Journal
BIOCHEMICAL JOURNAL
Volume 401, Issue -, Pages 753-761Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20061508
Keywords
fibrinogen; integrin alpha II beta 3; phospholipase C gamma 2 (PLC gamma 2); platelet spreading; signalling; Vav
Categories
Funding
- Wellcome Trust Funding Source: Medline
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Vav proteins belong to the family. of guanine-nucleotide-exchange factors for the Rho/Rac family of small G-proteins. In addition, they serve as important adapter proteins for the activation of PLC gamma (phospholipase C gamma) isoforms by ITAM (immunoreceptor tyrosine-based activation motif) receptors, including the platelet collagen receptor GPVI (glycoprotein VI). Vav proteins are also regulated downstream of integrins, including the major platelet integrin alpha IIb beta 3, which has recently been shown to regulate PLC gamma 2. In the present study, we have investigated the role of Vav family proteins in filopodia and lamellipodia formation on fibrinogen using platelets deficient in Vav1 and Vav3. Wild-type mouse platelets undergo a limited degree of spreading on fibrinogen, characterized by the formation of numerous filopodia and limited lamellipodia structures. Platelets deficient in Vav1 and Vav3 exhibit reduced filopodia and lamellipodia formation during spreading on fibrinogen. This is accompanied by reduced alpha IIb beta 3-mediated PLC gamma 2 tyrosine phosphorylation and reduced Ca2+ mobilization. In contrast, the G-protein agonist thrombin stimulates full spreading of control and Vav1/3-deficient platelets. Consistent with this, stimulation of F-actin (filamentous actin) formation and Rac activation by thrombin is not altered in Vav-deficient cells. These results demonstrate that Vav1 and Vav3 are required for optimal spreading and regulation of PLC gamma 2 by integrin alpha II beta 83, but that their requirement is by-passed upon G-protein receptor activation.
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