Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets

Abstract

IntroductionPlatelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kd membrane-spanning glycoprotein whose expression is restricted to several hematopoietic cell types including platelets, monocytes, neutrophils, certain T lymphocytes, and vascular endothelial cells. [1][2][3][4] The functions of PECAM-1 are diverse and include angiogenesis, 5 vasculogenesis, 6 integrin regulation, 7,8 transendothelial migration of leukocytes, 9-11 and T-and B-cell antigen receptor function, 12,13 though the role of this molecule in platelets is unclear. When PECAM-1 was cloned, it was assigned to the family of cell adhesion molecules on the basis of structural similarities. 4 PECAM-1 is involved in adhesion, though much attention has been directed recently to studying its ability to participate in signal transduction. The cytoplasmic tail of PECAM-1 contains a conserved motif called an immunoreceptor tyrosine-based inhibitory motif (ITIM), which underlies its signaling properties and is shared by a growing family of inhibitory receptors. These include immunoglobulin G (IgG) receptor Fc␥RIIB, killer inhibitory receptors, and signal regulatory proteins, but PECAM-1 is the only ITIM-bearing receptor reported to be expressed in platelets. 14,15 Therefore, it has been proposed that PECAM-1 be assigned to the immunoglobulin-ITIM family of receptors. 14 The ligand-binding properties of PECAM-1 are complex. It has the capacity for homophilic interactions 3,16 and heterophilic interactions with a number of molecules that include integrin ␣ v ␤ 3 and CD38. 17,18 PECAM-1 becomes phosphorylated on tyrosine residues in response to a variety of stimuli that include PECAM-1 cross-linking, 19 activation of the high-affinity receptor for IgE (Fc⑀RI), 20 shear stress, 21 and oxidative stress. 22 Furthermore, we have recently reported that platelet activation through the collagen receptor glycoprotein VI (GPVI) and through thrombin receptors results in PECAM-1 tyrosine phosphorylation and that this is not dependent on platelet aggregation and secretion, 23 though tyrosine phosphorylation is enhanced by aggregation. 24 The tyrosine residues that become phosphorylated in PECAM-1 have been mapped and fall within the ITIM. 25 Phosphorylated ITIMs recruit signaling molecules, such as the tyrosine phosphatases SHP-1 and SHP-2, which bind to the motif through Src-homology 2 domain interactions. Indeed, both SHP-1 and SHP-2 have been shown to associate with tyrosine-phosphorylated PECAM-1, [24][25][26] and PECAM-1 ITIM phosphopeptides activate these phosphatases in vitro. 19,25,26 Generally, these protein tyrosine phosphatases exhibit inhibitory effects by counteracting tyrosine kinase-dependent pathways, though SHP-2 has been shown to positively regulate growth factor receptor signaling. 27 Immunoreceptor tyrosine-based activatory motif (ITAM)-bearing receptors have a critical place in the regulation of platelet function. 28 Indeed, the collagen receptor GPVI-FcR ␥-chain complex signals through an ITAM on the cytoplasmic tail of the FcR ...

Platelet adhesion signalling and the regulation of thrombus formation

“…The roles of nitric oxide (NO) and prostacyclin (PGI2) are well established in the inhibition of platelet function (Geiger, 2001;Radomski et al, 1987). However, platelet activation can also be inhibited by signalling through the adhesion molecule PECAM-1 (also known as CD31) (Cicmil et al, 2002;Jones et al, 2001;Patil et al, 2001). PECAM-1 is expressed on several blood cell types and on endothelial cells, and is associated with the regulation of a range of processes, including trans-endothelial migration of leukocytes, regulation of cell activation and regulation of apoptosis .…”

Platelet receptors and signaling in the dynamics of thrombus formation

“…PECAM-1 plays a role in attenuating thrombus formation involving GP VI, GP Ib, and thrombin-mediated platelet activation, as well as normal integrin αIIbβ3-mediated platelet function. [105][106][107][108] Like PECAM-1, ESAM, a molecule on the platelet surface, seems to have a restraining role on thrombus growth and stability. 88 Recent data also suggest that activation of αIIβb3, and likely that of other integrins, is not an irreversible process but rather a dynamic and bi-directional process, in particular for some agonists such as ADP and for strongly activated procoagulant or coated platelets with prolonged calcium elevation.…”

CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo

“…These include prostacylin and nitric oxide released from endothelium and the immunoglobulin (Ig)-immunoreceptor tyrosine-based inhibitory motif (ITIM) superfamily member, platelet endothelial cell adhesion molecule-1 (PECAM-1) that serves an autoregulatory role when platelets come into contact with each other after exposure to collagen. [1][2][3][4] Given the importance of collagen in promoting platelet adhesion and thrombus formation, particularly involving glycoprotein VI (GPVI)/Fc receptor (FcR)-␥-chain signaling, it is essential that natural inhibitors that contribute to autoregulatory mechanisms that modulate signaling between collagen and the GPVI/FcR␥ chain are characterized in platelets.…”