New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway
New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway
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DOI：
10.1128/mcb.20.19.7109-7120.2000
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发表时间：
2000-10-01
影响因子：
5.3
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Gu, HH;Maeda, H;Neel, BG
大多数（如果不是全部）细胞因子都会激活磷脂酰肌醇 3-激酶 (PI-3K)。尽管许多细胞因子受体具有 PI-3K p85 亚基的直接结合位点，但其他细胞因子受体，例如白细胞介素 3 (IL-3) 受体 β 共同链 (β c) 和 IL-2 受体 β 链 (IL-2R β) 缺乏此类位点，因此它们激活 PI-3K 的机制尚不清楚。在这里，我们发现原癌蛋白 Shc 通过招募 Grb2-Sos 复合物响应细胞因子的刺激来促进 Ras 激活，也向 PI-3K/Akt 通路发出信号。对 Y-->F 和 beta c 的“add-back”突变体的分析表明，Shc 结合位点 Y577 是响应细胞因子刺激而 Gab2 磷酸化所需的主要位点。当直接与缺乏其他细胞质酪氨酸的 IL-2R beta 突变体融合时。 Shc可以促进Gab2酪氨酰磷酸化。 Shc 与 Grb2 结合的三个酪氨酰磷酸化位点的突变会阻断 Shc 嵌合体引发 Gab2 酪氨酰磷酸化的能力。具有失活 SH2 或 SH3 结构域的 Grb2 突变体的过表达也会阻断细胞因子刺激的 Gab2 磷酸化。大多数细胞因子刺激的 PI-3K 活性与 Gab2 相关，无法结合 PI-3K 的 Gab2 突变体的诱导表达会显着损害 IL-3 诱导的 Akt 激活和细胞生长。嵌合受体实验表明，Shc 还向 PI-3K/Akt 通路发出信号以响应 IL-2。我们的结果表明，缺乏直接 PI-3K 结合位点的细胞因子受体通过 Shc/Grb2/Gab2/PI-3K 通路激活 Akt，从而调节细胞存活和/或增殖。
Most, if not all, cytokines activate phosphatidylinositol 3-kinase (PI-3K). Although many cytokine receptors have direct binding sites for the p85 subunit of PI-3K, others, such as the interleukin-3 (IL-3) receptor beta common chain (beta c) and the IL-2 receptor beta chain (IL-2R beta), lack such sites, leaving the mechanism by which they activate PI-3K unclear. Here, we show that the protooncoprotein Shc, which promotes Ras activation by recruiting the Grb2-Sos complex in response to stimulation of cytokine stimulation, also signals to the PI-3K/Akt pathway. Analysis of Y--> F and "add-back" mutants of beta c show's that Y577, the Shc binding site, is the major site required for Gab2 phosphorylation in response to cytokine stimulation. When fused directly to a mutant form of IL-2R beta that lacks other cytoplasmic tyrosines. Shc can promote Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation. Overexpression of mutants of Grb2 with inactive SH2 or SH3 domains also blocks cytokine-stimulated Gab2 phosphorylation. The majority of cytokine-stimulated PI-3K activity associates with Gab2, and inducible expression of a Gab2 mutant unable to bind PI-3K markedly impairs IL-3-induced Akt activation and cell growth. Experiments with the chimeric receptors indicate that Shc also signals to the PI-3K/Akt pathway in response to IL-2, Our results suggest that cytokine receptors lacking direct PI-3K binding sites activate Akt via a Shc/Grb2/Gab2/PI-3K pathway, thereby regulating cell survival and/or proliferation.