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CD226

From Wikipedia, the free encyclopedia
Protein found in humans
CD226
Available structures
PDBOrtholog search:PDBeRCSB
List of PDB id codes

6ISA,6ISC,6ISB,6O3O

Identifiers
AliasesCD226, DNAM-1, DNAM1, PTA1, TLiSA1, CD226 molecule
External IDsOMIM:605397;MGI:3039602;HomoloGene:4787;GeneCards:CD226;OMA:CD226 - orthologs
Gene location (Human)
Chromosome 18 (human)
Chr.Chromosome 18 (human)[1]
Chromosome 18 (human)
Genomic location for CD226
Genomic location for CD226
Band18q22.2Start69,831,158bp[1]
End69,961,803bp[1]
Gene location (Mouse)
Chromosome 18 (mouse)
Chr.Chromosome 18 (mouse)[2]
Chromosome 18 (mouse)
Genomic location for CD226
Genomic location for CD226
Band18|18 E4Start89,195,091bp[2]
End89,290,353bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • monocyte

  • granulocyte

  • blood

  • lymph node

  • gonad

  • testicle

  • spleen

  • appendix

  • sural nerve

  • epithelium of colon
Top expressed in
  • blood

  • zygote

  • spleen

  • thymus

  • mesenteric lymph nodes

  • embryo

  • bone marrow

  • secondary oocyte

  • subcutaneous adipose tissue

  • esophagus
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo /QuickGO
Orthologs
SpeciesHumanMouse
Entrez

10666

225825

Ensembl

ENSG00000150637

ENSMUSG00000034028

UniProt

Q15762

Q8K4F0

RefSeq (mRNA)

NM_001303618
NM_001303619
NM_006566

NM_001039148
NM_001039149
NM_178687

RefSeq (protein)

NP_001290547
NP_001290548
NP_006557

NP_001034238
NP_848802

Location (UCSC)Chr 18: 69.83 – 69.96 MbChr 18: 89.2 – 89.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CD226 (Cluster ofDifferentiation 226),PTA1 (outdated term, 'platelet and T cell activation antigen 1')[5] orDNAM-1 (DNAXAccessoryMolecule-1)[5] is a~65 kDa  immunoglobulin-like transmembraneglycoprotein expressed on the surface ofnatural killer cells,NK T cell,B cells,dendritic cells,hematopoietic precursor cells,platelets,monocytes andT cells.[6]

DNAM-1 geneCD226 is conserved between human and mice. In humans the CD226gene is located onchromosome 18q22.3.[7] In mice the CD226 gene is located on chromosome 18E4.

Structure

[edit]

DNAM-1 is composed of three domains: an extracellular domain of 230amino acids with two immunoglobin-likeV-set domains and eight N-glycosylation sites, a transmembrane domain of 28 amino acids and acytosolic domain of 60 amino acids containing four putativetyrosine residues and oneserine residue forphosphorylation.[8]

Signaling

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Upon engagement to itsligand, DNAM-1 is phosphorylated byprotein kinase C. Then adhesive moleculeLFA-1 crosslinks with DNAM-1 that results in recruitment of DNAM-1 tolipid rafts and promotes association withactincytoskeleton. Cross-linking with LFA-1 also induce phosphorylation on Tyr128 and Tyr113 byFyn Src kinase.[9]

DNAM-1 andCD244 together promotes phosphorylation ofSH2 domain ofSLP-76. This leads to activation ofphospholipase Cγ2, Ca2+ influx, cytoskeletal reorganization,degranulation, andsecretion.[8]

Function

[edit]

DNAM-1 mediates cellularadhesion to other cells bearing its ligands, nectin moleculeCD112 and nectin-like proteinCD155,[10][11] that are broadly distributed on normal neuronal, epithelial, fibroblastic cells, dendritic cells, monocytes and on infected ortransformed cells.

DNAM-1 promoteslymphocyte signaling,lymphokine secretion andcytotoxicity ofNK cells and cytotoxic CD8+T lymphocytes.[6] Cross-linking of DNAM-1 withantibodies causes cellular activation.[7]

DNAM-1 participates onplatelets activation and aggregation.[8]

DNAM-1 possibly plays a role in trans-endothelial migration of NK cells because it was shown that monoclonal antibodies against DNAM-1 or CD155 inhibit this process.[9]

DNAM-1 interaction with its ligands promotes killing of immature and mature dendritic cells, is involved in the crosstalk between NK cells and T lymphocytes and can lyse activated T lymphocytesduring graft versus host disease (GvHD).[8][9]

DNAM-1 also participates in theimmunological synapse where is colocalized with LFA-1.[9]

DNAM-1 regulation

[edit]

DNAM-1 expression on NK cells can be regulated by cell-cell interaction and by soluble factors. In human, IL-2 and IL-15 up-regulate DNAM-1 expression, whereasTGF-β, indolamine 2,3-dioxygenase and chronic exposure toCD155 can down-regulate DNAM-1 expression on NK cells.[9]

DNAM-1 and NK cells

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DNAM is involved in NK cell education, differentiation, cytokine production and immune synapse formation. DNAM-1 exerts synergistic roles in NK cells regulation with three molecules that areTIGIT,CD96 and CRTAM.[9]  

Cytotoxic response of NK cells might require synergistic activation from specific pairs of receptors. DNAM-1 could synergize with SLAM family member 2B4 (CD244) or with other receptors to induce full NK cell activation.[8]

DNAM-1 in cancer

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The role of DNAM-1 intumor environment was firstly describedin vivo using RMAlymphoma model. In this model, enforced expression of DNAM-1 ligands CD155 and CD112 increased tumor rejection. CD155 and CD112 are expressed on the surface of a wide number of tumor cells in solid and lymphoidmalignances such aslung carcinoma, primary humanleukemia,myeloma,melanoma,neuroblastoma,ovarian cancer,colorectal carcinoma, andEwing sarcoma cells.[9]

The role of DNAM-1 in the killing of tumor cells was supported with DNAM-/- mice model that was more susceptible to formation ofspontaneous fibrosarcoma.[8]  

It was shown that NK cells can kill leukemia and neuroblastoma cells expressing CD155 and block of CD155 or DNAM-1 results in inhibition of tumor cellslysis.[9]

In vivo, tumor cells are capable of evading DNAM-1 tumor suppressing mechanisms. Tumor cells can downregulate CD155 or CD112 to disable recognition of these DNAM-1 ligands. The other mechanism is a downregulation of DNAM-1 from the effector NK cell surface due to the chronic ligand (CD155) exposure.[9]

DNAM-1 was also used in T lymphocytes with achimeric antigen receptors (CAR) for the treatment of cancer.[12]

DNAM-1 and infections

[edit]

DNAM-1 has a relevant role in the process of recognizingvirus-infected cells during early infection for example in case ofcytomegalovirus infection by NK cells. DNAM-1 ligands are also expressed inantigen-presenting cells activated bytoll-like receptors and CD155 might be activated byDNA-damage response as was demonstrated forhuman immunodeficiency virus (HIV).[8]

DNAM-1 functionality during infections may be impaired by viralimmune evasion mechanisms. Viruses can downregulate production of surface CD112 and CD155 and thus avoid recognition of DNAM-1 expressed on NK cells. The other way is downregulation of DNAM-1 expressions that may occur during chronic infections.[8]

NK cells activated withinterferon α can kill HCV-infected cells in a DNAM-1 dependent manner.[13]

During the bacterial infection interaction between DNAM-1 and its ligands helps to mediate the migration of leukocytes from theblood tosecondary lymphoid organs or intoinflamed tissues.[9]

Soluble DNAM-1

[edit]

It is suggested that soluble DNAM-1 is a prognostic marker in some types of cancer and ingraft-versus-host-disease and that soluble DNAM-1 might play role in pathogenesis of some autoimmune diseases such assystemic lupus erythematosus,systemic sclerosis andrheumatoid arthritis.[14]

See also

[edit]

References

[edit]
  1. ^abcGRCh38: Ensembl release 89: ENSG00000150637Ensembl, May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000034028Ensembl, May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abFuchs A, Colonna M (October 2006). "The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance".Seminars in Cancer Biology.16 (5):359–366.doi:10.1016/j.semcancer.2006.07.002.PMID 16904340.
  6. ^abHuang Z, Qi G, Miller JS, Zheng SG (2020-07-24)."CD226: An Emerging Role in Immunologic Diseases".Frontiers in Cell and Developmental Biology.8: 564.doi:10.3389/fcell.2020.00564.PMC 7396508.PMID 32850777.
  7. ^ab"Entrez Gene: CD226 CD226 molecule".
  8. ^abcdefghde Andrade LF, Smyth MJ, Martinet L (March 2014)."DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins".Immunology and Cell Biology.92 (3):237–244.doi:10.1038/icb.2013.95.PMID 24343663.S2CID 57669.
  9. ^abcdefghijXiong P, Sang HW, Zhu M (November 2015)."Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity".Immunology.146 (3):369–378.doi:10.1111/imm.12516.PMC 4610626.PMID 26235210.
  10. ^Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, et al. (August 2003)."Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule".The Journal of Experimental Medicine.198 (4):557–567.doi:10.1084/jem.20030788.PMC 2194180.PMID 12913096.
  11. ^Tahara-Hanaoka S, Shibuya K, Onoda Y, Zhang H, Yamazaki S, Miyamoto A, et al. (April 2004)."Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112)".International Immunology.16 (4):533–538.doi:10.1093/intimm/dxh059.hdl:2241/102014.PMID 15039383.
  12. ^Wu MR, Zhang T, Alcon A, Sentman CL (April 2015)."DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma".Cancer Immunology, Immunotherapy.64 (4):409–418.doi:10.1007/s00262-014-1648-2.PMC 4370794.PMID 25549845.
  13. ^Stegmann KA, Björkström NK, Ciesek S, Lunemann S, Jaroszewicz J, Wiegand J, et al. (May 2012)."Interferon α-stimulated natural killer cells from patients with acute hepatitis C virus (HCV) infection recognize HCV-infected and uninfected hepatoma cells via DNAX accessory molecule-1".The Journal of Infectious Diseases.205 (9):1351–1362.doi:10.1093/infdis/jis210.PMC 3690562.PMID 22457290.
  14. ^Nakano M, Ayano M, Kushimoto K, Kawano S, Higashioka K, Inokuchi S, et al. (August 2021)."Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus".Scientific Reports.11 (1): 16162.Bibcode:2021NatSR..1116162N.doi:10.1038/s41598-021-95711-2.PMC 8352936.PMID 34373559.

Further reading

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External links

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This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.

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