HGNC Approved Gene Symbol:PRKCZ
Cytogenetic location:1p36.33 Genomic coordinates(GRCh38) :1:2,048,504-2,185,395 (from NCBI)
Protein kinase C (PKC)-zeta is an atypical member of the PKC family. Like other PKCs, PKC-zeta has an N-terminal regulatory domain, followed by a hinge region and a C-terminal catalytic domain. Second messengers stimulate PKCs by binding to the regulatory domain, translocating the enzyme from cytosol to membrane, and producing a conformational change that releases PKC autoinhibition. PKM-zeta, a brain-specific isoform of PKC-zeta generated from an alternative transcript, lacks the regulatory region of full-length PKC-zeta and is therefore persistently active (Hernandez et al., 2003).
Barbee et al. (1993) isolated a full-length cDNA clone encoding the PRKCZ isoform from a human brain cDNA library. The deduced 592-amino acid sequence had 95 to 96% identity to the sequences deduced from the previously described rat and mouse PRKC-zeta clones.
Hernandez et al. (2003) determined that the PKM-zeta transcript uses an alternative intronic promoter and differs from full-length PKC-zeta in its 5-prime end. Northern blot and RT-PCR analyses detected 2 Pkm-zeta transcripts that differed in the lengths of their 3-prime UTRs and were highly expressed in rat brain, but not in nonneural tissues. Two Pkc-zeta transcripts were detected in kidney, lung, testis, and cerebellum, but not in other brain regions examined. Western blot analysis of several rat tissues detected Pkc-zeta in brain and in most other tissues examined, but Pkm-zeta was only detected in brain.
Hernandez et al. (2003) determined that the PRKCZ gene contains 18 exons. The first 4 exons encode the 5-prime UTR and part of the regulatory domain of full-length PRKCZ, and they are separated from the 3-prime exons by a 75.7-kb intron. This intron contains an additional exon, 1-prime, that is used by the PKM-zeta transcript. The exon 1-prime sequence is highly conserved between rat, mouse, and human, and in all 3 species it contains a canonical cAMP response element and binding sites for NFKB (see164011) and CEBP (CEBPA;116897). The human promoter contains an additional partial CRE duplication.
In the course of searching for candidate genes that were potentially involved in a form of autosomal recessive early-onset parkinsonism (PARK7;606324) that maps to 1p36,van Duijn et al. (2001) found that the PRKCZ gene maps to that region; this was determined by scrutiny of the sequence provided by the Human Genome Project.
The results ofGong et al. (1999) suggested that the rat homolog of p62 (601530), named ZIP for 'PKC-zeta-interacting protein,' acts as a link that targets the activity of Kv-beta-2 (601142) and PKC-zeta.
Studies in rodent cells have suggested that atypical PKC (aPKC) isoforms (zeta, lambda, and iota (600539)) and protein kinase B (PKB;164730), as well as their upstream activators, phosphatidylinositol 3-kinase (PI3K; see171834) and 3-phosphoinositide-dependent protein kinase-1 (PDK1;605213), play important roles in insulin-stimulated glucose transport. Using preadipocyte-derived adipocytes,Bandyopadhyay et al. (2002) examined these requirements in a human cell type. These adipocytes were found to contain PKC-zeta, rather than PKC-lambda/iota, as their major aPKC. Expression of kinase-inactive forms of PDK1, PKC-zeta, and PKC-lambda effectively inhibited insulin-stimulated glucose transport. In contrast, expression of wildtype and constitutively active PKC-zeta or PKC-lambda increased glucose transport.
In higher eukaryotes, the small GTPase CDC42 (116952), acting through a PAR6 (607484)-aPKC (PKC-zeta) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division, and directed cell migration.Etienne-Manneville and Hall (2003) used primary rat astrocytes in a cell migration assay to demonstrate that PAR6-PKC-zeta interacts directly with and regulates glycogen synthase kinase-3-beta (GSK3-beta;605004) to promote polarization of the centrosome and to control the direction of cell protrusion. CDC42-dependent phosphorylation of GSK3-beta occurs specifically at the leading edge of migrating cells, and induces the interaction of APC (611731) protein with the plus ends of microtubules. The association of APC with microtubules is essential for cell polarization.Etienne-Manneville and Hall (2003) concluded that CDC42 regulates cell polarity through the spatial regulation of GSK3-beta and APC.
The constitutively active form of the aPKC-zeta isozyme, protein kinase M-zeta, is necessary and sufficient for long-term potentiation (LTP) and maintenance (Sacktor et al., 1993;Ling et al., 2002).Pastalkova et al. (2006) demonstrated that a cell-permeable protein kinase M-zeta inhibitor injected into rat hippocampus both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus,Pastalkova et al. (2006) concluded that the mechanism maintaining LTP sustains spatial memory.
Sajikumar et al. (2005) found that persistent PKM-zeta activity maintains potentiated responses, not only at the strongly tetanized pathway, but also at the weakly tetanized pathway. In contrast, an independent nontetanized pathway was unaffected by the inhibitor, indicating that the function of PKM-zeta was specific to the tagged synapses. To further delineate the specificity of the function of PKM-zeta in synaptic tagging, they examined synaptic crosstagging, in which late LTP in one input can transform early into late long-term depression (LTD) in a separate input or, alternatively, late LTD in one input can transform early into late LTP in a second input, provided that the tags of the weak inputs are set. Although the PKM-zeta inhibitor reversed late LTP, it did not prevent the persistent depression at the weakly stimulated, crosstagged LTD input. Conversely, although the agent did not reverse late LTD, it blocked the persistent potentiation of weakly tetanized, crosstagged synapses. Thus,Sajikumar et al. (2005) concluded that PKM-zeta is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and crosstagging.
Shema et al. (2007) found that in the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, PKM-zeta. The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form.
Zhang et al. (2007) found that downregulation of Dvl (DVL1;601365) abrogated axon differentiation in cultured embryonic rat hippocampal neurons, whereas overexpression of Dvl resulted in multiple axon formation. A complex of PAR3 (PARD3;606745), PAR6 (607485), and an aPKC, such as PKC-zeta, is required for axon-dendrite differentiation, andZhang et al. (2007) found that Dvl associated with Pkc-zeta in rat brain and transfected human embryonic kidney cells. The interaction of Dvl with Pkc-zeta resulted in stabilization and activation of Pkc-zeta. Expression of dominant-negative Pkc-zeta attenuated multiple axon formation due to Dvl overexpression in neurons, and overexpression of Pkc-zeta prevented axon loss due to Dvl downregulation. Wnt5a (164975), a noncanonical Wnt, activated Pkc-zeta and promoted axon differentiation, and downregulation of Dvl or inhibition of Pkc-zeta attenuated the Wnt5a effect on axon differentiation.Zhang et al. (2007) concluded that WNT5A and DVL promote axon differentiation mediated by the PAR3-PAR6-aPKC complex.
Formation of the apical surface and lumen is a fundamental step in epithelial organ development.Martin-Belmonte et al. (2007) showed that Pten (601728) localized to the apical plasma membrane during epithelial morphogenesis to mediate enrichment of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) at this domain during cyst development in a 3-dimensional Madin-Darby canine kidney cell system. Ectopic PtdIns(4,5)P2 at the basolateral surface caused apical proteins to relocalize to the basolateral surface. Annexin-2 (ANX2;151740) bound PtdIns(4,5)P2 and was recruited to the apical surface. Anx2 bound Cdc42 and recruited it to the apical surface, and Cdc42 in turn recruited the Par6/aPKC complex to the apical surface. Loss of function of Pten, Anx2, Cdc42, or aPKC prevented normal development of the apical surface and lumen.Martin-Belmonte et al. (2007) concluded that PTEN, PtdIns(4,5)P2, ANX2, CDC42, and aPKC control apical plasma membrane and lumen formation.
Coureuil et al. (2009) demonstrated that the type IV pili-mediated adhesion of N. meningitidis to brain endothelial cells recruits the Par3/Par6/Prkcz polarity complex that plays a pivotal role in the establishment of eukaryotic cell polarity and formation of intercellular junctions. This recruitment leads to the formation of ectopic intercellular junctional domains at the site of bacteria-host cell interaction and subsequently to depletion of junctional proteins at the cell-cell interface with opening of the intercellular junctions of the brain-endothelial interface.
Li et al. (2010) found that Pkmz maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of Pkmz in the ACC, and inhibiting Pkmz by a selective inhibitor, zeta-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization.Li et al. (2010) concluded that PKMZ in the ACC acts to maintain neuropathic pain.
Shema et al. (2011) reported that overexpression in the rat neocortex of the protein kinase C isozyme PKM-zeta enhanced long-term memory, whereas a dominant-negative PKMZ disrupted memory, even long after memory had been formed.
Using confocal microscopy,Barnett et al. (2012) showed that after immunization, Bcl6 (109565), Il21r (605383), and Prkcz colocalized with the microtubule-organizing center in a polarized manner to 1 side of the plane of division in mouse germinal center B cells, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B cells from mice lacking Icam1 (147840) failed to divide asymmetrically.Barnett et al. (2012) proposed that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.
Using isoelectric focusing in combination with suitable inhibitors in lymphoblastoid cell lines (LCLs) from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (see254500), or Waldenstrom macroglobulinemia (see153600), whose paraprotein targeted paratarg-7 (STOML2;608292) and who were carriers of hyperphosphorylated paratarg-7 (615121),Preuss et al. (2011) demonstrated that PRKCZ is the active kinase responsible for phosphorylation at ser17 of paratarg-7, which was confirmed by coimmunoprecipitation experiments. Analysis of LCLs from patients and controls showed that phosphorylation of paratarg-7 occurred in both, but dephosphorylation was inhibited in patients carrying hyperphosphorylated paratarg-7. Protease inhibitor experiments with LCLs revealed that PPP2CA (176915) is responsible for the dephosphorylation of the hyperphosphorylated form of paratarg-7.
Leitges et al. (2001) created mice with targeted disruption of the Prkcz gene. These mice, although grossly normal, showed phenotypic alterations in secondary lymphoid organs reminiscent of those of Tnfr1 (191190)- and Ltbr (600979)-deficient mice. The lack of Prkcz in embryonic fibroblasts severely impaired I-kappa-B-dependent transcriptional activity as well as cytokine-induced phosphorylation of p65 (164014). Also, a cytokine-inducible interaction of Prkcz with p65 was detected that required the prior degradation of I-kappa-B. Although in Prkcz -/- embryonic fibroblasts this kinase was not necessary for IKK (see603258) activation, in lung, which abundantly expresses Prkcz, IKK activation was inhibited.
Martin et al. (2002) found that the loss of Prkcz in mice impaired signaling through the B-cell receptor (see112205), resulting in inhibition of cell proliferation and survival, as well as defects in the activation of Erk (see MAPK3;601795) and the transcription of NF-kappa-B-dependent genes. Furthermore, Prkcz-null mice were unable to mount an optimal T cell-dependent immune response.
Lee et al. (2013) targeted exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-zeta and PKM-zeta (Prkcz -/- mice). Prkcz -/- mice showed normal behavior in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behavior. Notably, Prkcz -/- mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wildtype littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz -/- mice. In vitro, ZIP and scrambled ZIP inhibited PKM-zeta, PKC-lambda, and PKC-zeta with similar inhibition constant (Ki) values. Chelerythrine was a weak inhibitor of PKM-zeta (Ki = 76 micromolar).Lee et al. (2013) concluded that their findings showed that absence of PKM-zeta does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-zeta is not present.
To further investigate the involvement of PKM-zeta in the maintenance of long-term potentiation and memory,Volk et al. (2013) generated transgenic mice lacking PKC-zeta and PKM-zeta. They found that both conventional and conditional PKC-zeta/PKM-zeta knockout mice showed normal synaptic transmission and long-term potentiation at Schaffer collateral-CA1 synapses, and had no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reversed long-term potentiation in PKC-zeta/PKM-zeta knockout mice, indicating that the effects of ZIP are independent of PKM-zeta.
Bandyopadhyay, G., Sajan, M. P., Kanoh, Y., Standaert, M. L., Quon, M. J., Lea-Currie, R., Sen, A., Farese, R. V.PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes. J. Clin. Endocr. Metab. 87: 716-723, 2002. [PubMed:11836310,related citations] [Full Text]
Barbee, J. L., Deutscher, S. L., Loomis, C. R., Burns, D. J.The cDNA sequence encoding human protein kinase C-zeta. Gene 132: 305-306, 1993. [PubMed:8224878,related citations] [Full Text]
Barnett, B. E., Ciocca, M. L., Goenka, R., Barnett, L. G., Wu, J., Laufer, T. M., Burkhardt, J. K., Cancro, M. P., Reiner, S. L.Asymmetric B cell division in the germinal center reaction. Science 335: 342-344, 2012. [PubMed:22174128,images,related citations] [Full Text]
Coureuil, M., Mikaty, G., Miller, F., Lecuyer, H., Bernard, C., Bourdoulous, S., Dumenil, G., Mege, R.-M., Weksler, B. B., Romero, I. A., Couraud, P.-O., Nassif, X.Meningococcal type IV pili recruit the polarity complex to cross the brain endothelium. Science 325: 83-87, 2009. [PubMed:19520910,images,related citations] [Full Text]
Etienne-Manneville, S., Hall, A.Cdc42 regulates GSK-3-beta and adenomatous polyposis coli to control cell polarity. Nature 421: 753-756, 2003. [PubMed:12610628,related citations] [Full Text]
Gong, J., Xu, J., Bezanilla, M., van Huizen, R., Derin, R., Li, M.Differential stimulation of PKC phosphorylation of potassium channels by ZIP1 and ZIP2. Science 285: 1565-1569, 1999. [PubMed:10477520,related citations] [Full Text]
Hernandez, A. I., Blace, N., Crary, J. F., Serrano, P. A., Leitges, M., Libien, J. M., Weinstein, G., Tcherapanov, A., Sacktor, T. C.Protein kinase M-zeta synthesis from a brain mRNA encoding an independent protein kinase C-zeta catalytic domain: implications for the molecular mechanism of memory. J. Biol. Chem. 278: 40305-40316, 2003. [PubMed:12857744,related citations] [Full Text]
Lee, A. M., Kanter, B. R., Wang, D., Lim, J. P., Zou, M. E., Qiu, C., McMahon, T., Dadgar, J., Fischbach-Weiss, S. C., Messing, R. O.Prkcz null mice show normal learning and memory. Nature 493: 416-419, 2013. [PubMed:23283171,images,related citations] [Full Text]
Leitges, M., Sanz, L., Martin, P., Duran, A., Braun, U., Garcia, J. F., Camacho, F., Diaz-Meco, , M. T., Rennert, P. D., Moscat, J.Targeted disruption of the zeta-PKC gene results in the impairment of the NF-kappa-B pathway. Molec. Cell 8: 771-780, 2001. [PubMed:11684013,related citations] [Full Text]
Li, X.-Y., Ko, H.-G., Chen, T., Descalzi, G., Koga, K., Wang, H., Kim, S. S., Shang, Y., Kwak, C., Park, S.-W., Shim, J., Lee, K., Collingridge, G. L., Kaang, B.-K., Zhuo, M.Alleviating neuropathic pain hypersensitivity by inhibiting PKM-zeta in the anterior cingulate cortex. Science 330: 1400-1404, 2010. [PubMed:21127255,related citations] [Full Text]
Ling, D. S. F., Benardo, L. S., Serrano, P. A., Blace, N., Kelly, M. T., Crary, J. F., Sacktor, T. C.Protein kinase M-zeta is necessary and sufficient for LTP maintenance. Nature Neurosci. 5: 295-296, 2002. [PubMed:11914719,related citations] [Full Text]
Martin, P., Duran, A., Minguet, S., Gaspar, M.-L., Diaz-Meco, M.-T., Rennert, P., Leitges, M., Moscat, J.Role of zeta-PKC in B-cell signaling and function. EMBO J. 21: 4049-4057, 2002. [PubMed:12145205,images,related citations] [Full Text]
Martin-Belmonte, F., Gassama, A., Datta, A., Yu, W., Rescher, U., Gerke, V., Mostov, K.PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128: 383-397, 2007. [PubMed:17254974,images,related citations] [Full Text]
Pastalkova, E., Serrano, P., Pinkhasova, D., Wallace, E., Fenton, A. A., Sacktor, T. C.Storage of spatial information by the maintenance mechanism of LTP. Science 313: 1141-1144, 2006. [PubMed:16931766,related citations] [Full Text]
Preuss, K.-D., Pfreundschuh, M., Fadle, N., Regitz, E., Raudies, S., Murwaski, N., Ahlgrimm, M., Bittenbring, J., Klotz, M., Schafer, K.-H., Held, G., Neumann, F., Grass, S.Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood 118: 3340-3346, 2011. [PubMed:21791414,related citations] [Full Text]
Sacktor, T. C., Osten, P., Valsamis, H., Jiang, X., Naik, M. U., Sublette, E.Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. Proc. Nat. Acad. Sci. 90: 8342-8346, 1993. [PubMed:8378304,related citations] [Full Text]
Sajikumar, S., Navakkode, S., Sacktor, T. C., Frey, J. U.Synaptic tagging and cross-tagging: the role of protein kinase M-zeta in maintaining long-term potentiation but not long-term depression. J. Neurosci. 25: 5750-5756, 2005. [PubMed:15958741,images,related citations] [Full Text]
Shema, R., Haramati, S., Ron, S., Hazvi, S., Chen, A., Sacktor, T. C., Dudai, Y.Enhancement of consolidated long-term memory by overexpression of protein kinase M-zeta in the neocortex. Science 331: 1207-1210, 2011. [PubMed:21385716,related citations] [Full Text]
Shema, R., Sacktor, T. C., Dudai, Y.Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. Science 317: 951-953, 2007. [PubMed:17702943,related citations] [Full Text]
van Duijn, C. M., Dekker, M. C. J., Bonifati, V., Galjaard, R. J., Houwing-Duistermaat, J. J., Snijders, P. J. L. M., Testers, L., Breedveld, G. J., Horstink, M., Sandkuijl, L. A., van Swieten, J. C., Oostra, B. A., Heutink, P.PARK7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am. J. Hum. Genet. 69: 629-634, 2001. [PubMed:11462174,related citations] [Full Text]
Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y., Huganir, R. L.PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory. Nature 493: 420-423, 2013. [PubMed:23283174,images,related citations] [Full Text]
Zhang, X., Zhu, J., Yang, G.-Y., Wang, Q.-J., Qian, L., Chen, Y.-M., Chen, F., Tao, Y., Hu, H.-S., Wang, T., Luo, Z.-G.Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nature Cell Biol. 9: 743-754, 2007. [PubMed:17558396,related citations] [Full Text]
Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PRKCZ
Cytogenetic location: 1p36.33 Genomic coordinates(GRCh38) : 1:2,048,504-2,185,395(from NCBI)
Protein kinase C (PKC)-zeta is an atypical member of the PKC family. Like other PKCs, PKC-zeta has an N-terminal regulatory domain, followed by a hinge region and a C-terminal catalytic domain. Second messengers stimulate PKCs by binding to the regulatory domain, translocating the enzyme from cytosol to membrane, and producing a conformational change that releases PKC autoinhibition. PKM-zeta, a brain-specific isoform of PKC-zeta generated from an alternative transcript, lacks the regulatory region of full-length PKC-zeta and is therefore persistently active (Hernandez et al., 2003).
Barbee et al. (1993) isolated a full-length cDNA clone encoding the PRKCZ isoform from a human brain cDNA library. The deduced 592-amino acid sequence had 95 to 96% identity to the sequences deduced from the previously described rat and mouse PRKC-zeta clones.
Hernandez et al. (2003) determined that the PKM-zeta transcript uses an alternative intronic promoter and differs from full-length PKC-zeta in its 5-prime end. Northern blot and RT-PCR analyses detected 2 Pkm-zeta transcripts that differed in the lengths of their 3-prime UTRs and were highly expressed in rat brain, but not in nonneural tissues. Two Pkc-zeta transcripts were detected in kidney, lung, testis, and cerebellum, but not in other brain regions examined. Western blot analysis of several rat tissues detected Pkc-zeta in brain and in most other tissues examined, but Pkm-zeta was only detected in brain.
Hernandez et al. (2003) determined that the PRKCZ gene contains 18 exons. The first 4 exons encode the 5-prime UTR and part of the regulatory domain of full-length PRKCZ, and they are separated from the 3-prime exons by a 75.7-kb intron. This intron contains an additional exon, 1-prime, that is used by the PKM-zeta transcript. The exon 1-prime sequence is highly conserved between rat, mouse, and human, and in all 3 species it contains a canonical cAMP response element and binding sites for NFKB (see 164011) and CEBP (CEBPA; 116897). The human promoter contains an additional partial CRE duplication.
In the course of searching for candidate genes that were potentially involved in a form of autosomal recessive early-onset parkinsonism (PARK7; 606324) that maps to 1p36, van Duijn et al. (2001) found that the PRKCZ gene maps to that region; this was determined by scrutiny of the sequence provided by the Human Genome Project.
The results of Gong et al. (1999) suggested that the rat homolog of p62 (601530), named ZIP for 'PKC-zeta-interacting protein,' acts as a link that targets the activity of Kv-beta-2 (601142) and PKC-zeta.
Studies in rodent cells have suggested that atypical PKC (aPKC) isoforms (zeta, lambda, and iota (600539)) and protein kinase B (PKB; 164730), as well as their upstream activators, phosphatidylinositol 3-kinase (PI3K; see 171834) and 3-phosphoinositide-dependent protein kinase-1 (PDK1; 605213), play important roles in insulin-stimulated glucose transport. Using preadipocyte-derived adipocytes, Bandyopadhyay et al. (2002) examined these requirements in a human cell type. These adipocytes were found to contain PKC-zeta, rather than PKC-lambda/iota, as their major aPKC. Expression of kinase-inactive forms of PDK1, PKC-zeta, and PKC-lambda effectively inhibited insulin-stimulated glucose transport. In contrast, expression of wildtype and constitutively active PKC-zeta or PKC-lambda increased glucose transport.
In higher eukaryotes, the small GTPase CDC42 (116952), acting through a PAR6 (607484)-aPKC (PKC-zeta) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division, and directed cell migration. Etienne-Manneville and Hall (2003) used primary rat astrocytes in a cell migration assay to demonstrate that PAR6-PKC-zeta interacts directly with and regulates glycogen synthase kinase-3-beta (GSK3-beta; 605004) to promote polarization of the centrosome and to control the direction of cell protrusion. CDC42-dependent phosphorylation of GSK3-beta occurs specifically at the leading edge of migrating cells, and induces the interaction of APC (611731) protein with the plus ends of microtubules. The association of APC with microtubules is essential for cell polarization. Etienne-Manneville and Hall (2003) concluded that CDC42 regulates cell polarity through the spatial regulation of GSK3-beta and APC.
The constitutively active form of the aPKC-zeta isozyme, protein kinase M-zeta, is necessary and sufficient for long-term potentiation (LTP) and maintenance (Sacktor et al., 1993; Ling et al., 2002). Pastalkova et al. (2006) demonstrated that a cell-permeable protein kinase M-zeta inhibitor injected into rat hippocampus both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, Pastalkova et al. (2006) concluded that the mechanism maintaining LTP sustains spatial memory.
Sajikumar et al. (2005) found that persistent PKM-zeta activity maintains potentiated responses, not only at the strongly tetanized pathway, but also at the weakly tetanized pathway. In contrast, an independent nontetanized pathway was unaffected by the inhibitor, indicating that the function of PKM-zeta was specific to the tagged synapses. To further delineate the specificity of the function of PKM-zeta in synaptic tagging, they examined synaptic crosstagging, in which late LTP in one input can transform early into late long-term depression (LTD) in a separate input or, alternatively, late LTD in one input can transform early into late LTP in a second input, provided that the tags of the weak inputs are set. Although the PKM-zeta inhibitor reversed late LTP, it did not prevent the persistent depression at the weakly stimulated, crosstagged LTD input. Conversely, although the agent did not reverse late LTD, it blocked the persistent potentiation of weakly tetanized, crosstagged synapses. Thus, Sajikumar et al. (2005) concluded that PKM-zeta is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and crosstagging.
Shema et al. (2007) found that in the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, PKM-zeta. The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form.
Zhang et al. (2007) found that downregulation of Dvl (DVL1; 601365) abrogated axon differentiation in cultured embryonic rat hippocampal neurons, whereas overexpression of Dvl resulted in multiple axon formation. A complex of PAR3 (PARD3; 606745), PAR6 (607485), and an aPKC, such as PKC-zeta, is required for axon-dendrite differentiation, and Zhang et al. (2007) found that Dvl associated with Pkc-zeta in rat brain and transfected human embryonic kidney cells. The interaction of Dvl with Pkc-zeta resulted in stabilization and activation of Pkc-zeta. Expression of dominant-negative Pkc-zeta attenuated multiple axon formation due to Dvl overexpression in neurons, and overexpression of Pkc-zeta prevented axon loss due to Dvl downregulation. Wnt5a (164975), a noncanonical Wnt, activated Pkc-zeta and promoted axon differentiation, and downregulation of Dvl or inhibition of Pkc-zeta attenuated the Wnt5a effect on axon differentiation. Zhang et al. (2007) concluded that WNT5A and DVL promote axon differentiation mediated by the PAR3-PAR6-aPKC complex.
Formation of the apical surface and lumen is a fundamental step in epithelial organ development. Martin-Belmonte et al. (2007) showed that Pten (601728) localized to the apical plasma membrane during epithelial morphogenesis to mediate enrichment of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) at this domain during cyst development in a 3-dimensional Madin-Darby canine kidney cell system. Ectopic PtdIns(4,5)P2 at the basolateral surface caused apical proteins to relocalize to the basolateral surface. Annexin-2 (ANX2; 151740) bound PtdIns(4,5)P2 and was recruited to the apical surface. Anx2 bound Cdc42 and recruited it to the apical surface, and Cdc42 in turn recruited the Par6/aPKC complex to the apical surface. Loss of function of Pten, Anx2, Cdc42, or aPKC prevented normal development of the apical surface and lumen. Martin-Belmonte et al. (2007) concluded that PTEN, PtdIns(4,5)P2, ANX2, CDC42, and aPKC control apical plasma membrane and lumen formation.
Coureuil et al. (2009) demonstrated that the type IV pili-mediated adhesion of N. meningitidis to brain endothelial cells recruits the Par3/Par6/Prkcz polarity complex that plays a pivotal role in the establishment of eukaryotic cell polarity and formation of intercellular junctions. This recruitment leads to the formation of ectopic intercellular junctional domains at the site of bacteria-host cell interaction and subsequently to depletion of junctional proteins at the cell-cell interface with opening of the intercellular junctions of the brain-endothelial interface.
Li et al. (2010) found that Pkmz maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of Pkmz in the ACC, and inhibiting Pkmz by a selective inhibitor, zeta-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. Li et al. (2010) concluded that PKMZ in the ACC acts to maintain neuropathic pain.
Shema et al. (2011) reported that overexpression in the rat neocortex of the protein kinase C isozyme PKM-zeta enhanced long-term memory, whereas a dominant-negative PKMZ disrupted memory, even long after memory had been formed.
Using confocal microscopy, Barnett et al. (2012) showed that after immunization, Bcl6 (109565), Il21r (605383), and Prkcz colocalized with the microtubule-organizing center in a polarized manner to 1 side of the plane of division in mouse germinal center B cells, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B cells from mice lacking Icam1 (147840) failed to divide asymmetrically. Barnett et al. (2012) proposed that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.
Using isoelectric focusing in combination with suitable inhibitors in lymphoblastoid cell lines (LCLs) from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (see 254500), or Waldenstrom macroglobulinemia (see 153600), whose paraprotein targeted paratarg-7 (STOML2; 608292) and who were carriers of hyperphosphorylated paratarg-7 (615121), Preuss et al. (2011) demonstrated that PRKCZ is the active kinase responsible for phosphorylation at ser17 of paratarg-7, which was confirmed by coimmunoprecipitation experiments. Analysis of LCLs from patients and controls showed that phosphorylation of paratarg-7 occurred in both, but dephosphorylation was inhibited in patients carrying hyperphosphorylated paratarg-7. Protease inhibitor experiments with LCLs revealed that PPP2CA (176915) is responsible for the dephosphorylation of the hyperphosphorylated form of paratarg-7.
Leitges et al. (2001) created mice with targeted disruption of the Prkcz gene. These mice, although grossly normal, showed phenotypic alterations in secondary lymphoid organs reminiscent of those of Tnfr1 (191190)- and Ltbr (600979)-deficient mice. The lack of Prkcz in embryonic fibroblasts severely impaired I-kappa-B-dependent transcriptional activity as well as cytokine-induced phosphorylation of p65 (164014). Also, a cytokine-inducible interaction of Prkcz with p65 was detected that required the prior degradation of I-kappa-B. Although in Prkcz -/- embryonic fibroblasts this kinase was not necessary for IKK (see 603258) activation, in lung, which abundantly expresses Prkcz, IKK activation was inhibited.
Martin et al. (2002) found that the loss of Prkcz in mice impaired signaling through the B-cell receptor (see 112205), resulting in inhibition of cell proliferation and survival, as well as defects in the activation of Erk (see MAPK3; 601795) and the transcription of NF-kappa-B-dependent genes. Furthermore, Prkcz-null mice were unable to mount an optimal T cell-dependent immune response.
Lee et al. (2013) targeted exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-zeta and PKM-zeta (Prkcz -/- mice). Prkcz -/- mice showed normal behavior in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behavior. Notably, Prkcz -/- mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wildtype littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz -/- mice. In vitro, ZIP and scrambled ZIP inhibited PKM-zeta, PKC-lambda, and PKC-zeta with similar inhibition constant (Ki) values. Chelerythrine was a weak inhibitor of PKM-zeta (Ki = 76 micromolar). Lee et al. (2013) concluded that their findings showed that absence of PKM-zeta does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-zeta is not present.
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