Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2.
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.
Schuebel
K E
KE
Department of Pathology, State University of New York at Stony Brook, University Hospital, Level 2, Room 718-B, Stony Brook, NY 11794-7025, USA.
Movilla
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N
Rosa
J L
JL
Bustelo
X R
XR
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D015513:Oncogene Proteins; D011506:Proteins; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins; C490565:Vav2 protein, mouse; D014443:Tyrosine; D019204:GTP-Binding Proteins