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Blood, 15 July 2007, Vol. 110, No. 2, pp. 529-535.
Prepublished online as a Blood First Edition Paper on March 20, 2007May 11, 2007; DOI 10.1182/blood-2006-11-058107.
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Submitted November 14, 2006
Accepted February 20, 2007
Diverging signaling events control the pathway of GPVI downregulation in vivo
Tamer Rabie, David Varga-Szabo, Markus Bender, Rastislav Pozgaj, Francois Lanza, Takashi Saito, Stephen P Watson, and Bernhard Nieswandt*
University of Wurzburg, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Wurzburg, Germany
Inserm, U311, EFS-Alsace, Strasbourg, F-67065, Universite Louis Pasteur, Strasbourg, France
Laboratory of Cell Signaling, RIKEN Research Center for Allergy & Immunology, Yokohama, Japan
Centre for Cardiovascular Sciences, Institute of Biomedical Research, Division of Medical Sciences, Medical School, Univ of Birmingham, Birmingham, United Kingdom
University of Wurzburg, Institute of Clinical Biochemistry & Pathobiochemistry, Wurzburg, Germany
* Corresponding author; email: bernhard.nieswandt{at}virchow.uni-wuerzburg.de.
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 (GP)VI non-covalently 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-downregulation occurs through two distinct pathways, namely ectodomain shedding or internalization/degradation 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/degradation. This route of GPVI loss is not associated with thrombocytopenia or altered thrombin responses. These results reveal the existence of two distinct signaling pathways downstream of the FcR-ITAM and show that it is possible to uncouple GPVI downregulation from undesired side effects with obvious therapeutic implications.
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