G
i1 and Gi3 Are Required for Epidermal Growth Factor–Mediated Activation of the Akt-mTORC1 Pathway
Cong Cao1,2,
Xuesong Huang1,
Yuyuan Han1,
Yinsheng Wan3,
Lutz Birnbaumer4,
Geng-Sheng Feng5,
John Marshall6,
Meisheng Jiang7, and
Wen-Ming Chu1,2*
1 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
2 Pathobiology Graduate Program, Brown University, Providence, RI 02912, USA.
3 Department of Biology, Providence College, Providence, RI 02918, USA.
4 Laboratory of Neurobiology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
5 Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
6 Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.
7 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Abstract:
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 
subunits of the heterotrimeric guanine nucleotide–binding proteins (G proteins) Gi1 and Gi3 are critical for this activation process. Both Gi1 and Gi3 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 Gi1 and Gi3 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 , but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Gi1 and Gi3 largely inhibited EGF-induced cell growth, migration, and survival and the accumulation of cyclin D1. Overall, this study suggests that Gi1 and Gi3 lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Gi proteins in mediating EGFR signaling.
* To whom correspondence should be addressed. E-mail: wen-ming_chu{at}brown.edu
