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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-05-1533. This Article Full Text (PDF) All Versions of this Article: 2002-05-1533v1 101/4/1409    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Larson, M. K Articles by Parise, L. V Search for Related Content PubMed PubMed Citation Articles by Larson, M. K Articles by Parise, L. V Social Bookmarking                   What's this? Submitted May 24, 2002 Accepted October 1, 2002 Identification of P2Y12-dependent and independent mechanisms of glycoprotein VI-mediated Rap1 activation in platelets Mark K Larson, Hong Chen, Mark L Kahn, Anne M Taylor, Jean-Etienne Fabre, Richard M Mortensen, Pamela B Conley, and Leslie V Parise* Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Center for Thrombosis and Hemostasis, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA Departments of Physiology and Medicine, University of Michigan, Ann Arbor, MI, USA Millennium Pharmaceuticals Inc., South San Francisco, CA, USA * Corresponding author; email: parise{at}med.unc.edu. Glycoprotein (GP) VI is a critical platelet collagen receptor, yet the steps involved in GPVI-mediated platelet activation remain incompletely understood. Because activation of Rap1, an abundant small GTPase in platelets, contributes to integrin IIbß3 activation, we asked whether and how GPVI signaling activates Rap1 in platelets. Here we show that platelet Rap1 is robustly activated upon addition of convulxin, a GPVI-specific agonist. Using a reconstituted system in RBL-2H3 cells, we found that GPVI-mediated Rap1 activation is dependent on FcR but independent of another platelet collagen receptor, 2ß1. Interestingly, GPVI-mediated Rap1 activation in human platelets is largely dependent on ADP signaling through the P2Y12 and not the P2Y1 receptor. However, experiments with specific ADP-receptor antagonists and platelets from knockout mice deficient in P2Y1 or the P2Y12-associated G-protein, Gi2, indicate that human and murine platelets also have a significant P2Y12-independent component of GPVI-mediated Rap1 activation. The P2Y12-independent component is dependent upon PI 3-kinase and is augmented by epinephrine-mediated signaling. P2Y12-dependent and independent components are also observed in GPVI-mediated platelet aggregation, further supporting a role for Rap1 in aggregation. These results define mechanisms of GPVI-mediated platelet activation and implicate Rap1 as a key signaling protein in GPVI-induced platelet signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. Canobbio, L. Stefanini, L. Cipolla, E. Ciraolo, C. Gruppi, C. Balduini, E. Hirsch, and M. 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