SEARCH:   Advanced

Blood, 1 January 2008, Vol. 111, No. 1, pp. 165-174. Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-04-086983. This Article Full Text (PDF) All Versions of this Article: blood-2007-04-086983v1 111/1/165    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 Berndt, M. C Search for Related Content PubMed PubMed Citation Articles by Gardiner, E. E Articles by Berndt, M. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 24, 2007 Accepted August 24, 2007 Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: De-ITAM-ising FcRIIa Elizabeth E Gardiner, Denuja Karunakaran, Jane F. Arthur, Fi-Tjen Mu, Maree S Powell, Ross I Baker, P Mark Hogarth, Mark L Kahn, Robert K Andrews, and Michael C Berndt* Department of Immunology, Monash University, Melbourne, Australia The Burnet Institute, Melbourne, Australia Haemophilia Centre of Western Australia, Royal Perth Hospital, & Dept of Medicine & Pharmacology, University of Western Australia, Perth, Australia Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States * Corresponding author; email: michael.berndt{at}med.monash.edu.au. Collagen binding to glycoprotein (GP)VI induces signals critical for platelet activation in thrombosis. Both ligand-induced GPVI signaling through its co-associated Fc-receptor -chain (FcR) immunoreceptor tyrosine-activation motif (ITAM), and the calmodulin inhibitor, W7, dissociate calmodulin from GPVI and induce metalloproteinase-mediated GPVI ectodomain shedding. We investigated whether signaling via another ITAM-bearing receptor on platelets, FcRIIa, also downregulates GPVI expression. Agonists that signal through FcRIIa, the mAbs VM58 or 14A2, potently induced GPVI shedding, inhibitable by the metalloproteinase inhibitor, GM6001. Unexpectedly, FcRIIa also underwent rapid proteolysis in platelets treated with agonists for FcRIIa (VM58/14A2) or GPVI/FcR (the snake toxin, convulxin), generating an ~30-kDa fragment. Immunoprecipitation/pull-down experiments showed FcRIIa also bound calmodulin and W7 induced FcRIIa cleavage. However, unlike GPVI, the ~30-kDa FcRIIa fragment remained platelet-associated, and proteolysis was unaffected by GM6001, but inhibited by a membrane-permeable calpain inhibitor, E64d; consistent with this, µ-calpain cleaved an FcRIIa tail-fusion protein at 222Lys/223Ala and 230Gly/231Arg, upstream of the ITAM domain. These findings suggest simultaneous activation of distinct extracellular (metalloproteinase-mediated) and intracellular (calpain-mediated) proteolytic pathways irreversibly inactivating platelet GPVI/FcR and FcRIIa, respectively. Activation of both pathways was observed with immunoglobulin from heparin-induced thrombocytopenia (HIT) patients, suggesting novel mechanisms for platelet dysfunction via FcRIIa following immunological insult. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Braking platelet activation: deactivating the receptors Koneti A. Rao Blood 2008 111: 3. [Full Text] [PDF] This article has been cited by other articles: H. Kubagawa, S. Oka, Y. Kubagawa, I. Torii, E. Takayama, D.-W. Kang, G. L. Gartland, L. F. Bertoli, H. Mori, H. Takatsu, et al. Identity of the elusive IgM Fc receptor (Fc{micro}R) in humans J. Exp. Med., November 23, 2009; 206(12): 2779 - 2793. [Abstract] [Full Text] [PDF] B. Boylan, C. Gao, V. Rathore, J. C. Gill, D. K. Newman, and P. J. Newman Identification of Fc{gamma}RIIa as the ITAM-bearing receptor mediating {alpha}IIb{beta}3 outside-in integrin signaling in human platelets Blood, October 1, 2008; 112(7): 2780 - 2786. [Abstract] [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020