i1 and Gαi3 Are Required for Epidermal Growth Factor–Mediated Activation of the Akt-mTORC1 Pathway

C Cao, X Huang, Y Han, Y Wan, L Birnbaumer… - Science …, 2009 - science.org
C Cao, X Huang, Y Han, Y Wan, L Birnbaumer, GS Feng, J Marshall, M Jiang, WM Chu
Science signaling, 2009science.org
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 α subunits of the heterotrimeric guanine nucleotide–
binding proteins (G proteins) Gαi1 and Gαi3 are critical for this activation process. Both Gαi1
and Gαi3 formed complexes with growth factor receptor binding 2 (Grb2)–associated
binding protein 1 (Gab1) and the EGF receptor (EGFR) and were required for the …
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 α subunits of the heterotrimeric guanine nucleotide–binding proteins (G proteins) Gαi1 and Gαi3 are critical for this activation process. Both Gαi1 and Gαi3 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 Gαi1 and Gαi3 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 α, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Gαi1 and Gαi3 largely inhibited EGF-induced cell growth, migration, and survival, and the accumulation of cyclin D1. Overall, this study suggests that Gαi1 and Gαi3 lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Gαi proteins in mediating EGFR signaling.
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