The insulin receptor substrate (IRS)-1 recruits phosphatidylinositol 3-kinase to Ret: evidence for a competition between Shc and IRS-1 for the binding to Ret
The insulin receptor substrate (IRS)-1 recruits phosphatidylinositol 3-kinase to Ret: evidence for a competition between Shc and IRS-1 for the binding to Ret
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胰岛素受体底物 (IRS)-1 将磷脂酰肌醇 3-激酶招募到 Ret：Shc 和 IRS-1 之间竞争与 Ret 结合的证据
DOI：
10.1038/sj.onc.1204049
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发表时间：
2001
期刊：
影响因子：
8
通讯作者：
M. Santoro
中科院分区：
文献类型：
--
作者：
R. Melillo;F. Carlomagno;G. D. Vita;P. Formisano;G. Vecchio;A. Fusco;M. Billaud;M. Santoro
Ret的酪氨酸1062代表了多个信号分子的胞浆内对接位点，对于Ret介导的磷脂酰肌醇3-激酶（PI3-K）的激活至关重要。PI3-K反过来又参与诱导Ret介导的细胞存活和肿瘤转化。我们已经研究了Ret刺激PI3-K的机制。在这里，我们发现胰岛素受体底物-1 （IRS-1）是酪氨酸磷酸化的，并与PI3-K的p85调节亚基相关，以响应Ret激活。IRS-1与Ret共免疫沉淀，IRS-1的共表达导致Ret介导的Akt（PKB）激活增强，PKB是PI3-K的真正效应。IRS-1与PTB结构域的关联依赖于Ret的酪氨酸1062的磷酸化。天冬酰胺1059 （delN1059）的缺失和亮氨酸1061 （L1061P）的替代，这两种Ret突变在先天性巨结肠（Hirschsprung病）家族中被发现，损害IRS-1与Ret的结合以及Ret介导的Akt（PKB）刺激。最后，我们发现Shc，先前被鉴定为Ret的Y1062的另一个配体，与IRS-1竞争与Ret pY1062的结合。综上所述，这些发现表明IRS-1是导致Ret介导的PI3-K激活的信号通路的一个组成部分，这一途径可以被hirschsprung相关的Ret突变靶向。Shc和IRS-1与Ret pY1062的选择性结合可以调节不同细胞内信号通路的激活，并在Ret激活后引发不同的生物学反应。
Tyrosine 1062 of Ret, which represents an intracytoplasmic docking site for multiple signaling molecules, is essential for Ret-mediated activation of phosphatidylinositol 3-Kinase (PI3-K). PI3-K, in turn, has been implicated in inducing cell survival and neoplastic transformation mediated by Ret. We have examined the mechanisms by which Ret stimulates PI3-K. Here we show that the Insulin Receptor Substrate-1 (IRS-1) is tyrosine phosphorylated and associated with the p85 regulatory subunit of PI3-K in response to Ret activation. IRS-1 coimmunoprecipitates with Ret and co-expression of IRS-1 results in the potentiation of Ret-mediated activation of Akt(PKB), a bona fide effector of PI3-K. The association with the PTB domain of IRS-1 depends on the phosphorylation of tyrosine 1062 of Ret. The deletion of asparagine 1059 (delN1059) and the substitution of leucine 1061 (L1061P), two Ret mutations identified in families affected by congenital megacolon (Hirschsprung's disease), impair the binding of IRS-1 to Ret as well as Ret-mediated Akt(PKB) stimulation. Finally, we show that Shc, which was previously identified as another ligand of Y1062 of Ret, competes with IRS-1 for the binding to Ret pY1062. All together, these findings suggest that IRS-1 is a component of the signaling pathway which leads to Ret-mediated PI3-K activation, a pathway which can be targeted by Hirschsprung-associated Ret mutations. The alternative binding of Shc and IRS-1 to Ret pY1062 can be a system to modulate the activation of different intracellular signaling pathways and to elicit different biological responses following Ret activation.
胰岛素受体底物-1 增强生长激素诱导的增殖。
影响因子：
4.8
作者：
Liang,L;Zhou,T;Jiang,J;Pierce,JH;Gustafson,TA;Frank,SJ
通讯作者：
Frank,SJ
影响因子：
56.9
作者：
Bonni, A;Brunet, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
56.9
作者：
SKOLNIK, EY;BATZER, A;SCHLESSINGER, J
通讯作者：
SCHLESSINGER, J