Vav3 GTP Exchange Factor (GEF) of Rac1, RhoA and Cdc42.

Vav3 is a member of the Vav family (the others being Vav1 and Vav2) of guanine nucleotide exchange factors (GEFs) for Rho-family GTPases such as Rac1, RhoA, and RhoG. Full-length Vav3 shares 69% and 66% identity at the amino acid level with Vav1 and Vav2, respectively, and is ubiquitously expressed. Vav3 mRNA is found in cells of most of the major organ systems (e.g., nervous, cardiovascular, immune, renal, and hepatic systems, to name a few). Vav3 is involved in integrin-mediated signaling, wound healing, angiogenesis, bone remodeling, development of the cerebellum, an area important for motor coordination, and GABAergic innervation of the brainstem which controls cardiovascular, respiratory, and renal functions. Besides full-length Vav3, there is a truncated version (Vav3.1; a.k.a. Vav3, isoform 2) consisting of the three carboxyl terminal domains (SH3, SH2, SH3) differentially expressed in a variety of normal tissues. Vav3.1 mRNA is differentially expressed in cancer tissue compared to full-length Vav3 mRNA, with down-regulation of the former and no change in the latter.

Vav3 contains a calponin homology (CH) domain, an acidic domain (AC), the Dbl homology (DH) and pleckstrin homology (PH) domains which are common to all Rho GEFs, an atypical cysteine-rich zinc finger (C1) domain, a proline rich domain, a Src homology-2 (SH2) domain, and two Src homology-3 (SH3) domains flanking the single SH2 region. Mutational analysis revealed that only the C1 and DH domains are essential for Vav3 GEF activity with the C1 region being involved in binding with the GTPase substrate. Vav3 GEF activity is dependent upon tyrosine phosphorylation which unlocks Vav3 from its “closed” conformation. In Vav3’s unphosphorylated, closed state, the helix of the AC auto-inhibits the DH domain. The AC’s inhibitory conformation is further stabilized through interactions with the CH and DH/PH domains. Inhibition is removed by tyrosine kinase (TK)-mediated phosphorylation of the conserved Tyr174 residue (on Vav3, Tyr173 corresponds to Vav1 Tyr174 based on Vav1 amino acid numbering) in the AC helix.

Like the other Vav proteins, Vav3 is phosphorylated (activated) following ligand binding to a variety of receptor tyrosine kinases (TKs), including EGF receptor, PDGF receptor, insulin receptor, and insulin-like growth factor I receptor. In addition, B-cell and/or T-cell receptor stimulation also results in phosphorylation of Vav3. The SH3-SH2-SH3 C-terminal domains bind directly with the auto-phosphorylated cytoplasmic tails of the receptor TKs while the B- and T-cell receptors activate cytosolic TKs.

Unlike Vav1 and Vav2, the expression of N-terminal truncated versions of Vav3 does not cause oncogenic transformation in cells but does induce the formation of actin-based structures such as membrane ruffles, lamellipodia, and stress fibers. However, over-expression of Vav3 is associated with the progression of various cancers. Recent research has focused on breast and prostate cancer as Vav3 activates the estrogen and androgen receptors. Suppression of Vav3 expression can enhance anti-cancer treatments.


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