Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2

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Abstract
We show here that Vav‐2, a member of the Vav family of oncoproteins, acts as a guanosine nucleotide exchange factor (GEF) for RhoG and RhoA‐like GTPases in a phosphotyrosine‐dependent manner. Moreover, we show that Vav‐2 oncogenic activation correlates with the acquisition of phosphorylation‐independent exchange activity. In vivo , wild‐type Vav‐2 is activated oncogenically by tyrosine kinases, an effect enhanced further by co‐expression of RhoA. Likewise, the Vav‐2 oncoprotein synergizes with RhoA and RhoB proteins in cellular transformation. Transient transfection assays in NIH‐3T3 cells show that phosphorylated wild‐type Vav‐2 and the Vav‐2 oncoprotein induce cytoskeletal changes resembling those observed by the activation of the RhoG pathway. In contrast, the constitutive expression of the Vav‐2 oncoprotein in rodent fibroblasts leads to major alterations in cell morphology and to highly enlarged cells in which karyokinesis and cytokinesis frequently are uncoupled. These results identify a regulated GEF for the RhoA subfamily, provide a biochemical explanation for vav family oncogenicity, and establish a new signaling model in which specific Vav‐like proteins couple tyrosine kinase signals with the activation of distinct subsets of the Rho/Rac family of GTPases.