Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function

被引:162
作者
Paz, K
Liu, YF
Shorer, H
Hemi, R
LeRoith, D
Quan, M
Kanety, H
Seger, R
Zick, Y [1 ]
机构
[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel
[3] Chaim Sheba Med Ctr, Inst Endocrinol, IL-52621 Tel Hashomer, Israel
[4] NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA
[5] NIDDK, Mol & Cellular Endocrinol Branch, Bethesda, MD 20892 USA
关键词
D O I
10.1074/jbc.274.40.28816
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Incubation of cells with insulin leads to a transient rise in Tyr phosphorylation of insulin receptor substrate (IRS) proteins, accompanied by elevation in their Ser(P)/Thr(P) content and their dissociation from the insulin receptor (IR), Wortmannin, a phosphatidylinositol 3-kinase inhibitor, selectively prevented the increase in Ser(P)/Thr(P) content of IRS-1, its dissociation from IR, and the decrease in its Tyr(P) content following 60 min of insulin treatment. Four conserved phosphorylation sites within the phosphotyrosine binding/SAIN domains of IRS-1 and IRS-S served as in vitro substrates for protein kinase B (PKB), a Ser/Thr kinase downstream of phosphatidylinositol 3-kinase, Furthermore, PKB and IRS-1 formed stable complexes in vivo, and overexpression of PKB enhanced Ser phosphorylation of IRS-l. Overexpression of PKB did not affect the acute Tyr phosphorylation of IRS-l; however, it significantly attenuated its rate of Tyr dephosphorylation following 60 min of treatment with insulin. Accordingly, overexpression of IRS-1(4A), lacking the four potential PKB phosphorylation sites, markedly enhanced the rate of Tyr dephosphorylation of IRS-I, while inclusion of vanadate reversed this effect. These results implicate a wortmannin-sensitive Ser/Thr kinase, different from PKB, as the kinase that phosphorylates IRS-I and acts as the feedback control regulator that turns off insulin signals by inducting the dissociation of IRS proteins from IR, In contrast, insulin-stimulated PKB-mediated phosphorylation of Ser residues within the phosphotyrosine binding/SAIN domain of IRS-1 protects IRS-1 from the rapid action of protein-tyrosine phosphatases and enables it to maintain its Tyr-phosphorylated active conformation. These findings implicate PHB as a positive regulator of IRS-l functions.
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页码:28816 / 28822
页数:7
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