Platelet endothelial cell adhesion molecule (PECAM) is a 130-kDa membrane glycoprotein and a member of the immunoglobulin (Ig) gene superfamily. PECAM was initially found in platelets (Newman et al. 1982); subsequently, it was also identified in endothelial cells (Newman et al. 1990) and leukocyte subtypes (Dangerfield et al. 2002). Because of its abundant expression in endothelial cells, PECAM is also recognized as an endothelial cell marker for immunohistochemical analyses. PECAM is a multifunctional signaling molecule regulating platelet function, thrombosis, vascular integrity, leukocyte transmigration, and leukocyte immune response (Newman and Newman 2003; Woodfin et al. 2007). In addition, as a critical mechanosensor protein, endothelial PECAM senses fluid shear stress for vascular remodeling (Osawa et al. 2002).
There is growing evidence that PECAM transduces signals that suppress programmed cell death, thereby contributing to vascular remodeling and integrity. Homophilic PECAM interactions prevent mitochondria-dependent apoptosis in endothelial cells (Bird et al. 1999; Gao et al. 2003). In PECAM-deficient mice, although physiological vascularization is normal, tumor angiogenesis (Cao et al. 2009) and retinal vascular development (Dimaio et al. 2008) are attenuated. The molecular basis for how PECAM accomplishes its anti-apoptotic role has yet to be elucidated. Various disease models show that loss of PECAM enhances vascular permeability (Biswas et al. 2006; Carrithers et al. 2005; Graesser et al. 2002).
Earlier studies show that PECAM is required for the transendothelial migration of leukocytes (Muller et al. 1993). However, accumulating evidence indicates that the ability of PECAM-1 to mediate leukocyte transmigration appears to be stimulus specific and can be governed by the genetic background of the experimental animal (Woodfin et al. 2007). Recent studies demonstrate the multiple regulatory roles of PECAM, including inhibiting platelet activation (Rathore et al. 2003), inhibiting dendritic cell maturation (Clement et al. 2014), and regulating T-cell immunity and tolerance (Ma et al. 2010; Ross et al. 2011). PECAM transduces inhibitory signals to the cell by recruiting, via its two ITIMs, SHP-1 (Clement et al. 2014) or SHP-2 (Newman et al. 2001).
Mechanosensing Role of PECAM
The ability of endothelial cells to sense fluid shear stress from blood flow is critically important for vascular remodeling; impaired vascular remodeling causes vascular diseases, including atherosclerosis. PECAM-1 is necessary for flow-induced vascular remodeling (Chen and Tzima 2009). PECAM forms a mechanosensory complex with vascular endothelial cadherin and the vascular endothelial growth factor (VEGF) receptor (Tzima et al. 2005). Fluid shear stress leads to tyrosine phosphorylation of PECAM (Osawa et al. 2002), which in turn activates integrin and causes changes to elements of the cytoskeletal architecture, such as vimentin (Collins et al. 2012; Conway et al. 2013).
Extensive studies reveal that PECAM is a multifunctional molecule. Extracellular PECAM is important for homophilic PECAM-PECAM interactions that transduce survival signals to endothelial cells and is also important for heterophilic PECAM interactions that inhibit the activation of dendritic cells and CD4+ T cells. Such interactions induce PECAM oligomerization – leading to tyrosine phosphorylation within PECAM’s ITIM motif and subsequently to the recruitment of phosphatases to transduce inhibitory signals into the cell.
- Dangerfield J, Larbi KY, Huang M-T, Dewar A, Nourshargh S. PECAM-1 (CD31) Homophilic Interaction Up-Regulates α6β1on Transmigrated Neutrophils In Vivo and Plays a Functional Role in the Ability of α6Integrins to Mediate Leukocyte Migration through the Perivascular Basement Membrane. J. Exp. Med. 2002;196:1201–12.PubMedPubMedCentralCrossRefGoogle Scholar
- Kitazume S, Imamaki R, Kurimoto A, Ogawa K, Kato M, Yamaguchi Y, Tanaka K, Ishida H, Ando H, Kiso M, Hashii N, Kawasaki N, Taniguchi N. Interaction of platelet endothelial cell adhesion molecule (PECAM) with alpha2,6-sialylated glycan regulates its cell surface residency and anti-apoptotic role. J Biol Chem. 2014a;289:27604–13.PubMedPubMedCentralCrossRefGoogle Scholar
- Lee C, Liu A, Miranda-Ribera A, Hyun SW, Lillehoj EP, Cross AS, Passaniti A, Grimm PR, Kim BY, Welling PA, Madri JA, DeLisser HM, Goldblum SE. NEU1 sialidase regulates the sialylation state of CD31 and disrupts CD31-driven capillary-like tube formation in human lung microvascular endothelia. J Biol Chem. 2014;289:9121–35.PubMedPubMedCentralCrossRefGoogle Scholar
- Lertkiatmongkol, P., C. Paddock, D.K. Newman, J. Zhu, M.J. Thomas, and P.J. Newman. The role of sialylated glycans in human PECAM-1-mediated trans-homophilic interactions and endothelial cell barrier function. J Biol Chem. 2016;291:26216–225.Google Scholar
- Ma L, Mauro C, Cornish GH, Chai JG, Coe D, Fu H, Patton D, Okkenhaug K, Franzoso G, Dyson J, Nourshargh S, Marelli-Berg FM. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance. Proc Natl Acad Sci USA. 2010;107:19461–6.PubMedPubMedCentralCrossRefGoogle Scholar
- Ross EA, Coughlan RE, Flores-Langarica A, Bobat S, Marshall JL, Hussain K, Charlesworth J, Abhyankar N, Hitchcock J, Gil C, Lopez-Macias C, Henderson IR, Khan M, Watson SP, MacLennan IC, Buckley CD, Cunningham AF. CD31 is required on CD4+ T cells to promote T cell survival during Salmonella infection. J Immunol. 2011;187:1553–65.PubMedPubMedCentralCrossRefGoogle Scholar
- Sachs UJ, Andrei-Selmer CL, Maniar A, Weiss T, Paddock C, Orlova VV, Choi EY, Newman PJ, Preissner KT, Chavakis T, Santoso S. The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J Biol Chem. 2007;282:23603–12.PubMedCrossRefGoogle Scholar
- Wong CW, Wiedle G, Ballestrem C, Wehrle-Haller B, Etteldorf S, Bruckner M, Engelhardt B, Gisler RH, Imhof BA. PECAM-1/CD31 trans-homophilic binding at the intercellular junctions is independent of its cytoplasmic domain; evidence for heterophilic interaction with integrin alphavbeta3 in Cis. Mol Biol Cell. 2000;11:3109–21.PubMedPubMedCentralCrossRefGoogle Scholar