Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins.
We report here the identification and characterization of a novel Vav family member, Vav-3. Signaling experiments demonstrate that Vav-3 participates in pathways activated by protein tyrosine kinases. Vav-3 promotes the exchange of nucleotides on RhoA, on RhoG and, to a lesser extent, on Rac-1. During this reaction, Vav-3 binds physically to the nucleotide-free states of those GTPases. These functions are stimulated by tyrosine phosphorylation in wild-type Vav-3 and become constitutively activated upon deletion of the entire calponin-homology region. Expression of truncated versions of Vav-3 leads to drastic actin relocalization and to the induction of stress fibers, lamellipodia, and membrane ruffles. Moreover, expression of Vav-3 alters cytokinesis, resulting in the formation of binucleated cells. All of these responses need only the expression of the central region of Vav-3 encompassing the Dbl homology (DH), pleckstrin homology (PH), and zinc finger (ZF) domains but do not require the presence of the C-terminal SH3-SH2-SH3 regions. Studies conducted with Vav-3 proteins containing loss-of-function mutations in the DH, PH, and ZF regions indicate that only the DH and ZF regions are essential for Vav-3 biological activity. Finally, we show that one of the functions of the Vav-3 ZF region is to work coordinately with the catalytic DH region to promote both the binding to GTP-hydrolases and their GDP-GTP nucleotide exchange. These results highlight the role of Vav-3 in signaling and cytoskeletal pathways and identify a novel functional cross-talk between the DH and ZF domains of Vav proteins that is imperative for the binding to, and activation of, Rho GTP-binding proteins.
Movilla
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Department of Pathology, State University of New York at Stony Brook, University Hospital, Stony Brook, New York 11794-7025, USA.
Bustelo
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D016475:3T3 Cells / Q000166:cytology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics; D002451:Cell Compartmentation; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010750:Phosphoproteins; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D016335:Zinc Fingers / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D001798:Blood Proteins; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; C512843:Mcf2 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins; C496621:VAV3 protein, human; C496622:Vav3 protein, mouse; C039077:platelet protein P47; D020741:rho GTP-Binding Proteins