Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action

被引：769

作者：

Aguirre, V ^{[1
]}

Werner, ED ^{[1
]}

Giraud, J ^{[1
]}

Lee, YH ^{[1
]}

Shoelson, SE ^{[1
]}

White, MF ^{[1
]}

机构：

[1] Harvard Univ, Howard Hughes Med Inst, Joslin Diabet Ctr, Sch Med, Boston, MA 02215 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2002年 / 277卷 / 02期

关键词：

D O I：

10.1074/jbc.M101521200

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：

Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast trihybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling.

引用

页码：1531 / 1537

页数：7

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