Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen

Abstract

Platelet responses to collagen are mediated by the combined actions of the integrin ␣ 2 ␤ 1 , which serves as a major collagenbinding receptor, and the GPVI/FcR␥-chain complex, which transmits collagen-specific activation signals into the cell interior through the action of an immunoreceptor tyrosine-based activation motif within the cytoplasmic domain of the FcR␥-chain. Despite much progress in identifying components of the signaling pathway responsible for collagen-induced platelet activation, virtually nothing is known about the regulatory elements that modulate this important hemostatic event. PECAM-1, a recently recognized member of the inhibitory receptor family, contains a functional immunoreceptor tyrosine-based inhibitory motif within its cytoplasmic domain that, when tyrosine phosphorylated, recruits and activates the protein-tyrosine phosphatase, SHP-2. To test the hypothesis that PECAM-1 functions to regulate GPVI/FcR␥-chain-mediated platelet activation, the responses of wild-type versus PECAM-1-deficient murine platelets to GPVI-specific agonists were compared. Four distinct GPVI/FcR␥-chain-dependent responses were found to be significantly exaggerated in platelets derived from PE-CAM-1-deficient mice, including Mg ؉؉ -independent adhesion to immobilized fibrillar collagen, collagen-induced platelet aggregation, platelet aggregation induced by the GPVI-specific agonist collagen-related peptide, and GPVI/FcR␥-chain-induced dense granule secretion. Together, these data provide compelling evidence that PECAM-1 modulates platelet responses to collagen, and they implicate this novel member of the inhibitory receptor family in the regulation of primary hemostasis. IntroductionPlatelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kd member of the immunoglobulin (Ig) superfamily that is expressed on the surface of circulating platelets, endothelial cells, neutrophils, monocytes, and certain T-lymphocyte subsets. The extracellular domain of PECAM-1 is composed of 6 extracellular Ig-like homology units, 1 the amino-terminal 2 of which mediates PECAM-1-PECAM-1 homophilic interactions. 2,3 Antibodies to the extracellular domain have been shown to have profound physiologic and cell biologic effects, including delaying leukocyte transendothelial migration 4-6 and inhibiting angiogenesis. 7 The extracellular domain of PECAM-1 also serves as a portal for entry into endothelial cells of certain strains of Plasmodium falciparuminfected erythrocytes. 8,9 The PECAM-1 cytoplasmic domain also plays a key biologic role because a large number of extracellular stimuli (reviewed in Newman 10 ) have been shown to result in the phosphorylation of 2 key tyrosine residues, located at positions 663 and 686 of the cytoplasmic domain. 11 The sequence surrounding each of these 2 tyrosine residues conforms to an immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when phosphorylated, provides a major docking site for the src homology 2 (SH2) domaincontaining protein tyrosine phosphatase (PTP), SHP-2. 11-14 ...

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

“…1,2 The subtle phenotype was most evident at concentrations of collagen at 1 g/mL but was not so evident at higher concentrations of collagen 10 to 30 g/mL. This was also the case using CRP as the GPVI-selective agonist.…”

“…1,2 However, based on several studies, it would appear that platelets contain multiple Ig-ITIM superfamily members that are likely to have a modulatory role in regulating platelet-collagen interactions. Several reports suggest that platelets contain other Ig-ITIM superfamily members, including G6B and TREM (triggering receptors expressed on myeloid cells)-like transcript-1 (TLT-1), that may attenuate platelet function.…”

“…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.…”

Platelet Activation in Cats with Hypertrophic Cardiomyopathy

“…In platelets, PECAM‐1 is present both in alpha granules as well as on the platelet plasma membrane 34. In endothelial cells, the molecule is located on the plasma membrane and is concentrated at endothelial cell‐cell junctions.…”

“…PECAM‐1 has been shown to have proinflammatory activity through the promotion of leukocyte‐endothelial translocation and transmission of systemic signals associated with endothelial stress 37. Unlike platelet P‐selectin, which supports neutrophil‐platelet and platelet‐endothelial interactions, platelet PECAM is an inhibitory molecule that has been proposed to limit thrombus formation by limiting platelet‐platelet interactions as well as platelet adhesion to collagen 34, 38, 39. These studies have suggested that PECAM‐1 serves to regulate thrombus formation and thereby inhibit vessel occlusion.…”