Vav1 GTP Exchange Factor (GEF) of Rac1, RhoA and Cdc42.

Vav1 is one of three members of the Vav family (the others being Vav2 and Vav3) of guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav1 is regarded primarily as a Rac GEF, but it can also activate RhoA, RhoG, and perhaps Cdc42 (Cdc42 is controversial). Vav1 is expressed predominantly, if not exclusively, in hematopoietic-derived cells. Vav1 GEF’s activity is regulated by direct tyrosine phosphorylation.

Vav1 was originally identified as a proto-oncogene after N-terminal truncation (amino acids 1-66). Full-length Vav1 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, two Src homology-3 (SH3) domains flanking the single SH2 region, and two nuclear localization signals (NLS). Vav-T, a shorter transcript variant of VAV1, contains just the C-terminal SH3 domain and is only detectable in mouse testicular germ cells.

Vav1 GEF activity requires tyrosine phosphorylation which unlocks Vav1 from its “closed” conformation. In Vav1’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 Tyr174 in the AC helix. Besides Tyr174, Tyr142 and Tyr160 (AC domain), Tyr541 and Tyr544 (zinc finger domain), and Tyr836 (SH3 domain) are phosphorylated. Although Tyr142, Tyr160, and Tyr174 are conserved within the Vav family, the most studied is Tyr174 as it exerts the strongest control over Vav1 activation.

Phosphorylation-induced activation of Vav1 follows: 1. ligand binding to cell surface receptors (e.g., T-cell, B-cell and Fcg receptors) either directly linked to TKs or those that activate cytosolic TKs in response to extracellular stimuli; 2. Activation of either the receptor TKs or cytosolic TKs (e.g., Src, Syk, Janus, Tec, and Abl family TKs); and 3. Vav1 phosphorylation.  Receptor-mediated Vav1 activation is through a direct cytoplasmic interaction between Vav1’s SH2 domain and the auto-phosphorylated tails of receptor TKs. The PH domain interacts with two lipid products of phosphatidylinositol 3-kinase (PI3K) to further regulate Vav1. Phosphatidylinositol 4,5-biphosphosphate (PIP2) inhibits Vav1 activation while phosphatidylinositol facilitates activation.

Vav1 regulates multiple cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T- and B-cells, natural killer cells, and osteoclasts) through activation of Rho-family GTPases. Such functions include gene transcription, development and activation of the immune system (e.g., T and B-cells), and re-arrangement of the actin cytoskeleton. Actin remodeling underlies many Vav1-mediated functions, such as formation of the immunological synapse, integrin clustering, phagocytosis, platelet aggregation, integrin-mediated T-cell spreading, and lipid raft clustering. 3,4,5-triphosphate (PIP3) facilitates activation.

There are no N-terminally truncated Vav1 proteins reported in cancer; however, ectopic expression of wild-type Vav1 is observed in multiple cancers. Additionally, abnormal phosphorylation of Vav1 has also been reported in some cancers which would lead to over-activation of the GEF. As under normal physiological conditions, Vav1’s role in cancer is considered to be as a GEF for Rho-family GTPases.

References

Aghazadeh B. et al. 2000. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell. 102, 625-633.

Lopez-Lago M. et al. 2000. Tyrosine phosphorylation mediates both activation and downmodulation of the biological activity of Vav. Mol. Cell. Biol. 20, 1678-1691.

Hornstein I. et al. 2004. Vav proteins, masters of the world of cytoskeleton organization. Cell. Signal. 16, 1-11.

Bustelo X.R. 2014. Vav family exchange factors: an integrated regulatory and functional view. Small GTPases. 5,9.

Cook D.R. et al. 2014. Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease. Oncogene. 33, 4021-4035.

Van Buul J.D. et al. 2014. Rho GAPs and GEFs: Controling switches in endothelial cell adhesion. Cell. Adh. Migr. 8, 108-1214.

Katzav S. 2015. Vav1: A Dr. Jekyll and Mr. Hyde protein – good for the hematopoietic system, bad for cancer. Oncotarget. 6, 28731-28742.