Schuebel K E, Movilla N, Rosa J L, Bustelo X R
Department of Pathology, State University of New York at Stony Brook, University Hospital, Level 2, Room 718-B, Stony Brook, NY 11794-7025, USA.
EMBO J. 1998 Nov 16;17(22):6608-21. doi: 10.1093/emboj/17.22.6608.
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.
我们在此表明，原癌蛋白Vav家族成员Vav-2作为RhoG和RhoA样GTP酶的鸟苷酸交换因子（GEF），以磷酸酪氨酸依赖性方式发挥作用。此外，我们表明Vav-2的致癌激活与获得磷酸化非依赖性交换活性相关。在体内，野生型Vav-2被酪氨酸激酶致癌激活，RhoA的共表达进一步增强了这种效应。同样，Vav-2原癌蛋白在细胞转化中与RhoA和RhoB蛋白协同作用。在NIH-3T3细胞中的瞬时转染试验表明，磷酸化的野生型Vav-2和Vav-2原癌蛋白诱导细胞骨架变化，类似于通过激活RhoG途径所观察到的变化。相比之下，Vav-2原癌蛋白在啮齿动物成纤维细胞中的组成型表达导致细胞形态发生重大改变，并导致细胞高度增大，其中核分裂和胞质分裂经常解偶联。这些结果确定了RhoA亚家族的一种受调控的GEF，为vav家族的致癌性提供了生化解释，并建立了一种新的信号模型，其中特定的Vav样蛋白将酪氨酸激酶信号与Rho/Rac家族GTP酶不同亚群的激活偶联起来。
