1999 Fiscal Year Final Research Report Summary
Role of tyrosine and serine phosphorylation in insulin's metabolic signaling and its disturbance.
Project/Area Number |
10671060
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Metabolomics
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Research Institution | Toyama Medical and Pharmaceutical University |
Principal Investigator |
HARUTA Tetsuro Toyama Medical and Pharmaceutical University, Hospital, Assistant professor, 附属病院, 助手 (00293308)
|
Project Period (FY) |
1998 – 1999
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Keywords | Insulin receptor substrate-1 / rapamycin / mammalian target of rapamycin / insulin action / degradation / adipocyte / phosphatydylinositol 3-kinase |
Research Abstract |
Insulin receptor substrate-1 (IRS-1) is a major substrate of the insulin receptor and acts as a docking protein for Src homology 2 domain containing signaling molecules that mediate many of the pleiotropic actions of insulin. Insulin stimulation elicits serine/threonine phosphorylation of IRS-1, which produces a mobility shift on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by degradation of IRS-1 after prolonged stimulation. We investigated the molecular mechanisms and the functional consequences of these phenomena in 3T3-L1 adipocytes. PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor blocked both the insulin-induced electrophoretic mobility shift and degradation of IRS-1. Adenovirus mediated expression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110ィイD1CAAXィエD1) induced a mobility shift and degradation of IRS-1, both of which were inhibited by rapamycin. Lactacystin, a specific proteasome inhibitor, inhibited insulin-induced degradation of IRS-1 without any effect on its electrophoretic mobility. Inhibition of the mobility shift did not significantly affect tyrosine phosphorylation of IRS-1 or downstream insulin signaling. In contrast, blockade of IRS-1 degradation resulted in sustained activation of Akt, p70 S6 kinase and MAP kinase during prolonged insulin treatment. These results indicate that insulin-induced serine/threonine phosphorylation and degradation of IRS-1 are mediated by a rapamycin-sensitive pathway, which is downstream of PI 3-kinase and independent of ras/MAP kinase. The pathway leads to degradation of IRS-1 by the proteasome, which plays a major role in down-regulation of certain insulin actions during prolonged stimulation.
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Research Products
(2 results)