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J. Biol. Chem., Vol. 279, Issue 52, 53955-53962, December 24, 2004

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Vav1 and Vav3 Have Critical but Redundant Roles in Mediating Platelet Activation by Collagen^*

Andrew C. Pearce¶, Yotis A. Senis, Daniel D. Billadeau||, Martin Turner**, Steve P. Watson, and Elena Vigorito**

From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom, the ^**Laboratory for Lymphocyte Signalling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom, the ^||Department of Immunology, Mayo Graduate School, Mayo Clinic, Rochester, Minnesota 55905, and the Centre for Cardiovascular Studies, Institute of Biomedical Research, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

Vav family proteins are guanine nucleotide exchange factors for the Rho/Rac family of small GTP-binding proteins. In addition, they have domains that mediate protein-protein interactions, including one Src homology 2 (SH2) and two Src homology 3 (SH3) domains. Vav1, Vav2, and Vav3 play a crucial role in the regulation of phospholipase C (PLC) isoforms by immuno-tyrosine-based activation motif (ITAM)-coupled receptors, including the T- and B-cell antigen receptors. We have reported in platelets, however, that Vav1 and Vav2 are not required for activation of PLC2 in response to stimulation of the ITAM-coupled collagen receptor glycoprotein VI (GPVI). Here we report that Vav3 is tyrosinephosphorylated upon activation of GPVI but that Vav3-deficient platelets also exhibit a normal response upon activation of the ITAM receptor. In sharp contrast, platelets deficient in both Vav1 and Vav3 show a marked inhibition of aggregation and spreading upon activation of GPVI, which is associated with a reduction in tyrosine phosphorylation of PLC2. The phenotype of Vav1/2/3 triple-deficient platelets is similar to that of Vav1/3 double-deficient cells. These results demonstrate that Vav3 and Vav1 play crucial but redundant roles in the activation of PLC2 by GPVI. This is the first time that absolute redundancy between two protein isoforms has been observed with respect to the regulation of PLC2 in platelets.

Received for publication, September 9, 2004

^* This work was supported in part by the Wellcome Trust, the British Heart Foundation, and the Biotechnology and Biological Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Holds a Medical Research Council Senior Fellowship.

Holds a British Heart Foundation Research Chair.

^¶ A Wellcome Trust Prize Student. To whom correspondence should be addressed. Tel.: 44-121-4158679; Fax: 44-121-4146919; E-mail: a.c.pearce{at}bham.ac.uk.

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