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 PECAM1gene found on chromosome17q23.3.[5][6][7][8] PECAM-1 plays a key role in removing aged neutrophils from the body.
Structure
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
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
CD31 is normally found on endothelial cells, platelets, macrophages and Kupffer cells, granulocytes, lymphocytes (T cells, B cells, and NK cells), megakaryocytes, and osteoclasts.
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]
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
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
PECAM-1 is also important for angiogenesis because it enables the formation of new blood vessels through the cell-cell adhesion.[25]
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
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
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
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]
^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. PMID1690453.
^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. PMID8661055.
^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. PMID8921400.
^Leong, Anthony S-Y, Cooper, Kumarason, Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. p. 103. ISBN978-1-84110-100-2.
^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. PMID14517436. S2CID33204411.
^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. PMID32500259. S2CID219313556.
^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. PMID32417429. S2CID218678428.
Wong MX, Jackson DE (2004). "Regulation of B cell activation by PECAM-1: implications for the development of autoimmune disorders". Current Pharmaceutical Design. 10 (2): 155–161. doi:10.2174/1381612043453504. PMID14754395.
