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Blood, 15 July 2007, Vol. 110, No. 2, pp. 529-535.
Prepublished online as a Blood First Edition Paper on May 11, 2007; DOI 10.1182/blood-2006-11-058107.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Diverging signaling events control the pathway of GPVI down-regulation in vivo
Tamer Rabie1,
David Varga-Szabo1,
Markus Bender1,
Rastislav Pozgaj1,
Francois Lanza2,
Takashi Saito3,
Stephen P. Watson4, and
Bernhard Nieswandt1,5
1 University of Würzburg, Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, Würzburg, Germany;
2 Institut National de la Santé et de la Recherche Médicale, U311, Etablissement Français du Sang, Alsace; Strasbourg, France; Université Louis Pasteur, Strasbourg, France;
3 Laboratory of Cell Signaling, Rikagaku Kenkyusho (RIKEN) Research Center for Allergy and Immunology, Yokohama, Japan;
4 Centre for Cardiovascular Sciences, Institute of Biomedical Research, Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham, United Kingdom;
5 University of Würzburg, Institute of Clinical Biochemistry and Pathobiochemistry, Würzburg, Germany
Coronary artery thrombosis is often initiated by platelet activation on collagen-rich subendothelial layers in the disrupted atherosclerotic plaque. The activating platelet collagen receptor glycoprotein VI (GPVI) noncovalently associates with the Fc receptor  -chain (FcR), which signals through its immunoreceptor-tyrosine–based activation motif (ITAM) via the adaptor LAT leading to the activation of phospholipase C2 (PLC2). GPVI is a promising antithrombotic target as anti-GPVI antibodies induce the irreversible loss of the receptor from circulating platelets by yet undefined mechanisms in humans and mice and long-term antithrombotic protection in the latter. However, the treatment is associated with transient but severe thrombocytopenia and reduced platelet reactivity to thrombin questioning its clinical usefulness. Here we show that GPVI down-regulation occurs through 2 distinct pathways, namely ectodomain shedding or internalization/intracellular clearing, and that both processes are abrogated in mice carrying a point mutation in the FcR-associated ITAM. In mice lacking LAT or PLC2, GPVI shedding is abolished, but the receptor is irreversibly down-regulated through internalization/intracellular clearing. This route of GPVI loss is not associated with thrombocytopenia or altered thrombin responses. These results reveal the existence of 2 distinct signaling pathways downstream of the FcR-ITAM and show that it is possible to uncouple GPVI down-regulation from undesired side effects with obvious therapeutic implications.
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