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

• Published in: The Journal of biological chemistry 2004-12, Vol.279 (52), p.53955-53962
• Main Authors: Pearce, Andrew C., Senis, Yotis A., Billadeau, Daniel D., Turner, Martin, Watson, Steve P., Vigorito, Elena
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Blood Platelets - chemistry; Blood Platelets - physiology; CD36 Antigens - chemistry; CD36 Antigens - physiology; Cell Cycle Proteins; Collagen - pharmacology; Enzyme Activation - physiology; Enzyme Precursors - metabolism; Guanine Nucleotide Exchange Factors; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Oncogene Proteins - deficiency; Oncogene Proteins - genetics; Oncogene Proteins - physiology; Phospholipase C gamma; Phosphorylation; Phosphotyrosine - metabolism; Platelet Activation - drug effects; Platelet Activation - physiology; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-vav; Receptors, Collagen - chemistry; Receptors, Collagen - physiology; src-Family Kinases - metabolism; Syk Kinase; Type C Phospholipases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M410355200

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 Cγ (PLCγ) 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 PLCγ2 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 PLCγ2. 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 PLCγ2 by GPVI. This is the first time that absolute redundancy between two protein isoforms has been observed with respect to the regulation of PLCγ2 in platelets.