Role of Rab5 in EGF receptor-mediated signal transduction
Role of Rab5 in EGF receptor-mediated signal transduction
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DOI：
10.1078/0171-9335-00381
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发表时间：
2004-07-01
影响因子：
6.6
通讯作者：
Stahl, PD
中科院分区：
文献类型：
--
作者：
Barbieri, MA;Fernandez-Pol, S;Stahl, PD
活化的表皮生长因子受体（EGFR）募集介导受体运输和信号传导的细胞内蛋白。Rab 5和Rin 1是一种具有Rab 5鸟嘌呤核苷酸交换因子结构域的多功能蛋白质，已被证明可以调节EGFR内吞作用（Barbieri等人，2000; Tall等人，2001年）。在这项研究中，我们证明，显性负Rab 5（Rab 5：S34 N）和全长Rin 1的过表达选择性地阻断EGF激活的Raf-Erk 1/2激酶途径和EGF刺激的[H-3]胸苷掺入DNA，而不影响JN和p38激酶途径的活性。Rab 5：S34 N和Rin 1的表达也阻断EGF对cyclin D1转录的诱导。与此相反，Rin 1：A，一个天然的剪接变异体Rin 1缺乏47个氨基酸的Vps 9 p域或Rab 5的表达，增加激活的Raf-Erk 1/2-和细胞周期蛋白D1的转录响应EGF。这些结果表明Rab 5和Raf/Erk信号转导通路在EGF诱导的细胞增殖中起着重要和选择性的作用，并突出了Rab 5在EGF信号转导中的新功能。
Activated epidermal growth factor receptor (EGFR) recruits intracellular proteins that mediate receptor trafficking and signaling. Rab5 and Rin1, a multifunctional protein with a Rab5 guanine nucleotide exchange factor domain, have been shown to regulate EGFR endocytosis (Barbieri et al., 2000; Tall et al., 2001). In this study, we demonstrate that overexpression of both dominant negative Rab5 (Rab5:S34N) and full-length Rin1 selectively block EGF activation of the Raf-Erk1/2 kinase pathway and EGF-stimulated incorporation of [H-3]thymidine into DNA without affecting the activity of JN and p38 kinase pathways. Expression of Rab5: S34N and Rin1 also block EGF induction of cyclin D1 transcription. In contrast, expression of Rin1: A, a natural splice variant of Rin1 lacking 47 amino acids in the Vps9p domain or Rab5, increase both activation of Raf-Erk1/2- and cyclin D1 transcription in response to EGF. These results indicate that Rab5 and the Raf/Erk signal transduction pathway play essential and selective roles in EGF-induced cell proliferation, and highlight a new function for Rab5 in EGF signaling.