title: Vav family proteins are required for optimal regulation of PLCgamma2 by integrin alphaIIbbeta3.
abstract: 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 PLCgamma (phospholipase Cgamma) 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 alphaIIbbeta3, which has recently been shown to regulate PLCgamma2. 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 alphaIIbbeta3-mediated PLCgamma2 tyrosine phosphorylation and reduced Ca(2+) 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 PLCgamma2 by integrin alphaIIbbeta3, but that their requirement is by-passed upon G-protein receptor activation.
authors.affiliation: Centre for Cardiovascular Sciences, Institute of Biomedical Research, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. a.c.pearce@bham.ac.uk
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Pearce
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: Simon D J
authors.initials: SD
authors.lastname: Calaminus
authors.forename: Elena
authors.initials: E
authors.lastname: Vigorito
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D005340:Fibrinogen; D051966:Phospholipase C gamma