tagccgtatg ttattttttg taccccgaaa accggctcta cctgctgttg tttctcccag agctccagca agaccagata t ttgctcaga cgatgcaaaa ggaatttcta agcatcctta aaaatacaaa agattaacat gaacggcat t gcacgaaggg attcctgtaa tgtatccgaa t tgggactaa tgccattaag aatgtcagat tgtacacatc gcttcttcag ;ccagatcaga itattctagaa Ltagtgatgaa iatgtttacag tctaaaacaa *ttcaaatgtt *aatatacaca tattgtttgt *gccttcttga *agcttctggc *gctgcacttc tttttatgaa gcctaaat tc ccacagaggt tgaaaaaact ttctgtatca ttcccttaat gtcagtgaaa ttgagaatgc tttgtttact tccttgcatt acaaaaattg catacaattt acatttataa atatgaattg gcgaaagaaa gcaattcaaa t aatet cc tg atatatacat agtttgaatg cagttgttgc tgtttaatag ttttttcccc tgtagttttc tggtaaacac agctttatgg atcatactaa ttaaactgtq gtgaaggtac tatagtagtt ggatatatca agtgcactca aagaaccctt tatatgtact tggcccctct cccgagttcc gcctgctgga tatttgacct atgacctttg octcctagct acactgccgc taacagcagt gcttttcaag tacttctttg gtgcattgaa tctattattg agaatgcaat a ttattgggcat atggccttgc a ttgtctcacg t ataggatttc a cagtgacaga a tagcatatgg a caacttgtgc a tttcaacctg gtccctgaca tagtatgagt gggcggcct t gattgcttcg cacaat tcac tacgacaggc ttgttttttg ggatattttg tgagcaagat tcgttatcat ttggcctatc agagaagtca Ct tcgggaca ggggaggctg tggcagcccc ctgtactgtt ttactgcact tgggattcag ccagatttgg aaatttctga aaaccaaagc tctttgtgaa aaaaaatgat agtgcactaa tataaacacg gccctgaaaa aagcaaaata tttgctttza tttgtagctg ttcttttgaa cactagaatt ttctttcctt agtagctgtc agctgtgatt1 cttcattaaa ctagatgaat gttcagtatt tgtgtaagga cttgaaagag gaggagccaa aaagttagga tccaatataa atatagaaat gtttccictaa iaaactaaag 5 tacttgactc i .Ccttccctct actccattcat .ttgtatcac a .ttgttaaca a ;caaccagga t .agcataagt a igcttgatgt t ;tatacagag a .atccgtttt a tgtccccac c iaacagaagt 9 ;tgatatctg t .aaagctata g ktgtcagata c igtgaaaaga a iaagcaaatg c ~ctctgccat t ggactggat t gcctagaaat aactgataca t taaca tatc atctagactt acactacatt aacaagct tg tttttttgtg cacaaagtca tcagtttcca aaattgagat ttacaagaga aagccggtga gtactggaga tgaaggaaga aatggatcca gggattgtta tgatgaggg t actcgaatag ggtttatttt accatttctt CCtttCtgtt at tactg tt t cctttatagt cttatttact aggaggaata cgatgggttt aaatggttac ttttggcttc aatttttatg gtttcagtga ccaggtgaag ctCttttgct aagtgtgtct tttagttaag aagataaacc ggatgcgcca taaactgcca agacatttgc tgcatata atacattttt :aagtttatt iagcatggca Ictagcaagt :cacatggaa ~gcttctcca qggcataaat :tcctaaatt :tttctcctc iaccaggaat LatgacagcaI :tcttgtttt agaatcaaca ;agtggctag Iaatgcctgaa Lcaaaaaata ~gtttttctg :cCCgccttt rgtgtgtattt gacaaatac c accttacta a 'gtatttaaa g agtaattgt g actcgaaaa c aataaatta a acagaggatt aagctgtttg 120 tactcaactg 180 tcaggctcat 240 ggaaatggaa 300 tgttttgtta 360 tttttgattt 420 ttttttgggt 480 cgctgacaaa 540 Ctttttaaaa 600 gaaaaggaaa 660 agggcacaaa 720 aggccacttg 780 tgcaggttga 840 gctgcattaa 900 ggggatgcct 960 Ccctccaaa 1020 Cacaaaaata 1080 tggatagata 1140 gagtggcatg 1200 caaacttctt 1260 attttttcaa 1320 attttcatca 1380 tcttacactt 1440 tgatatactq 1500 ggaaagacag 1560 aatgcaaggt 1620 atgcaaaact 1680 aacccagtgc 1740 ggtcctcaaa 1800 cccaagctgg 1860 ctttgagagt 1920 gtaacaaagg 1980 tacttacctt 2040 taaaagagtt 2100 actacctaac 2160 gttttcatct 2220 gtgttatacg 2280 ggtgcttctt 2340 ttactcatct 2400 ttcagaactt 2460 acatttggga 2520 ttaaattagg 2580 taggatcatc 2640 gaaagaatct 2700 gacctgatgg 2760 taagtgccct 2820 actagtctgg 2880 atcttgggtc 2940 gggtattagg 3000 :ggaacccag 3060 :Cttttcctt 3120 ttaggatgtt 3180 ictgatttcc 3240 itatggcaag 3300 ~aattttgat 3360 :ttcagtgtc 3420 :taacatgtg 3480 :tcaagcacc 3540 ~attcttctt 3600 itttggcagg 3660 ;agtaaagtc 3720 ,aaagtgatg 3780 ,tactattct 3840 Latttttccc 3900 -117- ctctagaaag ccttaactat cattgtagtc ccatttctta gtgtttcaga cctgttcatc catgcaatgg agctgattaa gctaccagat ttctggtttg atgtggggat acgacagcaa ttttttaatt gttttaaaat taatgatttt atatactttg tgccagagag ttctgcctcc tcctcctttc acattctttt atcctttcaa agaggtttct catcagtcta cccatttctg gcagagaaat gcagttgaac ccaaagttca ggatgaaagg tgaggccgat agcctagacc acaaaacact gaaactcttc ctcatcttat ctttgtagta tttatcaagg tttctcaaaa gcaacagcac tcggagtagt ccagtgtagt gactctttgg cccaacagtg gcaggggtta ggattgtcag atcaagtaca cgttaagaat gtticatgca tctgaaattc aaatttaact *tggcaatcct acagctgtgg atcatctcgt cacctgaaat agggcatcaa ggaacttaac ttatatttaa cctgcaattg ttaatattca ataaaaccat ggcggaaact gtgtttgaaa ttattttatg aattaatcca gagaagtgct ctgtgatacc gtaaattatg cacgaccaaa tctgaaataa ttgctttaca ttcacgttcc caggcagccc cctggtagtg ctagaaaacc tagaagatga atgtgcatat gtaatgtttg catttacaaa aattgtgttt ttcattattc caaccccctc agatgcccag a tat ttggca gagcatgctg tcatgggaaa ggaagtcctt ctgcctgcct tgctttggct ttttaaagta ttttaacctt 9gtgtgtcag atggtatat t tttcaatttc ggaaagatt t ttgtagaata gttatgctaa tatggtcgta cattcgcact cttcacgtct agaattcaga tgaaagccct gggtgtccct cattcaaagt ccttgagtat aacacctgct tctttgatac accagctttg tctcat tgtg gtgt tgt tt t tCCtttcttt ttaagtttga tatatttaca gtttttctca tcacctacag tttccctcac ggtgggtttc taatgtctag aaaaaa ttatatttta tgagtcggcc tcataagtaa tccatattgg caaagcctat tgagtga tat agtgaaaacc gta tgacgag gtagattgca tcgcacctgc ttgttctgtg tgtgttgatt cacacacccg taggaaagaa gtaaacattg tctgctccca ctacaaacta agaaaatgt t atgttggtct tat ttttagt tttgtattta atttcagaga gtaaaagcat ttgtttggtt catgttaaag cctccacttc tatttaagac ctcactgtac ataaataaaa 3960 atgtctccat 4020 tattccctta 4080 aacttcctca 4140 tcagttgtgt 4200 gcaagctgtg 4260 tagaggaagC 4320 ttttatacat 4380 tttcggCttt 4440 cctacctCCC 4500 atttctttta 4560 cagagtgttt 4620 cgcacccctc 4680 cacagatctt 4740 tCtccgtgac 4800 ttgtttcaag 4860 aaaaggtact 4920 atgttgcctg 4980 gtgtgagcaa 5040 Ctctgtgtga 5100 tctatttgta 5160 aacaatttca 5220 tcattatttg 5280 tttctaaatc 5340 tcctctagtc 5400 tttccaaagg 5460- atctttgtga 5520 ttgtaaatga 5580 5616 .<210> 147 <211> 29 <212>. DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Primer 400> 147, gccgaattcc ttgtttttga tttgccaga 210> 148 211> 34 212> DNA <c213>. Artificial Sequence <220> 223> Description of Artificial Sequence:Primer 400> 148 gccgaattcc ggctttgact tctctgaatt tagg <210> 149 <211> 372 <212> DNA <213>. Homo sapiens <400> 149 gaattccttg tttttttgtg cacaaagtca tcagtttcca aaat tgagat ttacaagaga aagccggaat tttttgattt ttttttgggt cgctgacaaa ctttttaaaa gaaaaggaaa agggcacaaa tc 9ccagacatg tactttgaaa atcattagca tttttttatt aaacatcaag caccaacctg catcattggc atgagccaga gtgcaaccca t tgctctgta ttttagtacc act taggaac tattgtttgt gccttcttga agcttctggc gctgcactt c tttttatgaa gcctaaattc ttgttttttg ggatattttg tgagcaagat tcgttatcat ttggcctatc agagaagtca -118- C C <210> 150 <211> 1320 <212> DNA <213> Homo sapii <220> <221> CDS <222> (131* <400> 150 atg gcq gag gat Met Ala Giu Asp 1 gat ggt agg gat Asp Gly Arg Asp aga aac gac gag Arg Asn Asp Giu gtg cag gtg ggg Val Gin Val Giy s0 ggc ctg gtg gcc Gly Leo Val Ala ttc etc tgCcetc Phe Leu Cys Leu gac t cgc agg Asp Phe Arg Arg 100 tcc agt eta aca Ser Ser Leu. Thr 115 ttg aca aga att Leu Thr Arg Ile 130 3at gaa. ega att %sp Glu Arg Ile 14 5 Itt gaa aag gaa Ile Glu Lys Glu I iaa. att cag get a Ile Gin Ala I 180 ca, gaa gaa gte t lia Giu Glu Val P 195 :ct ttc aaa agc a ~ro Phe Lys Ser L 210 tcc tca gcg gee ccg agc ccg egg egg Ser Ser Ala Ala Pro Ser Pro Arg Arg 10 tgt qgg Cys Ala gac cct act Asp Pro Thr gag gag eag Glu Glu Gin atg gea gaa aca gag Met Ala Glu Thr Giu gag eag tte Giu Gin Phe gee ccc gag Ala Pro Giu 55 gag gee gag Giu Ala Glu 70 tet ett tge Ser Leu Cys ace ege aac Thr Arg Asn gct tge cag Ala Cys Gin gca gca gga kla Ala Gly 135 Ica ccc ttg L'hr Pro Leu I50 :at gac aaa is Asp Lys ita get gtt lie Ala Val tt gaa aga 4 he Glu Arg aa ttg ett .ys Leo Leu 215 gaa tgc eag gaa ctq Glu Cys Gin Glu Leu gag Gil gec Ala cga Arg age Ser t tg Leu 120 aaa Lys gaa Glu Ct t Leu tgt Cys ata Ile 200 atg Met gag Glu gtg Val get Ala gea Ala 105 aga Arg ace Thr tea Ser eat His atg Met 185 ttt Phe ata z Ile I gag Glu get Ala ttC Phe 90 gag Glu aeg Thr ett Leo gee Ala gaa Glu 170 Raa Ii u qgt 31y Ite ~le gag IGlu gee Ala 75 cgc Arg, get Ala ata Ile gat Asp ctg Leu 155 gaa Glu aat Asn ga t Asp tet Ser gag Glu ggc Gly gac Asp at t Ile tac Tyr gca Ala 140 atg Met ata Ile Gly cca Pro cag I tc Leo gag Glu tgg Trp ggc Giy at t Ile a ta Ile 125 cag Gin att Ile cag Gin aac Asn aat Asn 205 aaa Lys gag Glu gag .Glu atg Met ege Arg cat His 110 tgt Cys ttt Phe tgg Trp aat ~ttt Phe 190 tct Ser ;at tgc ICys pgac Asp etc Leo tee Ser gga Gly cag Gin gaa Giu ggt Giy tta Leo 175 aaa Lys cat His acaI eag Gin geg Ala gat Asp gag Glu eta Leo ttt Phe aat Asn tea Ser 160 att Ile gaa 31 u a tg 4et ttt 48 96 144 192 240 288 336 384 432 480 528 576 624 672 3m ~sp Thr I'he 220 cat tee ttt ttt caa cac ttc His Ser Phe Phe Gin His Phe 225 230 age tac aac eac atg Ser Tyr Asn His Met 235 atg gag aaa Met Giu Lys 720 aag agt tat gtg aat tat gtg cta agt Lys Ser Tyr Val Aen Tyr Val Leu Ser 245 -119- gaa aaa Glu Lys tca tca acc ttt cta Ser Ser Thr Phe Leu 250 atg aag Met Lys act tct Thr Ser gct aat Ala Asn 290 act gaa Thr Giu 305 ctt ttC Leu Phe aag aaa Lys Lys gaa agc Glu Ser ccg gta Pro Val 370 tgg gaa Trp Glu 385 gga aac Gly Asn agt gtc Ser Val att tcc Ile Ser Sca Ala caa Gin 275 t tg Leu tcc Ser t ta Leu gaa Giu aga Arg 355 act Thr gaa Giu tgg Trp atg M4et tca Ser 435 gcg Ala 260 gat Asp ga t Asp tca Ser tct Ser aga Arg 340 aga Arg cct Pro gac Asp tct Ser tta Leu 420 gac Asp gca Ala aaa Lys aca Thr gag Giu aag Lys 325 aga Arg gcc Ala gaa Giu aag Lys aaa Lys 405 aaa Lays agc Ser aaa gta gta gaa agc aaa agg aca Lys Val Val Giu Ser Lys Arg Thr 265 aga aca ata Arg Thr Ile 270 Icct Pro aga Arg ggt Gly 310 t tg Leu gta Val act Thr aaa Lys aat Asri 390 a ta Ile gac Asp gaa Giu agt Ser aaa Lys 295 aca Thr caa Gin gga Gly gaa Glu cat His 375 ttg Leu ctg Leu aga Arg gact Asp 99t Gly 280 agt Ser gta Val cat His act Thr agc Ser 360 cga Arg aat gat Asn Asp gtt agt Val Ser tcc tta Ser Leu gga acc Gly Thr 330 cct caa Pro Gin 345 aga ata Arg Ile gct aga Ala Arg gtt Val gac Asp t tg Leu 315 cag Gin agt 8cr cct Pro aaa Lys gtg Val 395 aaa Lays gaa Giu aaa Lys 300 agg Arg caa Gin aca Thr gt t Val aga Arg 380 a tg Met 285 cag Gin tct Scr caa Gin aaa Lys tca Ser 365 cag Gin gaa Giu tct. 8cr cac His gac Asp aag Lys 350 aag Lys gca Ala act *Thr gcg Ala aag Lys ct t Leu 335 aaa Lys agt Ser tgg Trp gga Gly cgg Arg 415 gaa Gi u gta Val aat Asn 320 aat Asn aaa Lys cag Gin Ctt Leu gag 3iu 400 ica L'hr 81i6 864 912 960 1008 1056 1104 1152 1200 1248 1296 1320 aga tct ggc Arg Ser Gly ttg cat tat Leu His Tyr agg aaa tat Arg Lye Tyr ttc aac aac 410 :gg agg rrp Arg 425 :ga acc atg aag aaa Thr Met Lys Lys cta aaa ctg Leu Lye Leu 430 <210> 151 <211> 439 <212> PRT <213> Homo sapiens <400> 151 Met Ala Giu Asp Vai Ser Ser Ala Aia Pro Ser Pro Arg Arg Cys Ala 1 5 10 Asp Gly Arg Asp Aia Asp Pro Thr Giu Giu Gin Met Ala Giu Thr Glu 25 Arg Aen Asp Glu Giu Gin Phe Glu Cys Gin Giu Leu Leu Giu Cys Gln 40 Val Gin Val Gly Ala Pro Giu Giu Giu Glu Giu Giu Giu Giu Asp Ala 55 Ala Leu Glu Ala Ser Leu -120- Ala Ala Phe Arg 0. Trp Met Gly Arg Asp Ser Leu Asp 145 Ile Lys Ala Pro His 225 Lys Met Thr Ala Thr 305 Leu I Lys I Glu S Pro X 3 Trp C 385 Gly JA Ser V Phe Ser Thr 130 Glu Glu Ile Glu Phe 210 Ser Ser Lys Ser Dsn 290 31u ?he .ys 3er ral 170 ilu LSf ral Arc Let 115 Arc Arc Lys Gin Glu 195 Lys Phe Tyr Ala Gin 275 Leu Ser Leu Glu Arg 355 Thr Glu Trp Met Arg 100 1 Thr Ile Ile Glu Ala 180 Val Ser Phe Val Ala 260 Asp Asp Ser Ser Arg 340 Arg Pro Asp Ser Leu I 420 Thr Arg Asn Ser Ala Glu Ala Ile Ile His Gly Leu. Ala Ala Thr His 165 Ile Phe Lys Gin As 245 Ala Lys Thr Glu Lys 325 Arg Ala 3lu Lys Lys 105 .ys 105 110 Cys Gin Leu Arg Thr Ile Tyr Ile Cys Gin Phe Ala Pro 150 Asp Ala Glu Leu His 230 Tyr Lye Pro Arg Gly 310 Leu Val Thr I Lye Asn 3 390 Ile I Asp I Gly 135 Leu Lys Val Arg Leu 215 Phe Val Val Ser I Lys 295 Thr Gin I fly J flu S 7 His P 375 12( Lys Glu Leu Cys Ile 200 Met Ser .eu Val fly 280 Ser lal fis 'hr er 60 Lrg Th Sez His Met 185 Phe Ile Tyr Ser Glu 265 Asn Val Ser Gly Pro 345 Arg Ala 7 Leu Asp Ala 140 Ala Leu Met 155 Glu Giu Ile 170 Glu Asn Gly Gly Asp Pro Ile Ser Gin 220 Asn His Met 235 Glu Lys Ser 250 Ser Lys Arg Asp Val Glu Ser Asp Lys 300 Leu Leu Arg 315 Thr Gin Gin 330 Gin Ser Thr Ile Pro Val Arg Lys Arg 380 125 Gin Phe Giu Asn Ile Trp Gly Gin Asn Asn 205 Lys Met Ser Thr Met 285 Gin Ser Gin Lys Ser 365 GIn Asn Phe 190 Ser Asp Glu Thr Arg 270 Glu Ser His Asp Lys 350 Lys Ala I Leu 175 Lys His Thr Lys Phe 255 Thr Thr Ala Lys Leu 335 .ys 'er rrp Ser 160 Ile Glu Met Phe Ile 240 Leu Ile Glu Val Asn 320 Asn Lys Gin Leu Gly Val 395 Tyr Lys 410 Thr Met Arg Lys Tyr Gly Glu Asn Asn Lys Leu 430 -121- Ile Ser Ser Asp Ser Glu Asp 435 <210> 152 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 152 gccccgggga tcctcatggc ggaggatgtt tcctcagcg <210> 153 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 153 tcccggggat cctcacacca ggcccgcgtc ctc <210> 154 <211> 201 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (201) <400> 154 atg gcg gag. gat gtt tcc tca gcg gcc ccg agc ccg cgg.ggc tgt gcg Met Ala Glu Asp Val Ser Ser Ala Ala Pro Ser Pro Arg Gly Cys Ala 1 5 10 gat ggt agg gat gcc gac cct act gag gag cag atg gca gaa aca gag Asp Gly Arg Asp Ala Asp Pro Thr Glu Glu Gin Met Ala Glu Thr Glu 25 aga aac gac gag gag cag ttc gaa tgc cag gaa ctg ctc gag tgc cag Arg Asn Asp Glu Glu Gin Phe Glu Cys Gin Glu Leu Leu Glu Cys Gin 40 gtg cag gtg ggg gcc ccc gag gag gag gag gag gag gag gag gac gcg Val Gin Val Gly Ala Pro Glu Giu Glu Glu Glu Glu Glu Glu Asp Ala 55 ggc ctg gtg Gly Leu Val <210> 155 <211> 67 <212> PRT. <c213> Homo sapiens <400> 155. Met Ala Glu Asp Val Ser Ser Ala Ala Pro Ser Pro Arg Gly Cys Ala 1 5 10 -122- Asp Gly Arg Asp Ala Asp Pro Thr Glu Glu Gin Met Ala Glu Thr Glu 25 Arg Asn Asp Glu Glu Gin Phe Glu Cys Gin Giu Leu Leu Glu Cys Gin 40 Val Gin Val Gly Ala Pro Glu Giu Glu Glu Giu Glu Glu Glu Asp Ala 55 Gly Leu Val CK1<210> 156 <211> 38 <212> DNA tfl<213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 156 cgcaggatcc ccttcactcc tcttcatgag gcagcttc 38 <210> 157 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Priier <400> 157 ggatccgcta aatatctgta tctccatctt taacaagatc caaaggag 48 <210> 158 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 158 gccgacttcg agtttgagca g 21 <210> 159 <211> 1103 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (9)..(1094) <400> 159 ggatcccc ttc act cct ctt cat gag gca gct tct aag aac agg gtt gaa Phe Thr Pro Leu His Glu Ala Ala Ser Lys Asn Arg Val Glu 1 5 gta tgt tct ctt ctc tta agt tat ggt gca gac cca aca ctg ctc aat 98 Val Cys Ser Leu Leu Leu 5cr Tyr Gly Ala Asp Pro Thr Leu Leu Asn 20 25 tgt cac aat aaa agt gct ata gac ttg Cys His Asn Lys Ser Ala Ile Asp Leu -123- gct ccc aca cca Ala Pro Thr Pro 40 cag tta aaa Gin Leu Lys gaa Giu cga Arg gtg Val gct Ala aga Arg ctg Leu gtg Val tct Ser ctc Leu 175 act Thr. 9gt Gly gca Ala agt Ser ttt Phe3 255 cat HisC ag. Ar ga 4 Gli aal Asi 8( gci Ali aaa Lys cac His aaa Lys eta Leu 160 ctg Leu gct Ala atc Ile aag Lys 3tc J'al 240 ?ca kia ;ga fly a tt~ 9 Le~ a gct u Ala t ttc i Phe atct ISer gga Giy *gtg Val cat His 145 cac His agc Ser t ta Leu tca Ser gct Ala 225 aac Asn gct Ala get Ala a gca tat ai Ala Tyr gat gtt Asp Val aag cat Lys His cca tat Pro Tyr gca aac Ala Asn 1115 gca tct Ala Ser 130 gaa gca Giu Ala aga get Arg Ala tat ggg Tyr Gly cag atg Gin Met 195 tta ggt Leu Gly 210 gga gat Gly Asp tgc aga Cys Arg ggg tat a Gly Tyr; 2 gat gtg c Asp Val H ttt Prc ccc Prc 100 at c Ile gag Glu aag Lys gca Ala tgt Cys 180 gga Gly aat b-sn ;tC ;al ;ac .sp iac !60 a t 'is u Ph t c9. r Arl ca 4 GI 8! aa~ Lye aat Asr aaa Lys gtt Val tat Tyr 165 gat Asp aat Asn tca Ser gaa Glu att Ile 245 aga Arg gct Ala e a aaa ggc Lys Gly .55 atc aaa Ile Lys a aca cat gaa ai Thr His Git a aga aag caa ;Arg Lys Gin gaa aag act aGiu Lys Thr 120 gct cat aat Ala His Asn 135 aat qct ctg Asn Ala Leu 150 tgt ggt cat Cys Gly His cet aac att Pro Asn Ile gaa aat gta Giu Asn Val 200 gag gca gac Glu Ala Asp 215 act gta aaa Thr Val Lys 230 gaa ggg cgt Giu Gly Arg gtq tcc gtg Val Ser Val aaa gat aaa Lys Asp Lys 280 iaca gca ttg i Thr Ala Leu ata tgt gaa Ile Cys Giu 105 aaa gaa ttc Lys Glu Phe gat gtt gtt. Asp Val Val gat aat ett Asp Asn Leu 155 cta caa ace. Leu Gin Thr 170 ata tcc ctt Ile Ser Leu 185 cag caa ctc Gin Gin Leu aga caa ttg Arg Gin Leu aaa ctg tgt Lys Leu Cys 235 cag tct aca Gin Ser Thr 250 gtg gaa tat Val Glu Tyr 265 gga ggc ctt 5 Gly Gly Leu I cal Hi cts Let ttg Leu gaa Giu 140 ggt Gly tgc Cys cag Gin etc Leu ctg Leu 220 act rhr cca ?ro :tg ,eu ta ial ttgt aCys ttg aLeu act Thr 125 *gta *Val cag Gin cgc Az-g ggc Giy caa Gin 205 gaa Giu gtt Val ctt Leu eta Leu cct Pro 285 get Ala cta Leu 110 cct Pro gtg Val act Thr cta Leu ttt Phe 190 gag Giu get Ala cag Gin cat HIis cag 31n 270 tg jeu :tg caa get gca ,eu Gin Ala Ala ct ctg gaa atg er Leu Glu Met 194 242 290 338 386 434 482 530 578 626 674 722 770 818 866 914 275 cac aat gca His Asn Ala tgt tct tat Cys Ser Tyr 290 gga cat tat Gly His Tyr 295 gaa gtt gca gaa Glu Val Ala Glu ctt ctt gtt Leu Leu Vai 300 aaa cat Lys His tta cat Leu His 320 ctc cag Leu Gin 335 cct ttg Pro Leu gca Al a gca. Ala 9gt Gly ct t Leu gta gtt aat gta gct Val Val Asn Val Ala 310 gca gca aaa. gga aaa Ala Ala Lys Gly Lys 325 gca gac cct aca aaa Ala Asp Pro Thr Lys 340 gtt aaa gat gga gat Val Lys Asp Gly Asp 355 -124- gat tta t99 aaa ttt aca cct Asp Leu Trp Lys Phe Thr Pro 315 tat gaa att tgc aaa ctt ctg Tyr Glu Ile Cys Lys Leu Leu 330 aaa aac agg gat gga aat act Lys Asn Arg Asp Gly Asn Thr 345 350 aca gat att tagcggatc Thr Asp Ile 360 962 1010 1058 1203 <210> 160 <211> 362 <c212> PRT <213> Homo sapiens* <400> 160 Phe Thr Pro Leu His 1 5 Ser Leu Leu Leu Ser Ala Ala Gly Ala Ser Lys 10 Asp Pro 25 Asn Arg Val Thr Leu Leu Glu Val 1s Asn Cys Asn Leu Ala Phe Ser Gly Val His 145 His Lys Ala Asp Lys Pro Ala Ala 130 Glu Arg Ser Tyr Val His Tyr Asn 115 Ser Ala Ala Ala Ile Asp Leu Ala Pro Thr Pro Gln Leu Lys Glu Glu Thr Pro Pro 100 Ile Glu Lys Ala Phe Arg Gin Lys Asn Lys Val Tyr 165 Lys Ile 70 Thr Arg Glu Ala Asn 150 Cys Gly 55 Lys His Lys Lys His 135 Ala Gly 40 His Lys Glu Gln Thr 120 Asn Leu His Ser His Thr Ile 105 Lys Asp Asp. Leu Leu Leu Ala Cys Giu Val Asn Gln 170 Leu Ser 75 Leu Glu Phe Val Leu 155 Thr Gin Leu His Leu Leu Giu 140 Gly Cys Ala Glu Cys Leu Thr 125 Val Gin A.rg Ala Met Ala Leu 110 Pro Val Thr Leu Arg Val Ala Arg Leu Val Ser [LCu 175 Arg Glu Asn Ala Lys His Lys Leu 160 Leu Ser Tyr Gly Cys 180 Asp Pro Asn Ile Ile 5r Leu Gin Giy 185 Phe Thr Ala 190 Gin Met 195 Leu Gly 210 Gly Asp Cys Arg Asn Ser Glu Ile 245 Glu Asn Giu Ala 215 Thr Val 230 Giu Gly Val Gin 200 Asp Arg Lys Lys Arg Gin Gin Leu Gin Leu Leu Cys 235 Ser Thr 250 Gly Al a Ser Phe 255 -125- Ala Gly Tyr Asn Arg Val Ser Val Val Glu Tyr Leu Leu Gln His Gly 260 265 270 Ala Asp Val His Ala Lys Asp Lys Gly Gly Leu Val Pro Leu His Asn 275 280 285 Ala Cys Ser Tyr Gly His Tyr Glu Val Ala Glu Leu Leu Val Lys His 290 295 300 Gly Ala Val Val Asn Val Ala Asp Leu Trp Lys Phe Thr Pro Leu Hi~s 305 310 315 320 Glu Ala Ala Ala Lys Gly Lys Tyr Glu Ile Cys Lys Leu Leu Leu Gin 325 330 335 His Gly Ala Asp Pro Thr Lys Lys Asn Arg Asp Gly Asn Thr Pro Leu In340 345 350 Asp Leu Val Lys Asp Gly Asp Thr Asp Ile 355 360 <210> 161 <c211> 39 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 161 cgtcgaccca tggcggagtc ttcggataag ctctatcga 39 <210> 162 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 162 ggaaacgcgt ttggtgccag gatttactgt cagcttctt 39 <210> 163 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 163 cttaaacgcg ttgaaggaca aacaccttta gatttagtt 39 <210> 164 <211> 79 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 164 gtcgaaagcg gccgcttagc ctccgaactg tggatgcctc cacgctccat cgaccatacc ttcaggcctc ataatctgg 79 -126- 1 <210> 165 <211> 17 S<212> DNA S<213> Artificial Sequence <220> O <223> Description of Artificial Sequence:Primer <400> 165 tttgttcgcc cagactc 17 1" S<210> 166 1 <211> 22 <212> DNA <213> Artificial Sequence S<220> 0 <223> Description of Artificial Sequence:Primer <400> 166 tatgtttcag gttcaggggg ag 22 <210> 167 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 167 gcggaagctg gaggagtgac <210> 168 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 168 gtcactcctc cagcttccgc <210> 169 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 169 aagccctgaa gaagcagctc <210> 170 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 170 -127- gagctgcttc ttcagggctt <210> 171 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 171 cagacaccca accggaagga (2 <210> 172 l <211> n <212> DNA S<213> Artificial Sequence (1 <220> <223> Description of Artificial Sequence:Primer <400> 172 tccttccggt tgggtgtctg <210> 173 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 173 tccgcctcca ccaagagcct <210> 174 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 174 aggctcttgg tggaggcgga <210> 175 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer <400> 175 tggcctggtg gacatcgtta <210> 176 <211> <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Primer -128- <400>. 176 taacgatgtc caccaggcca <c210> 177 <211> 3308 <212> DNA <~213> Artificial Sequ.ence <220> <c223> Description of Artificial Seqluence:Parpla-Tank2b Fusion <220> <c221> CDS <222> (1)..43297) <400> 177 atg aga ggc tcc cat cac cat cac cat cac gat tac gat atc Met Arg Gly Ser His His His His His His Asn Tyrr Asp~ T1 cca acg acc Thr cta Leu tac Tyr ccc Pro gat Asp 9gC Gly ct t Leu gga Gl y act Thr 145 tgc Cyr. aag Lys gaa Giu cgt Arg gcc Ala so ag Lys gga Gly cac His cgg Arg gtg Val 130 ctg Leu aag Lys aag L.ys aac ctg Asn Leu cga ccc Arg Pro sag agc Lys Ser gac tcg Asp Ser aaa gtc Lys Val tcc atc Ser Ile 100 tgg gat Trp Asp 115 aca ggc Thr Gly ggt gac Gly Asp ggg tgt Gly Cys atg gtg Met Vai 180 tat Tyr atg Met ggg Gly ctc Leu cca Pro cgg Arg gac Asp aaa Lys ttt Phe atg Met 165 gac Asp ttt cag ggc gcc atg gat Phe Gin Gly Ala Met Asp 25 ccg gas t Pro Glu P :tc aaa ggc ~he Lys Gly gcg Ala cgc Arg cgg Arg 70 cac His cac His cag Gin Gly gca Ala 150 gag Giu ccg Pro gag Glu gcc Ala 55 atg Met tgg Trp cct Pro cag Gin cag Gln 135 gca aag L~ys ;ag 3lu tct Ser 40 tct Ser gcc Ala tac Tyr gac Asp aaa Lys 120 gat Asp gag Giu ata Ile sag tcg Ser tgc Cys ate Ile cac His gtt Val 105 gtc Val gga Gly tat Tyr ;aa :ca pgat *Asp *aag Lys atg Met ttc Phe 90 gag Glu aag Lys at t Ile gtc Val aag Lys 170 cag aag ctc tat Lys aaa Lys g tg Val 75 tcc Ser gtg Val aag Lys ggt Gly aag Lys 155 9gC Gly cta Leu tgt *Cys Icag Gin *tgc *Cys ga t Asp aca Thr agc Ser 140 tcc Ser cag Gin Gly Tyr agc Ser tcg Ser ttc Phe ggg Gi y Ala 125 sag Lys ac Asn gtg Val atg M4et cga Arg gag Glu ccc Pro tg Trp ttc Phe 110 ga Glu gca Al a aga Arg cgc Arg att Ile gte Val agc Ser atg Met aag Lys tct Ser gct Ala gag Giu agt Ser ctg Leu 175 3ac gag Gi u atc Ile ttt Phe gtg Val gag Giu gga Gi y aag Lys aeg Thr 160 tcc Ser cgc 96 144 192 240 288 336 384 432 480 528 576 Lys Pro Gln Leu 185 tgg tac cat cca ggc tgc Trp Tyr His Pro Gly Cys 195 ttt gte Phe Va 1 200 aag aac agg gag Lys Asn Arg Glu 190 ctg ggt ttc Leu Gly Phe C9~ Arc a ci Thi 225 3 3 gaa Glu aag Lys 9CC Ala aag Lys aag Lys 305 ga t Asp cag Gin gcc Al a t99 Trp aag Lys 385 gtg Val aac Asn act Thr gag Glu ccc Pro 210 gag Gi u 99a Gly aag Lys cta Leu aaa Lys 290 cag Gin Gly ctg Leu tgg Trp qta. Val 370 gtt i Val gcg S Ala tcc t Ser S :tc c Leu G~ 4 aaa c Lys L 450 tac agt gcg agt cag Ctc Tyr Ser Ala Ser Gin Leu 215 aaa gaa gcc ctg aag aag Lys Giu Ala Leu Lys Lys 230 -129- aag ggc Lys Gly cag ctc Gin Leu 235 aac Ly~ aai Ly4 aac Lys 275 gtg Val caa Gin atg Met gtc Val acc rhr 355 lcC rhr ~aa .,ys ;cc 1l a :Ct ~er ;ly 35 t c eu 3 aga 5Arc tct Sex 260 gct Ala tgt Cys gtg Val gtg Val ttc Phe 340 aag Lys cca Pro aag Lys acg Thr gct Ala 420 aag Lys 999 Gly aaa Lys 245 aaa Lys ggc gat gag gtg gat 99a gtg gat gaa gtg gcg Gly Asp Giu Val Asp Gly Val Asp Giu Val Ala 250 255 aaa gaa Lys Glu aaa gac aag gat agt aag ctt gaa aaa Lys Asp Lys Asp Ser Lys Leu Glu Lys 265 270 cag aac gac ctg atc Gin Asn Asp Leu Ile 280 tca act aat gac ctg Ser Thr Asn Asp Leu 295 CCt tct 999 gag tcg Pro Ser Gly Glu Ser 310 ttc ggt 9CC CtC Ctt Phe Gly Ala Leu Leu 325 aag agc gat 9CC tat Lys Ser Asp Ala Tyr 345 tgt atg gtc aag aca Cys Met Val Lys Thr 360 aag gaa ttc cga gaa Lys Glu Phe Arg Glu 375 cag gac cgt ata ttc Gin Asp Arg Ile Phe 390 cct ccg ccc tcc aca Pro Pro Pro Ser Thr 405 tca gca gat aag cca Ser Ala Asp Lys Pro 425 Ctg tcc cgg aac aag S Leu Ser Arg Asn Lys 440 ggg aag ttg acg ggg a Gly Lys Leu Thr Gly 455 tgg Trp aag Lys gc9 Ala ccc Pro 330 tac Tyr cag Gin atc Ile ccc Pro RCC kia 410 tta eu a t ~sp LCg ,'hr aac atc aag gac Asr gag Glu atc Ile 315 tgc Cys tgc Cys aca Thr tct Ser cca Pro 395 tCg Ser tcc Ser gaa Glu 9CC Al a Ile cta ILeu 300 ttg Leu gag Glu act Thr ccc Pro tac Tyr 380 gaa Glu gCt Al a aac Asn gtg Val aac Asn 460 Lys 285 ctC Leu gac Asp gaa Glu 999 Giy aac. Asn 365 ctc Leu acc Thr Cct Pro atg Met aag Lys 445 aag Lys Asp atc Ile cga Arg tgc Cys gac Asp 350 C9g Arg aag Lys agc Ser gct Ala aag Lys 430 gcc Ala gct Ala gag cta Glu Leu ttc aac Phe Asn gta gct Val Ala 320 tcg ggt Ser Gly 335 gtc act Val Thr aag gag Lys Glu aaa ttg Lys Leu 9CC tcc Ala Ser 400 gct gtg Ala Val 415 atc ctg Ile Leu atg att Met Ile tCc ctg Ser Leu 672 720 768 816 864 912 960 1008 1056 1104 1152 1200 1248 1296 1344 1392 1440 atc agc acc aaa Ile Ser Thr Lys gag gtg gaa aag Glu Val Glu Lys aat aag aag atg Asn Lys Lys Met -130- geg tci Val Ser 490 cag gag Gin Giu ttc ctc cag Phe Leu Gin 495 tta gcg cac Leu Ala His 510 gtt gaa get Val Glu Val 505 atc Ile gtg Vai Gly 545 tta Leu cac His ctt Leu cag Gin tgg Trp 625 ccg Pro aaa Lys aag Lys aag a Lys 1 cct t ProI 705 9CC a Ala M~ Ct Let 9CC Ala 530C cag Gin act Thr tct Ser ggc Gi y ctt Leu 610 9gC Gly t cc Ser acc rhr :tc Phe iag .yS ta jeu Ltg let ;tcc Ser 515 cca Pro 9Cc Val cci Leu gcg Ala ctg Leu 595 c tg Leu cgt Arg aag Lys ggg Gly tac Tyr 675 ctg Leu gat Asp ccc Pro cct tgg Pro Trp aga ggg Arg Gly aag gag Lys Glu~ aaa gga Lys Gly 565 cat gec His Val 580 geg gac Val Asp gag gac Giu Asp gtg ggt Val Giy gag gat Giu Asp 645 aac gct Asn Ala 660 ccc ctg Pro Leu aca gta Thr Val tta gtt Leu Val cca ece c Pro Ser 725 999 gca gag gtg Gly Ala Glu Val 520 aag tca ggg gct Lys Ser Gly Ala 535 aag gca gag cct Lys Aia Giu Pro 525 gcg cC( Ala Le~ gaa Gli. 550 Giy ceg Ltu atc Ile gac Asp acg Thr 630 C Ala eg Trp, gag Giu aat ksn ca :,er 710 kla 99t IGly gca Ala gag Glu gt Val aag Lys 615 geg Val att. Ile cac His at Ile cct Pro 695 gca Ala J ctg C atc Ile gct Aia aaa Lys aaa Lys 600 gaa Giu aec Ile gag Glu tC Ser gac ksp 580 ;at 1sp aac Asr gtg Val ggt Giy 585 gga Gly aac Asn g9t Gly cac His aaa Lys 665 tat Tyr acc Thr gat Asp aaa 1Lys gat Asp 570 999 Gly acc Thr agg Arg agc Ser eeC Phe 650 aat Asn ggc aaa Lys gtC Val ege Cys 730 tct Se, 555 cct Prc aag Lys aac Asn tat Tyr aac Asn 635 atg Met tc Phe cag Gin c Arg agc Ser 715 c cc .i Ser 540 :gaa gat Asp I tC Val tCC Ser egg Trp 620 aaa Lys aaa Lys acg Thr gat c Asp C Val C 700 gct C Ala L aai Ly aaS Ly- ect Ser ttc Phe C ac Tyr 605 ata Ile cteg Leu tta Leu iag ys ;aa flu ;aa ;lu cc *eu aaa s Ly: ag 5Arl 99~ -GI~ agt Sei 590 *tac Tyr tCc Phe gaa Glu tat Tyr tat Tyr 670 gag Glu gga Gi y ctg Leu caa Gin a agc Ser atg SMet I ctg r Leu 575 9C Aia aag Lys agg Arg cag Gin gaa Giu 655 ccc Pro gca Ala caa Gin aca E Thr I geg c Val 1 735 aag Lys aaa Lys 560 gaa Giu acc Thr ceg Leu tcc Ser a tg Met 640 gaa Glu aaa Lys Rtg Ja 1 ica rhr ;ca ~la :tc ~eu 1488 1536 1584 1632 1680 1728 1776 1824 1872 1920 1968 2016 2064 2112 2160 2208 2256 Leu Pro Ser [yr Lys Pro aat g geg aga Asn Gly Val Arg 740 agc cca gga gcc Ser Pro Gly Ala ace gca gat gct ccc tct tca Thr Ala Asp Mla Leu ser Ser 745 750 -131- 9cc agc Ala Ser oca tot ago cca tca agc ctt tct gca Pro Ser Ser Pro Ser Ser Leu Ser Ala agt ctt gac aac tta Ser Leu Asp Asn Leu 765 755 760 tct Ser gag Gi u 785 agc Ser ata Ile cac His aaa Lys aac Asn 865 gat Asp caa. Gin ttC Phe. cta Leu cac His 945 aat Asn ggt Giy aat Asn ggS Gi) 770 ggt Giy ata Ile ttt Phe aag Lys cta Leu 850 cca Pro ctg Leu agt Ser aac Asn tgg Trp 930 aac Asn gca kia atg 4et :aa 3mn agt Ser got Ala act Thr gag Glu gag Giu 835 att Ile tat Tyr tot Ser aca. Thr aga Arg 915 gaa Giu cat His att. Ile ttt Phe tat Tyr 995 ttt Phe t cc Ser caa. Gin aga Arg 820 ctg Leu aaa Lys tta Leu cct Pro gtt Val 900 tac Tyr aga Arg gcc Al a into Ile gga Gly 980 ;ta lai *toe Ser *agt *Ser ttc Phe 805 gaa Giu aag Lys gga Gly act Thr gat Asp. 885 cga Arg aat Asn tac Tyr at Asn cac His 965 gct E Ala C tat g Tyr C gaa Gil ttg Leu 790 gta Val cag Gin gag Giu gtc Vai ttg Leu 870 gat Asp gag Glu intt Ile rhr ;aa 3lu 950 ~aa ys Jgc ;iy ;ga ct 7.: Gl Ar at Ii at Ii ga GI 85 aa As aea Ly cat Hit ott Lei ec Hi 93! cge Arc Gi) att Ile at t Ile :9 tct ~u Ser g aaa .u Lys g aat *g Asn c act Thr t gga e Gly 840 g aga u Arg 5 acc Thr a gag s Giu cage Arg *aag .i Lys 920 cgg S Arg atg Met ttt Phe tat Tyr gga c GlyC 1000 tca Se z aac Lys Ott Leu t tg Leu 825 a to Ile Ott Leu tct Ser ttt Phe gat Asp 905 att Ile inga ta Leu )a t ksp, -tt he ?85 ;ga gta gtt agt tca a91 Vai Val Ser Ser Se~ 780 pgag Git 9 Gly 810 gat Asp aa t Asn atc Ile ggt Gly cag Gin 890 gga Gly cag Gin aaa Lys ttt Phe gaa Giu 970 got Ala ggt Gly gtt Val 79! Ctt Le. gta Val got Al a too Ser agt Ser 875 tot Ser ggt Gly eag Lys gaa Giu cat His 955 egg Arg gaa Gi u act Thr cca Pro gag aGiu tta *Leu tat *Tyr gga Gly 860 gga Gly gtg Val cat His gt t Val gtt Val 940 999 Gly cat His2 aac Asn I GlyC 998 Gi> ca c His gtt Val gga Gly 845 caa Gin aoa Thr gag Glu gca Ala- tgt Cys 925 tct Ser tct Ser ?cg kl1a :ct ~er :gt. 'YS I *ti Val cta Le. gag Gil 830 cat His caa Gin att Ile gaa Giu ggt Gly 910 eec Asn gee .Giu cot -Pro tac Tyr too Ser 990 cca Pro tgga r Gly gat Asp aatg aMet 815 atg aMet agg Arg ggt Gly ct t Leu gag Giu 895 gga Gly aag Lys gaa Giu ttt Phe ata Ile 975 aaa Lys gtt Val I aca Thr ttt Phe 800 gat Asp 999 Gly ceo His ott Leu ata Ile 880 atg Met atc Ile aaa Lys aac PAsn ;tg Jai 960 3gt 31y Igc 'er :ac i s 2304 2352 2400 2448 2496 2544 2592 2640 2688 2736 2784' 2832 2880 2928 2976 3024 3072 1005 eea gac age tot Lys Asp Arg Ser 1010 tgt tao att tgc oec egg cag Cys Tyr Ile Cys His Arg Gin ctg oto Leu Leu 1.020 ttt t9C 099 Phe Cys Arg 1015 gta acc ttg gga aag tct ttc ctg Val Thr Leu Giy Lys Ser Phe Leu 1025 1030 cat tct cct cca 99t cat cac tca. His Ser Pro Pro Gly His His Ser 1045 ggc cta gca tta gct gaa tat gtt Gly Leu Ala Leu Ala Giu Tyr Val 1060 cct gag tat tta att act tac cag Pro Glu Tyr Leu Ile Thr Tyr Gin 1075 1080 gat gga gcg tgg agg cat cca cag Asp Gly Ala Trp, Arg His Pro Gin 1090 1095 <210> 178 <211> 1099 <212> PRT <c213> Artificial Sequence <223> Description of Artificial Fusion -132- cag ttc agt Gin Phe Ser 1035 gtc act ggt Val Thr Gly 1050 att tac aga Ile Tyr Arg 1065 att atg agg Ile Met Arg ttc gga ggc Phe Gly Gly gca atg aaa atg gca Ala Met Lys Met Ala 1040 agg ccc agt. gra aat Arg Pro Ser Val Asn 1055 gga gaa cag gcr tat Giy Glu Gin Ala Tyr 1070 cct gaa ggt atg gtc Pro Glu Gly met Val 1085 taagcggccg c 3120 3168 3216 3264 3308 Sequence: Parpla-Tank2b <400> 178 Met I Thr ILeu Tyr Pro Asp Gly Leu Gly Thr 145 Cys Lys Gly Ser Asn Leu Arg Pro Lys Ser Asp Ser Lys Val Ser Ile 100 Trp Asp 115 Thr Gly Gly Asp Giy Cys Met Val 180 His His His 5 Tyr Phe Gin Met Ala Giu Gly Arg Ala Leu Arg Met 70 Pro His Trp Arg His Pro Asp Gin Gin Lys Gly Gin 135 Phe Ala Ala 150 Met Giu Lys 165 Asp Pro Giu His His His 10 Gly Ala Met 25 Ser Ser Asp 40 Ser Cys Lys Ala Ile Met Tyr His Phe 90 Asp Val Glu 105 Lys Val Lys 120 Asp Gly Ilie Giu Tyr Val Ile Giu Lys 170 Lys Pro Gin 185 Val Lys Asn Asp Tyr Asp Ile Pro Thr is Asp Pro Glu Phe Lys Lys Val 75 Ser Val1 Lys Gi y Lys 155 Gly Leu Arg Leu Cys Gin Cys; Asp Thr Ser 140 Ser Gin Gi y Glu Tyr Ser Ser Phe Giy Al a 125 Lys Asn Val Met Glu 205 Arg Giu Pro Trp Phe 110 Giu Al a Arg Arg Ile 190 Leu Lys- Gly Vai Giu Ser Ile Met Phe Lys Val Ser Giu Ala Gly Giu Lys Ser Thr 160 Leu Ser 175 Asp Arg Giy Phe Trp Tyr His 195 Pro Gly Cys, Phe 200 Arg Pro 210 Giu Tyr Ser Ala Gin Leu Lys Gly Phe 220 Ser Leu Leu Ala Thr Glu 225 Glu Gly Asp Lys Leu Asp 245 Lys Lys Lys Ser Lys Lys Glu Lys 260 Ala Leu Lys 275 Lys Lys Val 290 Lys Gin Gin 305 Asp Gly Met Gin Leu Val Ala Trp Thr 355 Trp Val Thr 370 Lys Val Lys 385 Val Ala Ala Asn Ser Ser Thr Leu Gly,. 435 Glu Lys Leu 450 Cys Ile Ser 465 Glu Vai Lys Asp Val Ser Ile Leu Ser I 515 Vai Ala Pro 530 Gly Gin Val I 545 Leu Thr Leu I Ala Gin Asn Asp Leu Cys Ser Vai Pro Val Phe 325 Phe Lys 340 Lys Cys Pro Lys Lys Gin Thr Pro 405 Ala Ser 420 Lys Leu Gly Gly Thr Lys i 1lu Ala 2 485 la Ser 500 ?ro Trp C -rg Giy I ys Giu c lys Gly G 565 Thi Ser 310 Gly Ser Met Glu Asp 390 Pro Ala Ser Lys Lys 170 ksn Lhr fly ys ;lu 50 ;ly Asn 295 Gly Ala Asp Val Phe 375 Arg Pro Asp Arg Leu 455 Glu Ile Lys Ala C Ser C 535 280 Asp Glu Leu Ala Lys 360 Arg Ile Ser Lys Asn 440 rhr i1al krg I 3er I ;lu 1 i20 ;iy P Lys Val Asp 265 Ile Leu Ser Leu Tyr 345 Lys Asp Ser Trp Asn Ile Lys Giu Leu 300 Ala Ile Leu 315 Pro Cys Glu 330 Tyr Cys Thr Lys Lys 285 Leu Asp Glu Gly -133- Gln Leu Pro Gly Val Lys Ser 235 240 Asp Gly Val Asp Glu Val Ala 250 255 Leu 270 Asp Ile Arg Cys Asp 350 Thr Gin Thr Pro Asn Arg Lys Glu Glu Ile Phe Thr Pro 425 Lys Gly 31u ilal eu 505 ral Pro Ala 410 Leu Asp Thr Lys Val 490 Gin Lys 365 Ser Tyr Leu 380 Pro Glu Thr 395 Ser Aia Pro Ser Asn Met Glu Val Lys 445 Ala Asn Lys 460 Met Asn Lys 475 Ser Giu Asp Glu Leu Phe Ala Giu Pro 525 Leu Ser Lys 540 Ser Giu Lys 555 Pro Asp Ser I Lys Ser Ala Lys 430 Ala Ala Lys Phe Leu 510 Val Lys Arg Gly Lys Ala Ala 415 Ile Met Ser Met Leu 495 Ala Glu Ser Met Leu 575 Leu Ser 400 Val Leu Ile Leu Glu 480 Gin His Val Lys Lys 560 "lu la Ala Gly Ile Asn Lys Ala Ala Vai Asp His Ser Ala His Val Leu 580 Glu Lys Gly Gly Lys Val Phe Ser Ala Thr 585 590 -134- Thr Asn Leu Gly Leu Val Asp Ile Val Lys Gly 595 600 Ser Tyr Tyr Lys Leu 605 Gin Trp 625 Pro Lys Lys Lys Pro 705 Ala Asn Pro Ser Glu 785 Ser Ile His Lys Asn i 865 Asp Gin Phe I' Leu 1 Leu 610 Gly Ser Thr Phe Lys 690 Leu Met Gly Ser Gly 770 Gly Ile Phe Lys Leu 850 Pro eu ;er ~sn ;rp Leu Arg Lys Gly Tyr 675 Leu Asp Pro Val Ser 755 Ser Ala Thr. Glu Glu 835 Ile Tyr Ser I Thr I Arg *J 915 Glu I Glu Val Glu Asn 660 Pro Thr Leu Pro Arg 740 Pro Phe Ser Gin Arg 820 Leu Lys Leu Pro /al )00 [yr Lrg Asp Gly Asp 645 Ala Leu Val Val Ser 725 Ser Ser Ser Ser Phe 805 Glu Lys Gly Thr Asp 885 Arg Asn 3 Tyr 'I As Th 63 Al Tr Gh1 Asr Sex 710 Ala Pro Ser Glu Leu 790 Val Gin Glu Val Leu 870 ksp ;lu le rhr p Lys 615 r Val 0 a Ile His Ile Pro 695 Ala Leu Gly Leu Leu 775 Glu Arg .Ile Ile Glu 855 Asn Lys His J Leu I His I 935 Gle Ile Glu Ser Asp 680 Gly Asp Pro Ala Ser 760 Ser Lys Asn Thr Gly 540 Arg rhr lu krg .ys )20 rg As G13 I His Lys 665 Tyr Thr Asp Ser Thr 745 Ala Ser Lys Leu Leu 825 Ile Leu Ser Phe Asp 905 Ile Arg I Arg Ser Phe 650 Asn Gly Lys Val Cys 730 Ala Ala Val Glu Gly 810 Asp Asn Ile Gly Gin 990 Gly Gin I Lys C Tyl Asr 63e Met Phe Gir Arg Ser 715 Tyr Asp Ser Val Val 795 Leu Val Ala Ser Ser 375 er ,ly .4's r Trp 620 i Lys Lys Thr Asp Val 700 Ala Lys Ala Ser Ser 780 Pro Glu I Leu Tyr Gly 860 Gly I Val G His A Val C 9 Ile Leu Leu Lys Glu 685 Glu Leu Pro Leu Leu 765 Ser Gly His 1al fly 845 In 'hr lu la .ys Phe I Glu Tyr Tyr 670 Glu Gly Leu Gin Ser 750 Asp Ser Val Leu Glu 830 His Gin Ile Glu Gly 910 Asn Arg Gin Glu 655 Pro Ala Gin Thr Val 735 Ser Asn Gly Asp Met 815 Met I Arg I Gly i Leu Glu !v 895 Gly I Lys I Ser Met 640 Glu Lys Val Thr Ala 720 Leu Cly Leu Thr Phe 800 Asp .ly His Aeu Ile 880 et *le ys flu Val Sen Giu Giu Asn 940 iis Gly Ser Pro Phe Vai 155 960 Asn His Ala Asn Arg Met Leu Phe Asn Ala Ile Ile His L.ys Giy Phe Asp Giu Arg His Ala Tyr Ile Gly 965 970 975 Gly Met Phe Gly Ala Giy Ile Tyr Phe Ala Giu Asn Ser Ser Lys Ser 980 985 990 Asn Gin Tyr Val Tyr Gly Ile Gly Gly Giy Thr Gly Cys Pro Val His 995 1000 1005 Lys Asp Arg Ser Cys Tyr Ile Cys His Arg Gin Leu Leu Phe Cys Arg 1010 1015 1020 Val Thr Leu Gly Lys Ser Phe Leu Gin Phe Ser Ala Met Lys Met Ala 1025 1030 1035 1040 His Ser Pro Pro Gly His His Ser Val Thr Gly Arg Pro Ser Val Asn cI1045 1050 1055 Giy Leu Ala Leu Ala Glu Tyr Val Ile Tyr Arg Gly Giu Gin Ala Tyr 1060 1065 1070 ciPro Glu Tyr LeuIle Thr Tyr Gin Ile Met Arg Pro Glu Gly Met Val 1075 1080 1085 Asp Giy Ala Trp Arg His Pro Gin Phe Gly Gly 1090 1095