Alternative titles; symbols
HGNC Approved Gene Symbol: PECAM1
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:64,319,415-64,390,860 (from NCBI)
PECAM1 is a member of the immunoglobulin (Ig) superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and particular T-cell subsets. It is also a major constituent of the endothelial cell intercellular junction, where up to an estimated 1 million molecules are concentrated. Because of this cellular expression pattern, PECAM1 is implicated in several functions, including transendothelial migration of leukocytes, angiogenesis, and integrin activation. Ig superfamily mediate cell adhesion (e.g., NCAM1 (116930), ICAM1 (147840), and VCAM1 (192225)) or antigen recognition (e.g., immunoglobulins, T-cell receptors, and MHC molecules). In addition, a subgroup comprising 30 members characterized by the presence of 1 or more immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their cytoplasmic domains has also been recognized. PECAM1, which has 6 ITIMs within its cytoplasmic domain, is a member of this subfamily (review by Newman, 1999).
Newman et al. (1990) demonstrated immunologic identity between a platelet integral membrane glycoprotein, the CD31 myelomonocytic differentiation antigen, and an endothelial cell protein that is enriched at intercellular junctions. The 130-kD translated sequence contains 6 extracellular immunoglobulin-like domains, 1 transmembrane domain, and 1 cytoplasmic domain, and was most similar to the cell adhesion molecule (CAM) subgroup of the immunoglobulin superfamily.
Using a PCR-based analysis of somatic cell hybrids, Gumina et al. (1996) mapped PECAM1 to chromosome 17 in the region 17q23-qter. By fluorescence in situ hybridization, they assigned the PECAM1 locus specifically to 17q23. Several adhesion molecules expressed on platelets and endothelium also localized to 17q. Xie and Muller (1996) mapped the Pecam1 gene to mouse chromosome 6, region F3-G1, by fluorescence in situ hybridization.
Newman (1997) reviewed the biology of PECAM1 and its role as an adhesion receptor in thrombosis, hemostasis, immunity, and inflammatory response.
Graft-versus-host disease (GVHD; see 614395) caused by poorly defined minor (i.e., other than HLA) histocompatibility antigens is a serious problem in recipients of bone marrow transplants. Behar et al. (1996) reasoned that a likely site for minor-locus alloantigens would be the cell surface of vascular endothelial cells, a point of first contact with transplanted tissue and its host. They sought polymorphisms in genes encoding molecules on the surface of such cells as a way of identifying new alloantigenic systems. They picked CD31 for study because it is constitutively expressed on vascular endothelial cells, bone marrow stem cells, platelets, and most circulating leukocytes. They found sequence variation in 2 parts of the extracellular domains and identified a polymorphism of CD31 that correlated with the results of phenotyping using anti-CD31 monoclonal antibodies and with the occurrence of acute GVHD in patients who had received bone marrow transplants.
Kroll et al. (2000) analyzed sera from 5 patients who presented with drug-induced immune thrombocytopenia after intake of carbimazole. The thrombocytopenia in these patients was relatively mild in comparison to that in patients with thrombocytopenia induced by quinidine. Reactivity with PECAM1 was demonstrated in the sera of these patients as well as in 20 sera from patients with quinidine-induced thrombocytopenia. The authors concluded that PECAM1 is an important target glycoprotein in drug-induced immune thrombocytopenia.
Jones et al. (2001) presented evidence indicating that PECAM1 serves as a physiologic negative regulator of platelet-collagen interactions that may function to negatively limit growth of platelet thrombi on collagen surfaces.
To reveal active repulsion of viable cells and to seek specific capture or 'tethering' of apoptotic cells, Brown et al. (2002) studied macrophage binding of viable and apoptotic leukocytes under conditions of flow. Brown et al. (2002) found that homophilic ligation of CD31 on viable leukocytes promoted their active, temperature-dependent 'detachment' under low shear, whereas such CD31-mediated detachment was disabled in apoptotic leukocytes, promoting tight binding and macrophage ingestion of dying cells. Brown et al. (2002) proposed that CD31 is an example of a cell-surface molecule that prevents phagocyte ingestion of closely apposed viable cells by transmitting detachment signals, and which changes function on apoptosis, promoting tethering of dying cells to phagocytes.
Mamdouh et al. (2003) demonstrated that there is a membrane network just below the plasmalemma at the cell borders of endothelial cells that is connected at intervals to the junctional surface. PECAM1, an integral membrane protein with an essential role in transendothelial migration, or diapedesis, is found in this compartment and constitutively recycles evenly along endothelial cell borders. During transendothelial migration, however, recycling PECAM is targeted to segments of the junction across which monocytes are in the act of migration. In addition, Mamdouh et al. (2003) showed that blockade of transendothelial migration with antibodies against PECAM specifically blocks the recruitment of this membrane to the zones of leukocyte migration, without affecting the constitutive membrane trafficking.
Tzima et al. (2005) investigated the pathway upstream of integrin (see 192975) activation leading to fluid shear stress response in vascular endothelial cells. They found that PECAM1, which directly transmits mechanical force, vascular endothelial cell cadherin (601120), which functions as an adaptor, and VEGFR2 (191306), which activates phosphatidylinositol-3-OH kinase, comprise a mechanosensory complex. Together, these receptors were sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, Pecam1 knockout mice did not activate NF-kappa-B (see 164011) and downstream inflammatory genes in regions of disturbed flow. Therefore, Tzima et al. (2005) concluded that this mechanosensing pathway is required for the earliest known events in atherogenesis.
By flow cytometric and immunoprecipitation analyses, Sachs et al. (2007) identified PECAM1 as a heterophilic binding partner of CD177 (162860). Surface plasmon resonance analysis indicated that this interaction was cation dependent and involved the heterophilic domains of PECAM1. Monocytes expressing CD177 failed to adhere to PECAM1 in the presence of monoclonal antibodies against CD177 or against domain 6 of PECAM1. The antibodies also inhibited transendothelial migration of neutrophils.
Bayat et al. (2010) noted that 3 linked SNPs within PECAM1 encode amino acid substitutions within Ig domain 1 (leu98 to val; L98V), Ig domain 6 (ser546 to asn; S546N), and the cytoplasmic doman (arg643 to gly; R643G), resulting in 2 major isoforms termed LSR and VNG. By screening human vascular endothelial cells (HUVECs) and neutrophils, they confirmed that the 3 SNPs were transmitted as a block, with VNG homozygotes, LSR homozygotes, and VNG/LSR heterozygotes detected. Flow cytometry demonstrated that both variants were expressed at equal levels and that their HUVECs were equally permeable. CD177 levels in neutrophils were variable, and CD177 migrated significantly faster through LSR-expressing HUVECs than through VNG-expressing HUVECs. LSR-expressing HUVECs also had reduced ITIM phosphorylation. Engagement of PECAM1 with recombinant CD177 suppressed antibody-induced ITIM phosphorylation in LSR-expressing cells. Bayat et al. (2010) proposed that heterophilic PECAM1/CD177 interactions affect the phosphorylation state of PECAM1, as well as endothelial junction integrity and neutrophil transmigration, in an allele-specific manner.
Bixel et al. (2010) found that antibodies against mouse Cd99 (313470) or Pecam1 trapped neutrophils between endothelial cells in vitro. In contrast, electron and 3-dimensional confocal microscopy of inflamed cremaster demonstrated that antibodies against Cd99 or Cd99l2 (300846) or Pecam1 gene deletion led to accumulation of neutrophils in vivo between endothelial cells and basement membrane rather than between endothelial cells. Antibodies against Cd99 or Cd99l2 in combination with Pecam1 deficiency resulted in additive inhibitory effects on leukocyte extravasation in 2 different inflammation models. Bixel et al. (2010) concluded that CD99 and CD99L2 act independently of PECAM1 but at the same site during diapedesis, i.e., between endothelial cells and the basement membrane.
Wu et al. (2009) found that Pecam1-knockout mice had significantly reduced trabecular bone volume and number of trabeculae in femoral and tibial long bones. In vitro analysis of bone marrow from Pecam1-knockout mice revealed increased numbers and size of osteoclasts, enhanced bone resorption on dentin substrates, and hypersensitivity to macrophage Csf (120420) and Rankl (TNFSF11; 602642). Osteoclast-like cells from wildtype bone marrow exhibited interactions between Pecam1, Syk (600085), and Shp1 (PTPN6; 176883), and the absence of these interactions in Pecam1-knockout cells resulted in dysregulation of Syk kinases and/or phosphatases and increased Syk tyrosine phosphorylation. Transplant of Pecam1-knockout bone marrow into wildtype mice also led to loss of trabecular bone. Wu et al. (2009) concluded that Pecam1 deficiency has severe effects on bone biology through altered Shp1 localization and activity, resulting in dysregulated osteoclastogenesis and hematopoiesis.
Ma et al. (2010) showed that Cd31 -/- mice controlled tumor growth following inoculation with a mouse bladder carcinoma, whereas tumor growth was uncontrollable in wildtype mice. Allograft rejection was also accelerated in Cd31 -/- mice. Loss of Cd31 interactions led to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells. Flow cytometric analysis showed that Zap70 (176947) phosphorylation at tyr493 was partially but consistently inhibited following Cd31 ligation. Cd31 signaling also prevented cell death and induced the antiapoptotic Erk (see MAPK3; 601795)-mediated pathway. Ma et al. (2010) concluded that CD31 has a unique role as a nonredundant comodulator of T-cell responses. They proposed that while regulating the size of clonal expansion, selective expression of CD31 by T cells, dendritic cells, and endothelium might reduce cytotoxicity to these cells by effector T cells.
By direct sequencing of cDNA for CD31 from 21 normal subjects, Behar et al. (1996) identified a single polymorphism, CTG-to-GTG, which led to a leu125-to-val substitution; they designated the resulting alleles CD31.11 (wildtype) and CD31.V. Among 163 subjects studied overall, the frequencies of CD31.L homozygotes (0.30), CD31.V homozygotes (0.28), and CD31.L/CD31.V heterozygotes (0.42) were a good fit to the Hardy-Weinberg equilibrium. Among the transplant recipients, 71% of those with acute GVHD had CD31 genotypes that were not identical to the donor's genotype, as compared with 22% of the recipients without GVHD (P = 0.004).
Bayat, B., Werth, S., Sachs, U. J. H., Newman, D. K., Newman, P. J., Santoso, S. Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S(356)N dimorphism of platelet endothelial cell adhesion molecule-1. J. Immun. 184: 3889-3896, 2010. [PubMed: 20194726] [Full Text: https://doi.org/10.4049/jimmunol.0903136]
Behar, E., Chao, N. J., Hiraki, D. D., Krishnaswamy, S., Brown, B. W., Zehnder, J. L., Grumet, F. C. Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease. New Eng. J. Med. 334: 286-291, 1996. [PubMed: 8532023] [Full Text: https://doi.org/10.1056/NEJM199602013340502]
Bixel, M. G., Li, H., Petri, B., Khandoga, A. G., Khandoga, A., Zarbock, A., Wolburg-Buchholz, K., Wolburg, H., Sorokin, L., Zeuschner, D., Maerz, S., Butz, S., Krombach, F., Vestweber, D. CD99 and CD99L2 act at the same site as, but independently of, PECAM-1 during leukocyte diapedesis. Blood 116: 1172-1184, 2010. [PubMed: 20479283] [Full Text: https://doi.org/10.1182/blood-2009-12-256388]
Brown, S., Heinisch, I., Ross, E., Shaw, K., Buckley, C. D., Savill, J. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418: 200-203, 2002. [PubMed: 12110892] [Full Text: https://doi.org/10.1038/nature00811]
Gumina, R. J., Kirschbaum, N. E., Rao, P. N., vanTuinen, P., Newman, P. J. The human PECAM1 gene maps to 17q23. Genomics 34: 229-232, 1996. [PubMed: 8661055] [Full Text: https://doi.org/10.1006/geno.1996.0272]
Jones, K. L., Hughan, S. C., Dopheide, S. M., Farndale, R. W., Jackson, S. P., Jackson, D. E. Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions. Blood 98: 1456-1463, 2001. [PubMed: 11520795] [Full Text: https://doi.org/10.1182/blood.v98.5.1456]
Kroll, H., Sun, Q.-H., Santoso, S. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a target glycoprotein in drug-induced thrombocytopenia. Blood 96: 1409-1414, 2000. [PubMed: 10942385]
Ma, L., Mauro, C., Cornish, G. H., Chai, J.-G., Coe, D., Fu, H., Patton, D., Okkenhaug, K., Franzoso, G., Dyson, J., Nourshargh, S., Marelli-Berg, F. M. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance. Proc. Nat. Acad. Sci. 107: 19461-19466, 2010. [PubMed: 20978210] [Full Text: https://doi.org/10.1073/pnas.1011748107]
Mamdouh, Z., Chen, X., Pierini, L. M., Maxfield, F. R., Muller, W. A. Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 421: 748-753, 2003. [PubMed: 12610627] [Full Text: https://doi.org/10.1038/nature01300]
Newman, P. J. The biology of PECAM-1. J. Clin. Invest. 99: 3-8, 1997. [PubMed: 9011572] [Full Text: https://doi.org/10.1172/JCI119129]
Newman, P. J. Switched at birth: a new family for PECAM-1. J. Clin. Invest. 103: 5-9, 1999. [PubMed: 9884328] [Full Text: https://doi.org/10.1172/JCI5928]
Newman, P. J., Berndt, M. C., Gorski, J., White, G. C., II, Lyman, S., Paddock, C., Muller, W. A. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247: 1219-1222, 1990. [PubMed: 1690453] [Full Text: https://doi.org/10.1126/science.1690453]
Sachs, U. J. H., Andrei-Selmer, C. L., Maniar, A., Weiss, T., Paddock, C., Orlova, V. V., Choi, E. Y., Newman, P. J., Preissner, K. T., Chavakis, T., Santoso, S. The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J. Biol. Chem. 282: 23603-23612, 2007. [PubMed: 17580308] [Full Text: https://doi.org/10.1074/jbc.M701120200]
Tzima, E., Irani-Tehrani, M., Kiosses, W. B., Dejana, E., Schultz, D. A., Engelhardt, B., Cao, G., DeLisser, H., Schwartz, M. A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437: 426-431, 2005. [PubMed: 16163360] [Full Text: https://doi.org/10.1038/nature03952]
Wu, Y., Tworkoski, K., Michaud, M., Madri, J. A. Bone marrow monocyte PECAM-1 deficiency elicits increased osteoclastogenesis resulting in trabecular bone loss. J. Immun. 182: 2672-2679, 2009. [PubMed: 19234161] [Full Text: https://doi.org/10.4049/jimmunol.0802398]
Xie, Y., Muller, W. A. Fluorescence in situ hybridization mapping of the mouse platelet endothelial cell adhesion molecule-1 (PECAM1) to mouse chromosome 6, region F3-G1. Genomics 37: 226-228, 1996. [PubMed: 8921400] [Full Text: https://doi.org/10.1006/geno.1996.0546]