Vav2 is one of three members of the Vav family (the others being Vav1 and Vav3) of guanine nucleotide exchange factors (GEFs) for Rho-family GTPases such as Rac1, RhoA, RhoG, and perhaps Cdc42 (Cdc42 is controversial). There are at least 3 splice variants of Vav2, distinguished by insertions in the acidic domain, the pleckstrin homology domain, and the Src homology-2/Src homology-3 linker domain. Vav2 shares 63% and 55% identity at the nucleic acid and amino acid level, respectively, with Vav1 and is ubiquitously expressed. Vav2 mRNA is found in a wide range of cell types in both mouse and human tissues, including cells of the endothelium, nervous system, and heart (cardiac muscle).
Vav2 contains a calponin homology (CH) domain, an acidic domain (AC), the Dbl homology (DH) and pleckstrin homology (PH) domains 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. Vav2 GEF activity requires tyrosine phosphorylation which unlocks Vav2 from its “closed” conformation. In Vav2’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 Vav2, Tyr172 corresponds to Vav1 Tyr174) in the AC helix.
Tyrosine phosphorylation-mediated Vav2 activation occurs following ligand binding to membrane-associated receptor TKs (e.g., EGF and PDGF) or receptors that activate cytosolic TKs (e.g., Src family kinases). With the former, Vav2 directly binds to the auto-phosphorylated growth factor receptors through its SH2 domain. Initial studies focused on Vav2 phosphorylation by the EGF receptor, revealing that Tyr142, Tyr159, and Tyr172 are phosphorylated (these residues are conserved across all three isoforms and correspond to Tyr142, Tyr160, and Tyr174, respectively, on Vav1). Interestingly, Vav2 also regulates EGF receptor internalization and degradation, an effect dependent on its GEF activity.
Vav2 has unique functions due at least in part to its ubiquitous expression. In rodent fibroblasts, Vav2 gene expression produces a morphological phenotype that differs from that of Vav1. In endothelial cells, Vav2 regulates cell adhesion, cell migration, mechanosensing, and angiogenesis. In the nervous system, Vav2 regulates the outgrowth and branching of neurites as well as exerting control over the activity and trafficking of the dopamine transporter following treatment with GDNF. In cardiac muscle, Vav2 is involved in cardiovascular (e.g., hypertension and cardiovascular disease) and renal homeostasis (e.g., kidney dysfunction). Vav2’s integral role in cell adhesion and subsequent motility involves a complex signaling cascade where vimentin controls EGF receptor-mediated phosphorylation of Vav2 Tyr142 and Tyr172 residues, resulting in activation of Vav2 GEF activity and subsequent Rac1 activation. Phosphorylated Vav2 localizes to vimentin-positive focal adhesions where Rac1 is activated, catalyzing formation of a focal adhesion kinase-positive/focal adhesion complex. Vav2 has also been implicated in glucose-stimulated insulin secretion whereby glucose stimulates Rac1 activity by way of Vav2 activation which then mediates remodeling of the actin cytoskeleton for the docking and release of insulin from secretory granules at the plasma membrane.
Like Vav1, Vav2 becomes oncogenic upon N-terminal truncation (though a longer deletion is necessary). As Vav2 regulates cell motility, invasion, and spreading, its activation is linked to cancer invasion and metastasis. In addition, its over-expression is associated with several cancers.
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