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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3561-3569
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Vav1, but not Vav2, contributes to platelet aggregation by CRP
and thrombin, but neither is required for regulation of
phospholipase C
Andrew C. Pearce,
Jonathan I. Wilde,
Gina M. Doody,
Denise Best,
Osamu Inoue,
Elena Vigorito,
Victor L. J. Tybulewicz,
Martin Turner, and
Steve P. Watson
From the Department of Pharmacology, University of
Oxford, United Kingdom; the National Institute for Medical Research,
London, United Kingdom; and the Lymphocyte Signaling and Development
Laboratory, Molecular Immunology Programme, The Babraham Institute,
Cambridge, United Kingdom.
We have investigated the role of the Rho and Rac family
small guanine triphosphate (GTP) exchange factors (RhoGEFs),
Vav1 and Vav2, in the activation of platelets by the immunoreceptor tyrosine-based activation motif (ITAM)-coupled collagen receptor GPVI and by the G protein-coupled receptor agonist thrombin.
The glycoprotein VI (GPVI)-specific agonist collagen-related peptide (CRP) and thrombin stimulated tyrosine phosphorylation of Vav1 but not
Vav2 in human platelets. Surprisingly, however, CRP did not activate
the low-molecular-weight G protein Rac and stimulated only a
small increase in activity of p21-associated kinase 2 (PAK2), despite
the fact that both proteins are regulated downstream of Vav1 in other
cells. Further, activation of Rac and PAK2 by thrombin was maintained
in platelets from mice deficient in Vav1. Activation of phospholipase C
(PLC) by GPVI and thrombin was unaltered in Vav1-, Vav2-, and
Vav1/Vav2-deficient platelets. A weak inhibition of late-stage
aggregation to CRP and thrombin was observed in platelets deficient in
Vav1 but not Vav2, whereas spreading on fibrinogen was not changed. The
present results demonstrate that neither Vav1 nor Vav2 lie upstream of
PLC or Rac in platelets, highlighting an important difference in their
role in signaling by ITAM-coupled receptors in other cell types. The
present study has provided evidence for a possible role of Vav1 but not
Vav2 in the later stages of platelet aggregation.
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