Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
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DOI：
10.1083/jcb.200108035
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发表时间：
2002-01-07
期刊：
影响因子：
--
通讯作者：
Scita G
中科院分区：
文献类型：
--
作者：
Innocenti M;Tenca P;Frittoli E;Faretta M;Tocchetti A;Di Fiore PP;Scita G
来自受体酪氨酸激酶（RTK）* 的信号传导需要小GTP酶Ras和Rac的顺序激活。Sons of sevenless（Sos-1）是一种双功能的鸟嘌呤核苷酸交换因子（GEF），在体内可激活Ras，在体外可显示Rac-GEF活性。然而，对Sos-1如何协调Ras和Rac活性的机械理解仍然缺失。在这里，我们证明了（a）在生理条件下，Sos-1，E3 b1和Eps 8在体内组装成三复合体;（B）Grb 2和E3 b 1通过它们的SH 3结构域与Sos-1上的相同结合位点结合，从而决定了具有Ras和Rac特异性GEF活性的Sos-1-Grb 2（S/G）或Sos-1-E3 b 1-Eps 8（S/E/E8）复合物的形成，分别为：（c）Sos-1-Grb 2复合物在RTK激活时被破坏，而S/E/E8复合物则没有;和（d）与前面的结果一致，生长因子对Ras的激活是短暂的，而Rac的激活是持续的。因此，Sos-1参与信号级联的两个不同的和差异调节的步骤允许Ras和Rac的协调激活以及它们在细胞内的信号传导的不同持续时间。
Signaling from receptor tyrosine kinases (RTKs)* requires the sequential activation of the small GTPases Ras and Rac. Son of sevenless (Sos-1), a bifunctional guanine nucleotide exchange factor (GEF), activates Ras in vivo and displays Rac-GEF activity in vitro, when engaged in a tricomplex with Eps8 and E3b1–Abi-1, a RTK substrate and an adaptor protein, respectively. A mechanistic understanding of how Sos-1 coordinates Ras and Rac activity is, however, still missing. Here, we demonstrate that (a) Sos-1, E3b1, and Eps8 assemble into a tricomplex in vivo under physiological conditions; (b) Grb2 and E3b1 bind through their SH3 domains to the same binding site on Sos-1, thus determining the formation of either a Sos-1–Grb2 (S/G) or a Sos-1–E3b1–Eps8 (S/E/E8) complex, endowed with Ras- and Rac-specific GEF activities, respectively; (c) the Sos-1–Grb2 complex is disrupted upon RTKs activation, whereas the S/E/E8 complex is not; and (d) in keeping with the previous result, the activation of Ras by growth factors is short-lived, whereas the activation of Rac is sustained. Thus, the involvement of Sos-1 at two distinct and differentially regulated steps of the signaling cascade allows for coordinated activation of Ras and Rac and different duration of their signaling within the cell.
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