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Blood, 1 January 2005, Vol. 105, No. 1, pp. 186-191. Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-07-2842. This Article Full Text (PDF) All Versions of this Article: 2004-07-2842v1 105/1/186    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 Stephens, G. Articles by Phillips, D. R Search for Related Content PubMed PubMed Citation Articles by Stephens, G. Articles by Phillips, D. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 23, 2004 Accepted August 13, 2004 Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen Gillian Stephens, Yibing Yan, Martine Jandrot-Perrus, Jean-Luc Villeval, Kenneth J Clemetson, and David R Phillips* Portola Pharmaceuticals Inc., South San Francisco, CA, USA Faculte Xavier Bichat, Institut National de la Sante et de la Recherche Medicale (INSERM) E348; INSERM U 362, Institut Gustave Roussy, Villejuif, Paris, France Millennuim Pharmaceuticals Inc., Cambridge, MA, USA Theodor Kocher Institute, University of Berne, Berne, Switzerland * Corresponding author; email: DPhillips{at}portola.com. Glycoprotein (GP) VI, the primary collagen receptor on platelets, has been shown to have variable expression, possibly as a consequence of immune modulation. The present study was designed to determine the mechanism by which GP VI clearance occurs. We found that direct activation of GP VI both by a GP VI specific antibody and by GP VI ligands (collagen and convulxin) reduced binding of biotinylated-convulxin to the stimulated platelets. Analysis of immunoblots of platelets and supernatants showed that the stimulated platelets contained less GP VI while the soluble fraction contained a 57 kDa cleavage product. Stimulation of platelets with PAR-1 agonists (TRAP peptide and thrombin) also caused GP VI cleavage although the amount of GP VI loss was less than that observed with direct GP VI ligands. The metalloproteinase (MMP) inhibitors GM6001 and TAPI prevented both the clearance of GP VI from the platelet surface, and the appearance of the soluble cleavage product. Induction of GP VI cleavage caused specific down-regulation of collagen-induced platelet aggregation, providing a mechanism for the modulation of platelet responsiveness to this important platelet agonist. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Nishikii, K. Eto, N. Tamura, K. Hattori, B. Heissig, T. Kanaji, A. Sawaguchi, S. Goto, J. Ware, and H. Nakauchi Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells J. Exp. Med., August 4, 2008; 205(8): 1917 - 1927. [Abstract] [Full Text] [PDF] L. F. Brass, L. Zhu, and T. J. Stalker Novel Therapeutic Targets at the Platelet Vascular Interface Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s43 - s50. [Abstract] [Full Text] [PDF] E. E. Gardiner, D. Karunakaran, J. F. Arthur, F.-T. Mu, M. S. Powell, R. I. Baker, P. M. Hogarth, M. L. Kahn, R. K. Andrews, and M. C. Berndt Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing Fc{gamma}RIIa Blood, January 1, 2008; 111(1): 165 - 174. [Abstract] [Full Text] [PDF] J. F. Arthur, Y. Shen, M. L. Kahn, M. C. Berndt, R. K. Andrews, and E. E. Gardiner Ligand Binding Rapidly Induces Disulfide-dependent Dimerization of Glycoprotein VI on the Platelet Plasma Membrane J. Biol. Chem., October 19, 2007; 282(42): 30434 - 30441. [Abstract] [Full Text] [PDF] T. Rabie, D. Varga-Szabo, M. Bender, R. Pozgaj, F. Lanza, T. Saito, S. P. Watson, and B. Nieswandt Diverging signaling events control the pathway of GPVI down-regulation in vivo Blood, July 15, 2007; 110(2): 529 - 535. [Abstract] [Full Text] [PDF] R. K. Andrews, D. Karunakaran, E. E. Gardiner, and M. C. Berndt Platelet Receptor Proteolysis: A Mechanism for Downregulating Platelet Reactivity Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1511 - 1520. [Abstract] [Full Text] [PDF] S. P. Jackson The growing complexity of platelet aggregation Blood, June 15, 2007; 109(12): 5087 - 5095. [Abstract] [Full Text] [PDF] B. Boylan, M. C. Berndt, M. L. Kahn, and P. J. Newman Activation-independent, antibody-mediated removal of GPVI from circulating human platelets: development of a novel NOD/SCID mouse model to evaluate the in vivo effectiveness of anti-human platelet agents Blood, August 1, 2006; 108(3): 908 - 914. [Abstract] [Full Text] [PDF]

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