Novel interactions in platelet biology: CLEC-2/podoplanin and laminin/GPVI.

We have identified a novel platelet membrane protein, CLEC-2 as a receptor for rhodocytin, a platelet-activating snake venom. CLEC-2 is specifically expressed in platelets and megakaryocytes, and has an atypical ITAM, which undergoes tyrosine phosphorylation by Src kinases, resulting in downstream signaling including Syk, SLP-76 and PLCgamma2. We found that CLEC-2 is the receptor for podoplanin, a sialoglycoprotein implicated in tumor-induced platelet aggregation and tumor metastasis. VWF bridges exposed collagen, at damaged vessels, to GPIb. Subsequently, GPVI binds to collagen, leading to integrin alpha2beta1 activation. We found that platelets adhere to laminin, another major ECM component, through integrin alpha6beta1, and are activated through GPVI. This is the first report on GPVI having a ligand, laminin, other than collagen. Laminin also interacts with VWF, leading to platelet adhesion via GPIb under sheer stress. The redundancy of platelet interactions with laminin and with collagen may serve to promote hemostasis at sites of damaged vessels.