Gαi1 and Gαi3 Are Required for Epidermal Growth Factor-Mediated Activation of the Akt-mTORC1 Pathway

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) G alpha(i1) and G alpha(i3) are critical for this activation process. Both G alpha(i1) and G alpha(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 G alpha(i1) and G alpha(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 G alpha(i1) and G alpha(i3) largely inhibited EGF-induced cell growth, migration, and survival, and the accumulation of cyclin D1. Overall, this study suggests that G alpha(i1) and G alpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for G alpha(i) proteins in mediating EGFR signaling.