Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells |
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Authors: | Araceli Arellano-Plancarte Kevin J. Catt |
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Affiliation: | a Department of Biochemistry, Center for Research and Advanced Studies of the National Polytechnic Institute, Cinvestav-IPN, A.P. 14-740, Mexico, 07360 D.F., Mexico b Section on Hormonal Regulation, PDEGEN, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA |
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Abstract: | To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulin-induced Akt Thr308 and its immediate downstream substrate GSK-3α/β in a time-dependent fashion, with ∼70% reduction at 15 min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser636/Ser639 that was prevented by selective blockade of EGFR tyrosine kinase activity with AG1478. Previous studies have shown that insulin-induced phosphorylation of IRS-1 on Ser636/Ser639 is mediated mainly by the PI3K/mTOR/S6K-1 sequence. Studies with specific inhibitors of PI3K (wortmannin) and mTOR (rapamycin) revealed that Ang II stimulates IRS-1 phosphorylation of Ser636/Ser639 via the PI3K/mTOR/S6K-1 pathway. Both inhibitors blocked the effect of Ang II on insulin-induced activation of Akt. Studies using the specific MEK inhibitor, PD98059, revealed that ERK1/2 activation also mediates Ang II-induced S6K-1 and IRS-1 phosphorylation, and the impairment of Akt Thr308 and GSK-3α/β phosphorylation. Further studies with selective inhibitors showed that PI3K activation was upstream of ERK, suggesting a new mechanism for Ang II-induced impairment of insulin signaling. These findings indicate that Ang II has a significant role in the development of insulin resistance by a mechanism that involves EGFR transactivation and the PI3K/ERK1/2/mTOR-S6K-1 pathway. |
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Keywords: | Ang II, angiotensin II AT1R, angiotensin type 1 receptor EGF, epidermal growth factor GPCRs, G protein-coupled receptors GSK-3, glycogen synthase kinase-3 IRS, insulin receptor substrate IR, insulin receptor mTOR, mammalian target of rapamycin PI3K, phosphatidylinositol 3-kinase RAS, renin-angiotensin system S6K-1, ribosomal S6 kinase-1 |
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