Cao Cong, Huang Xuesong, Han Yuyuan, Wan Yinsheng, Birnbaumer Lutz, Feng Geng-Sheng, Marshall John, Jiang Meisheng, Chu Wen-Ming
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Sci Signal. 2009 Apr 28;2(68):ra17. doi: 10.1126/scisignal.2000118.
The precise mechanism whereby epidermal growth factor (EGF) activates the serine-threonine kinase Akt and the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) remains elusive. Here, we report that the alpha subunits of the heterotrimeric guanine nucleotide-binding proteins (G proteins) Galpha(i1) and Galpha(i3) are critical for this activation process. Both Galpha(i1) and Galpha(i3) formed complexes with growth factor receptor binding 2 (Grb2)-associated binding protein 1 (Gab1) and the EGF receptor (EGFR) and were required for the phosphorylation of Gab1 and its subsequent interaction with the p85 subunit of phosphatidylinositol 3-kinase in response to EGF. Loss of Galpha(i1) and Galpha(i3) severely impaired the activation of Akt and of p70 S6 kinase and 4E-BP1, downstream targets of mTORC1, in response to EGF, heparin-binding EGF-like growth factor, and transforming growth factor alpha, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Galpha(i1) and Galpha(i3) largely inhibited EGF-induced cell growth, migration, and survival and the accumulation of cyclin D1. Overall, this study suggests that Galpha(i1) and Galpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Galpha(i) proteins in mediating EGFR signaling.
表皮生长因子（EGF）激活丝氨酸 - 苏氨酸激酶Akt和雷帕霉素哺乳动物靶蛋白（mTOR）复合物1（mTORC1）的确切机制仍不清楚。在此，我们报告异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）的α亚基Gα(i1)和Gα(i3)对于此激活过程至关重要。Gα(i1)和Gα(i3)均与生长因子受体结合2（Grb2）相关结合蛋白1（Gab1）和EGF受体（EGFR）形成复合物，并且是Gab1磷酸化及其随后响应EGF与磷脂酰肌醇3激酶的p85亚基相互作用所必需的。Gα(i1)和Gα(i3)的缺失严重损害了Akt以及mTORC1的下游靶点p70 S6激酶和4E - BP1对EGF、肝素结合表皮生长因子样生长因子和转化生长因子α的激活，但对胰岛素、胰岛素样生长因子或血小板衍生生长因子无影响。此外，Gα(i1)和Gα(i3)的缺失在很大程度上抑制了EGF诱导的细胞生长、迁移和存活以及细胞周期蛋白D1的积累。总体而言，本研究表明Gα(i1)和Gα(i3)位于EGFR的下游，但在Gab1介导的Akt和mTORC1激活的上游，从而揭示了Gα(i)蛋白在介导EGFR信号传导中的作用。
