Rac1 function is required for Src-induced transformation - Evidence of a role for Tiam1 and Vav2 in RAC activation by Src
Rac1 function is required for Src-induced transformation - Evidence of a role for Tiam1 and Vav2 in RAC activation by Src
复制标题
DOI：
10.1074/jbc.m302960200
复制
发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Servitja, JM;Marinissen, MJ;Gutkind, JS
原癌基因c-Src与包括结肠癌和乳腺癌在内的许多人类癌症的发生和进展有关。越来越多的证据表明Src的激活等位基因可以通过Ras-ERK依赖和非依赖途径诱导细胞转化。在这里，我们表明，Rac 1活性强烈升高Src转化的细胞，这种小G蛋白是一个关键组成部分的途径连接致癌Src细胞转化。我们进一步表明，Vav 2和普遍表达的Rac 1鸟嘌呤核苷酸交换因子Tiam 1的酪氨酸残基在转染活性和致癌Src的细胞中被磷酸化。此外，Tiam 1的磷酸化与过钒酸盐，酪氨酸磷酸酶的有效抑制剂处理的细胞中，部分抑制Src抑制剂SU 6656。使用Tiam 1的截短突变体，我们证明了多个位点可以被Src酪氨酸磷酸化。此外，Tiam 1与Src协同诱导Rac 1在体内的激活和膜皱褶的形成。类似地，Tiam 1也有效地增加了Src对JNK和c-jun启动子的激活。总之，这些结果表明，Vav 2和Tiam 1可能作为下游效应的Src，从而调节Rac 1依赖的途径，参与Src诱导的细胞转化。
The proto-oncogene c-Src has been implicated in the development and progression of a number of human cancers including those of colon and breast. Accumulating evidence indicates that activated alleles of Src may induce cell transformation through Ras-ERK-dependent and - independent pathways. Here we show that Rac1 activity is strongly elevated in Src-transformed cells and that this small G protein is a critical component of the pathway connecting oncogenic Src with cell transformation. We further show that Vav2 and the ubiquitously expressed Rac1 guanine nucleotide exchange factor Tiam1 are phosphorylated in tyrosine residues in cells transfected with active and oncogenic Src. Moreover, phosphorylation of Tiam1 in cells treated with pervanadate, a potent inhibitor of tyrosine phosphatases, was partially inhibited by the Src inhibitor SU6656. Using truncated mutants of Tiam1, we demonstrate that multiple sites can be tyrosine-phosphorylated by Src. Furthermore, Tiam1 cooperated with Src to induce activation of Rac1 in vivo and the formation of membrane ruffles. Similarly, activation of JNK and the c-jun promoter by Src were also potently increased by Tiam1. Together, these results suggest that Vav2 and Tiam1 may act as downstream effectors of Src, thereby regulating Rac1-dependent pathways that participate in Src-induced cell transformation.