In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 2, No. 68 ( 2009-04-28)
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 α subunits of the heterotrimeric guanine nucleotide–binding proteins (G proteins) Gα i1 and Gα i3 are critical for this activation process. Both Gα i1 and Gα 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 Gα i1 and Gα 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 α, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Gα i1 and Gα i3 largely inhibited EGF-induced cell growth, migration, and survival, and the accumulation of cyclin D1. Overall, this study suggests that Gα i1 and Gα i3 lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Gα i proteins in mediating EGFR signaling.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.2000118
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2009
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