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CD31

Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome17q23.3.[5][6][7][8] PECAM-1 plays a key role in removing aged neutrophils from the body.

PECAM1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPECAM1, CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM-1, endoCAM, platelet and endothelial cell adhesion molecule 1, PCAM-1
External IDsOMIM: 173445; MGI: 97537; HomoloGene: 47925; GeneCards: PECAM1; OMA:PECAM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5175

18613

Ensembl

ENSG00000261371

ENSMUSG00000020717

UniProt

P16284

Q08481

RefSeq (mRNA)

NM_000442

NM_001032378
NM_008816
NM_001305157
NM_001305158

RefSeq (protein)

NP_000433

NP_001027550
NP_001292086
NP_001292087
NP_032842

Location (UCSC)Chr 17: 64.32 – 64.41 MbChr 11: 106.55 – 106.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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PECAM-1 is a highly glycosylated protein with a mass of approximately 130 kDa.[9] The structure of this protein was determined by molecular cloning in 1990, when it was found out that PECAM-1 has an N-terminal domain with 574 amino acids, a transmembrane domain with 19 amino acids and a C-terminal cytoplasmic domain with 118 amino acids. The N-terminal domain consists of six extracellular Ig-like domains.[10]

Interactions

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PECAM-1 is a cell-cell adhesion protein[11] which interacts with other PECAM-1 molecules through homophilic interactions or with non-PECAM-1 molecules through heterophilic interactions.[12] Homophilic interactions between PECAM-1 molecules are mediated by antiparallel interactions between extracellular Ig-like domain 1 and Ig-like domain 2. These interactions are regulated by the level of PECAM-1 expression. Homophilic interactions occur, only when the surface expression of PECAM-1 is high. Otherwise, when expression is low, heterophilic interactions occur.[13]

Tissue distribution

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CD31 is normally found on endothelial cells, platelets, macrophages and Kupffer cells, granulocytes, lymphocytes (T cells, B cells, and NK cells), megakaryocytes, and osteoclasts.

Immunohistochemistry

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Micrograph of an angiosarcoma stained with a CD31 immunostain (dark brown).

In immunohistochemistry, CD31 is used primarily to demonstrate the presence of endothelial cells in histological tissue sections. This can help to evaluate the degree of tumor angiogenesis, which can imply a rapidly growing tumor. Malignant endothelial cells also commonly retain the antigen, so that CD31 immunohistochemistry can also be used to demonstrate both angiomas and angiosarcomas. It can also be demonstrated in small lymphocytic and lymphoblastic lymphomas, although more specific markers are available for these conditions.[14]

Function

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PECAM-1 is found on the surface of platelets, monocytes, neutrophils, and some types of T-cells, and makes up a large portion of endothelial cell intercellular junctions. The encoded protein is a member of the immunoglobulin superfamily and is likely involved in leukocyte transmigration, angiogenesis, and integrin activation.[5] CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium.[15][16]

Role in signaling

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PECAM-1 plays a role in cell signaling. In the cytoplasmic domain of PECAM-1 are serine and tyrosine residues which are suitable for phosphorylation. After the tyrosine is phosphorylated, PECAM-1 recruits Src homology 2 (SH2) domain–containing signaling proteins. These proteins can then initiate signaling pathways. Of all these proteins, the protein most widely reported as interacting with the PECAM-1 cytoplasmic domain is SH2 domain–containing protein-tyrosine phosphatase SHP-2.[17] Signaling through PECAM-1 leads to the activation of neutrophils, monocytes and leukocytes.[18]

Leukocyte transmigration

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PECAM-1 is involved in migration of monocytes and neutrophils,[19] natural killer cells,[20] Vδ1+ γδ T lymphocytes[21] and CD34+ hematopoietic progenitor cells[22] through the endothelial cells. Moreover, PECAM-1 is involved in transendothelial migration of recent thymic emigrants to the secondary lymphoid organs.[23] Mechanism of leukocyte transmigration can be explained by creating a homophilic interaction. In this interaction migrating leukocytes express PECAM-1 on the surface and then they react with PECAM-1 on the surface of endothelial cell.[24]

Angiogenesis

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PECAM-1 is also important for angiogenesis because it enables the formation of new blood vessels through the cell-cell adhesion.[25]

Role of CD31 in diseases

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Cancer

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PECAM-1 is expressed by many solid tumor cell lines such as hemangioma, angiosarcoma, Kaposi’s sarcoma, breast carcinoma, glioblastoma, colon carcinoma, skin carcinoma and other tumor cell lines.[26] On the surface of these tumor cells PECAM-1 mediates the adhesion to endothelial cells.[27] PECAM-1 modulates tumor growth by the formation of new endothelial cell tubes. In mice, this process can be inhibited using an anti-PECAM-1 antibody.[28]

Recently, it was found out that elderly patients with gastric cancer have high concentration of PECAM-1 in the serum. That suggests that the use of a serum PECAM-1 level can be a good prognostic marker.[29]

Atherosclerosis

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Inhibition of PECAM-1 leads to a reduction of atherosclerotic lesions in mice.[30] That means that PECAM-1 is involved in atherosclerosis. The exact mechanism, how PECAM-1 contributes to atherosclerosis is not known, but there are some theories. PECAM-1 can act as a mechanoresponsive molecule. Or the pathogenesis can be caused by the infiltration of leukocytes mediated by PECAM-1. Finally, polymorphisms in the PECAM-1 gene can lead to the progression of atherosclerosis.[31]

Disseminated intravascular coagulation

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Extensive microvascular thrombosis and increased microvascular permeability are main characteristics of disseminated intravascular coagulation, a fatal complication of sepsis. Patients with this devastating condition have high levels of PECAM-1 in the serum indicating PECAM-1 as a good diagnostic marker. Moreover, PECAM-1 can protect from the development of disseminated intravascular coagulation by inhibiting macrophage pyroptosis.[32]

Neuroinflammation

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PECAM-1 contributes to at least two of the nervous system diseases, multiple sclerosis and cerebral ischaemia. First signs of multiple sclerosis are defects in the blood brain barrier and leukocyte migration mediated by adhesion molecules such as PECAM-1. Moreover, monocytes in patients with multiple sclerosis express high level of PECAM-1. Cerebral ischaemia is caused by the accumulation of leukocytes, which then infiltrate brain parenchyma and release toxic compounds such as oxygen radicals. Interactions between leukocyte and endothelium are mediated by PECAM-1. High levels of soluble PECAM-1 can be used to diagnose both diseases. Increased PECAM-1 levels indicate damage in the blood brain barrier in patients with multiple sclerosis and high PECAM-1 levels can be used as a short-term prediction of a stroke in patients with cerebral ischaemia.[33]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000261371 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020717 – Ensembl, 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. ^ a b "Entrez Gene: platelet/endothelial cell adhesion molecule".
  6. ^ Newman PJ, Berndt MC, Gorski J, White GC, Lyman S, Paddock C, Muller WA (March 1990). "PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily". Science. 247 (4947): 1219–1222. Bibcode:1990Sci...247.1219N. doi:10.1126/science.1690453. PMID 1690453.
  7. ^ Gumina RJ, Kirschbaum NE, Rao PN, vanTuinen P, Newman PJ (June 1996). "The human PECAM1 gene maps to 17q23". Genomics. 34 (2): 229–232. doi:10.1006/geno.1996.0272. PMID 8661055.
  8. ^ Xie Y, Muller WA (October 1996). "Fluorescence in situ hybridization mapping of the mouse platelet endothelial cell adhesion molecule-1 (PECAM1) to mouse chromosome 6, region F3-G1". Genomics. 37 (2): 226–228. doi:10.1006/geno.1996.0546. PMID 8921400.
  9. ^ Simmons DL, Walker C, Power C, Pigott R (June 1990). "Molecular cloning of CD31, a putative intercellular adhesion molecule closely related to carcinoembryonic antigen". The Journal of Experimental Medicine. 171 (6): 2147–2152. doi:10.1084/jem.171.6.2147. PMC 2187965. PMID 2351935.
  10. ^ Newman PJ, Berndt MC, Gorski J, White GC, Lyman S, Paddock C, Muller WA (March 1990). "PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily". Science. 247 (4947): 1219–1222. Bibcode:1990Sci...247.1219N. doi:10.1126/science.1690453. PMID 1690453.
  11. ^ Albelda SM, Muller WA, Buck CA, Newman PJ (September 1991). "Molecular and cellular properties of PECAM-1 (endoCAM/CD31): a novel vascular cell-cell adhesion molecule". The Journal of Cell Biology. 114 (5): 1059–1068. doi:10.1083/jcb.114.5.1059. PMC 2289123. PMID 1874786.
  12. ^ DeLisser HM, Newman PJ, Albelda SM (October 1994). "Molecular and functional aspects of PECAM-1/CD31". Immunology Today. 15 (10): 490–495. doi:10.1016/0167-5699(94)90195-3. PMID 7945775.
  13. ^ Sun J, Williams J, Yan HC, Amin KM, Albelda SM, DeLisser HM (August 1996). "Platelet endothelial cell adhesion molecule-1 (PECAM-1) homophilic adhesion is mediated by immunoglobulin-like domains 1 and 2 and depends on the cytoplasmic domain and the level of surface expression". The Journal of Biological Chemistry. 271 (31): 18561–18570. doi:10.1074/jbc.271.31.18561. PMID 8702505.
  14. ^ Leong, Anthony S-Y, Cooper, Kumarason, Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. p. 103. ISBN 978-1-84110-100-2.
  15. ^ Zambello R, Barilà G, Manni S, Piazza F, Semenzato G (March 2020). "NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias". Cells. 9 (3): 768. doi:10.3390/cells9030768. PMC 7140687. PMID 32245149.
  16. ^ Glaría E, Valledor AF (January 2020). "Roles of CD38 in the Immune Response to Infection". Cells. 9 (1): 228. doi:10.3390/cells9010228. PMC 7017097. PMID 31963337.
  17. ^ Newman PJ, Newman DK (June 2003). "Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (6): 953–964. doi:10.1161/01.ATV.0000071347.69358.D9. PMID 12689916.
  18. ^ Elias CG, Spellberg JP, Karan-Tamir B, Lin CH, Wang YJ, McKenna PJ, et al. (June 1998). "Ligation of CD31/PECAM-1 modulates the function of lymphocytes, monocytes and neutrophils". European Journal of Immunology. 28 (6): 1948–1958. doi:10.1002/(SICI)1521-4141(199806)28:06<1948::AID-IMMU1948>3.0.CO;2-C. PMID 9645377. S2CID 32378668.
  19. ^ Muller WA, Weigl SA, Deng X, Phillips DM (August 1993). "PECAM-1 is required for transendothelial migration of leukocytes". The Journal of Experimental Medicine. 178 (2): 449–460. doi:10.1084/jem.178.2.449. PMC 2191108. PMID 8340753.
  20. ^ Berman ME, Xie Y, Muller WA (February 1996). "Roles of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in natural killer cell transendothelial migration and beta 2 integrin activation". Journal of Immunology. 156 (4): 1515–1524. doi:10.4049/jimmunol.156.4.1515. PMID 8568255. S2CID 1741600.
  21. ^ Poggi A, Zocchi MR, Carosio R, Ferrero E, Angelini DF, Galgani S, et al. (June 2002). "Transendothelial migratory pathways of V delta 1+TCR gamma delta+ and V delta 2+TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients: involvement of phosphatidylinositol 3 kinase and calcium calmodulin-dependent kinase II". Journal of Immunology. 168 (12): 6071–6077. doi:10.4049/jimmunol.168.12.6071. PMID 12055216. S2CID 82477153.
  22. ^ Voermans C, Rood PM, Hordijk PL, Gerritsen WR, van der Schoot CE (2000). "Adhesion molecules involved in transendothelial migration of human hematopoietic progenitor cells". Stem Cells. 18 (6): 435–443. doi:10.1634/stemcells.18-6-435. PMID 11072032. S2CID 37713443.
  23. ^ Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Möwes B, Radbruch A, Thiel A (March 2002). "Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood". The Journal of Experimental Medicine. 195 (6): 789–794. doi:10.1084/jem.20011756. PMC 2193736. PMID 11901204.
  24. ^ Mamdouh Z, Chen X, Pierini LM, Maxfield FR, Muller WA (February 2003). "Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis". Nature. 421 (6924): 748–753. Bibcode:2003Natur.421..748M. doi:10.1038/nature01300. PMID 12610627. S2CID 26318819.
  25. ^ DeLisser HM, Christofidou-Solomidou M, Strieter RM, Burdick MD, Robinson CS, Wexler RS, et al. (September 1997). "Involvement of endothelial PECAM-1/CD31 in angiogenesis". The American Journal of Pathology. 151 (3): 671–677. PMC 1857836. PMID 9284815.
  26. ^ Bergom C, Gao C, Newman PJ (October 2005). "Mechanisms of PECAM-1-mediated cytoprotection and implications for cancer cell survival". Leukemia & Lymphoma. 46 (10): 1409–1421. doi:10.1080/10428190500126091. PMID 16194886. S2CID 25682089.
  27. ^ Tang DG, Chen YQ, Newman PJ, Shi L, Gao X, Diglio CA, Honn KV (October 1993). "Identification of PECAM-1 in solid tumor cells and its potential involvement in tumor cell adhesion to endothelium". The Journal of Biological Chemistry. 268 (30): 22883–22894. doi:10.1016/S0021-9258(18)41609-2. PMID 8226797.
  28. ^ Zhou Z, Christofidou-Solomidou M, Garlanda C, DeLisser HM (1999). "Antibody against murine PECAM-1 inhibits tumor angiogenesis in mice". Angiogenesis. 3 (2): 181–188. doi:10.1023/a:1009092107382. PMID 14517436. S2CID 33204411.
  29. ^ Li Y, Guo XB, Wei YH, Kang XL (January 2021). "Serum CXCL13 and PECAM-1 can be used as diagnostic and prognostic markers in elderly patients with gastric cancer". Clinical & Translational Oncology. 23 (1): 130–138. doi:10.1007/s12094-020-02403-w. PMID 32500259. S2CID 219313556.
  30. ^ Stevens HY, Melchior B, Bell KS, Yun S, Yeh JC, Frangos JA (September 2008). "PECAM-1 is a critical mediator of atherosclerosis". Disease Models & Mechanisms. 1 (2–3): 175–81, discussion 179. doi:10.1242/dmm.000547. PMC 2562188. PMID 19048083.
  31. ^ Woodfin A, Voisin MB, Nourshargh S (December 2007). "PECAM-1: a multi-functional molecule in inflammation and vascular biology". Arteriosclerosis, Thrombosis, and Vascular Biology. 27 (12): 2514–2523. doi:10.1161/ATVBAHA.107.151456. PMID 17872453.
  32. ^ Luo L, Xu M, Liao D, Deng J, Mei H, Hu Y (August 2020). "PECAM-1 protects against DIC by dampening inflammatory responses via inhibiting macrophage pyroptosis and restoring vascular barrier integrity". Translational Research. 222: 1–16. doi:10.1016/j.trsl.2020.04.005. PMID 32417429. S2CID 218678428.
  33. ^ Kalinowska A, Losy J (December 2006). "PECAM-1, a key player in neuroinflammation". European Journal of Neurology. 13 (12): 1284–1290. doi:10.1111/j.1468-1331.2006.01640.x. PMID 17116209. S2CID 22437957.

Further reading

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