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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3611-3617. Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-04-1549. This Article Full Text (PDF) All Versions of this Article: 2004-04-1549v1 104/12/3611    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 Gardiner, E. E Articles by Andrews, R. K Search for Related Content PubMed PubMed Citation Articles by Gardiner, E. E Articles by Andrews, R. K Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 23, 2004 Accepted July 12, 2004 Regulation of Platelet Membrane Levels of Glycoprotein VI by a Platelet-Derived Metalloproteinase Elizabeth E Gardiner*, Jane F Arthur, Mark L Kahn, Michael C Berndt, and Robert K Andrews Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA * Corresponding author; email: elizabeth.gardiner{at}med.monash.edu.au. Thrombosis can be initiated when activated platelets adhere to injured blood vessels via the interaction of subendothelial collagen with its platelet receptor, glycoprotein (GP)VI. Here we observed that incubation of platelets with convulxin, collagen or collagen-related peptide (CRP) resulted in GPVI signaling-dependent loss of surface GPVI and the appearance of an ~55 kDa soluble fragment of GPVI as revealed by immunoblotting. EDTA or GM6001 (a metalloproteinase inhibitor with broad specificity) prevented this loss. In other receptor systems, calmodulin binding to membrane proximal cytoplasmic sequences regulates metalloproteinase-mediated ectodomain shedding. In this regard, we have previously shown that calmodulin binds to a positively-charged, membrane-proximal sequence within the cytoplasmic tail of GPVI. Incubation of platelets with calmodulin inhibitor W7 (150 µM) resulted in time-dependent loss of GPVI from the platelet surface. Both EDTA and GM6001 prevented this loss. Surface plasmon resonance demonstrated that W7 specifically blocked the association of calmodulin with an immobilized synthetic peptide corresponding to the calmodulin binding sequence of GPVI. These findings suggest that disruption of calmodulin binding to receptor cytoplasmic tails by agonist binding to the receptor triggers metalloproteinase-mediated loss of GPVI from the platelet surface. This process may represent a potential mechanism to regulate GPVI-dependent platelet adhesion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. C. Hughan, C. E. Hughes, O. J.T. McCarty, E. Schweighoffer, I. Soultanova, J. Ware, V. L.J. Tybulewicz, and S. P. Watson GPVI Potentiation of Platelet Activation by Thrombin and Adhesion Molecules Independent of Src Kinases and Syk Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 422 - 429. [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] B. Aktas, M. Pozgajova, W. Bergmeier, S. Sunnarborg, S. Offermanns, D. Lee, D. D. Wagner, and B. Nieswandt Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE) J. Biol. Chem., December 2, 2005; 280(48): 39716 - 39722. [Abstract] [Full Text] [PDF] S. Chattopadhyay, K. R. Santhamma, S. Sengupta, B. McCue, M. Kinter, G. C. Sen, and I. Sen Calmodulin Binds to the Cytoplasmic Domain of Angiotensin-converting Enzyme and Regulates Its Phosphorylation and Cleavage Secretion J. Biol. Chem., October 7, 2005; 280(40): 33847 - 33855. [Abstract] [Full Text] [PDF]

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