Galpha(i1) and Galpha(i3) 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) Galpha(i1) and Galpha(i3) are critical for this activation process. Both ... Galpha(i1) and Galpha(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 Galpha(i1) and Galpha(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 Galpha(i1) and Galpha(i3) largely inhibited EGF-induced cell growth, migration, and survival and the accumulation of cyclin D1. Overall, this study suggests that Galpha(i1) and Galpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Galpha(i) proteins in mediating EGFR signaling.
Mesh Terms:
Animals, Blotting, Western, Cell Line, Cell Movement, Cell Proliferation, Cell Survival, Cells, Cultured, Cyclin D, Cyclins, Epidermal Growth Factor, ErbB Receptors, Fibroblasts, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Models, Biological, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Binding, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors
Animals, Blotting, Western, Cell Line, Cell Movement, Cell Proliferation, Cell Survival, Cells, Cultured, Cyclin D, Cyclins, Epidermal Growth Factor, ErbB Receptors, Fibroblasts, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Models, Biological, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Binding, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors
Sci Signal
Date: Apr. 28, 2009
PubMed ID: 19401591
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