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Sci. Signal., 28 April 2009
Vol. 2, Issue 68, p. ra17
[DOI: 10.1126/scisignal.2000118]

RESEARCH ARTICLES

G{alpha}i1 and G{alpha}i3 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 {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.

* To whom correspondence should be addressed. E-mail: wen-ming_chu{at}brown.edu

Citation: C. Cao, X. Huang, Y. Han, Y. Wan, L. Birnbaumer, G. S. Feng, J. Marshall, M. Jiang, W. M. Chu, G{alpha}i1 and G{alpha}i3 Are Required for Epidermal Growth Factor–Mediated Activation of the Akt-mTORC1 Pathway. Sci. Signal. 2, ra17 (2009).

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