Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells.
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 Thr(308) and its immediate downstream substrate GSK-3alpha/beta in a time-dependent fashion, with approximately 70% reduction at 15 min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser(636)/Ser(639) 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 Ser(636)/Ser(639) 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 Ser(636)/Ser(639) 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 Thr(308) and GSK-3alpha/beta 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.
Arellano-Plancarte
Araceli
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.
Hernandez-Aranda
Judith
J
Catt
Kevin J
KJ
Olivares-Reyes
J Alberto
JA
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007328:Insulin; D011799:Quinazolines; D020032:Tyrphostins; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C101044:RTKI cpd; D013912:Threonine; D012694:Serine; D066246:ErbB Receptors; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt