J Biol Chem 2003,
PMID: 12510059
Greene, Michael W; Sakaue, Hiroshi; Wang, Lihong; Alessi, Dario R; Roth, Richard A
Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) is a negative regulator of insulin signaling. One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. Ser/Thr phosphorylation of IRS-1 correlates with IRS-1 degradation, yet the details of how this occurs are still unknown. In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. First, we found that inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin block the degradation. Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1.
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Text Mining Data
insulin receptor substrate-1 → insulin: "
Modulation of
insulin stimulated degradation of human
insulin receptor substrate-1 by Serine 312 phosphorylation
"
IRS-1 → Insulin: "
Insulin induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes
"
IRS-1 → insulin: "
In the present study we have examined the potential role of different signaling cascades in the insulin induced degradation of IRS-1
"
IRS-1 → insulin: "
Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide dependent kinase-1, were found to be deficient in the insulin stimulated degradation of IRS-1
"
IRS-1 → insulin: "
Conversely, overexpression of this enzyme potentiated insulin stimulated IRS-1 degradation
"
IRS-1 → insulin: "
Most important, an IRS-1 mutant in which Ser ( 312 ) was changed to alanine was found to be resistant to insulin stimulated IRS-1 degradation
"
c-Jun → insulin: "
Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser ( 312 ) phosphorylation yet completely blocked insulin stimulated c-Jun phosphorylation
"
c-Jun → mammalian target of rapamycin: "
Further, insulin stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin , indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser ( 312 ) in response to insulin
"
c-Jun → insulin: "
Further, insulin stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser ( 312 ) in response to insulin
"
IRS-1 → insulin: "
In summary, our results indicate that the insulin stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser ( 312 ) phosphorylation of IRS-1
"
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