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.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Animals, Binding Sites, Blood Proteins, Cell Compartmentation, Cell Cycle Proteins, Cell Transformation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Mice, Molecular Sequence Data, Multigene Family, Phosphoproteins, Protein Binding, Protein Structure, Secondary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-vav, Recombinant Proteins, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Zinc Fingers, rho GTP-Binding Proteins
3T3 Cells, Amino Acid Sequence, Animals, Binding Sites, Blood Proteins, Cell Compartmentation, Cell Cycle Proteins, Cell Transformation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Mice, Molecular Sequence Data, Multigene Family, Phosphoproteins, Protein Binding, Protein Structure, Secondary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-vav, Recombinant Proteins, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Zinc Fingers, rho GTP-Binding Proteins
Mol. Cell. Biol.
Date: Nov. 01, 1999
PubMed ID: 10523675
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