Gene interactions and pathways from curated databases and text-mining
Science signaling 2009, PMID: 19401591

Galpha(i1) and Galpha(i3) are required for epidermal growth factor-mediated activation of the Akt-mTORC1 pathway.

Cao, Cong; Huang, Xuesong; Han, Yuyuan; Wan, Yinsheng; Birnbaumer, Lutz; Feng, Geng-Sheng; Marshall, John; Jiang, Meisheng; Chu, Wen-Ming

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.

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Text Mining Data

serine-threonine kinase → epidermal growth factor (EGF): " 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 "

Gab1 → EGF: " 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 "

4E-BP1 → transforming growth factor alpha: " 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 "

4E-BP1 → heparin binding EGF-like growth factor: " 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 "

4E-BP1 → 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 "

4E-BP1 → insulin-like growth factor: " 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 "

4E-BP1 → insulin: " 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 "

Akt → transforming growth factor alpha: " 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 "

Akt → heparin binding EGF-like growth factor: " 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 "

Akt → 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 "

Akt → insulin-like growth factor: " 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 "

Akt → insulin: " 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 "

cyclin D1 → EGF: " In addition, ablation of Galpha ( i1 ) and Galpha ( i3 ) largely inhibited EGF induced cell growth, migration, and survival and the accumulation of cyclin D1 "

mTORC1 → Gab1: " 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 "

Akt → Gab1: " 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 "

Manually curated Databases

In total, 11 gene pairs are associated to this article in curated databases