PECAM-1 functions as a negative regulator of laminin-induced platelet activation

Abstract

Background: Interaction of resting platelets with exposed components of the subendothelial matrix is an important early activating event that takes place at sites of vascular injury. Platelet responses to collagen are mediated by integrin α 2β 1 and the glycoprotein (GP)VI-Fc receptor (FcR) γ-chain complex, whereas platelet activation by laminin is mediated by the related integrin, α 6β 1, and similarly requires signaling through GPVI-FcR γ-chain. Objective: Because the cell adhesion and signaling receptor PECAM-1 has previously been shown to dampen collagen-induced platelet activation, we sought to determine whether PECAM-1 might similarly regulate platelet activation by laminin. Methods/Results: We found that PECAM-1 became tyrosine phosphorylated on its cytoplasmic immunoreceptor tyrosine-based inhibitory motifs following adhesion of either human or murine platelets to immobilized laminin. Whereas the presence or absence of PECAM-1 had no effect on either the rate or extent of platelet adhesion or spreading on laminin, PECAM-1 inhibited laminin-induced phosphorylation of GPVI-FcR γ-chain immunoreceptor tyrosine-based activation motifs (ITAMs) and activation of its downstream effector, Syk kinase, and suppressed granule secretion. Conclusions: Taken together, these data are consistent with previous findings in platelets and other blood and vascular cells that PECAM-1 functions by modulating ITAM-mediated signaling pathways that amplify cellular activation. © 2010 International Society on Thrombosis and Haemostasis.