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| The EMBO Journal
(1998) 17, 6608–6621, doi:10.1093/emboj/17.22.6608 |
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| Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2 |
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| Kornel E. Schuebel1, Nieves Movilla1, José Luis Rosa2 and Xosé R. Bustelo1 |
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1 Department of Pathology, State University of New York at Stony Brook, University Hospital, Level 2, Room 718-B, Stony Brook, NY 11794-7025, USA 2 Present address: Unidad de Bioquímica (4178), Facultad de Medicina, Campus de Bellvitge, Universidad de Barcelona, C/ Feixa Llarga s/n, 08907 Hospitalet (Barcelona), Spain To whom correspondence should be addressed Xosé R. Bustelo, xbustelo@path.som.sunysb.edu Received 25 March 1998; Revised 14 September 1998; Accepted 15 September 1998. |
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| Abstract |
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| 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. |
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| Keywords: GDP–GTP exchange factors, phosphorylation, Rac, Rho, Vav family |
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