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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.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing Fc RIIa
Elizabeth E. Gardiner1,
Denuja Karunakaran1,
Jane F. Arthur1,
Fi-Tjen Mu1,
Maree S. Powell2,
Ross I. Baker3,4,
P. Mark Hogarth2,
Mark L. Kahn5,
Robert K. Andrews1, and
Michael C. Berndt1
1 Department of Immunology, Monash University, Melbourne, Australia;
2 The Burnet Institute, Melbourne, Australia;
3 Haemophilia Centre of Western Australia, Royal Perth Hospital, Perth, Australia;
4 Department of Medicine and Pharmacology, University of Western Australia, Perth, Australia; and
5 Department of Medicine, University of Pennsylvania, Philadelphia
Collagen binding to glycoprotein VI (GPVI) induces signals critical for platelet activation in thrombosis. Both ligand-induced GPVI signaling through its coassociated 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 by another ITAM-bearing receptor on platelets, FcRIIa, also down-regulates 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 approximate 30-kDa fragment. Immunoprecipitation/pull-down experiments showed that FcRIIa also bound calmodulin and W7 induced FcRIIa cleavage. However, unlike GPVI, the approximate 30-kDa FcRIIa fragment remained platelet associated, and proteolysis was unaffected by GM6001 but was 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 patients with heparin-induced thrombocytopenia (HIT), suggesting novel mechanisms for platelet dysfunction by FcRIIa after immunologic insult.
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