期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 8, 页码 4640-4645出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.051042298
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资金
- NCI NIH HHS [CA67891, CA73023] Funding Source: Medline
- NIDDK NIH HHS [DK 18849, R01 DK018849] Funding Source: Medline
Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-l) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-l from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine/threonine kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-l and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-l was blocked by inhibition of PI 3-kinase and the PTEN tumor suppessor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin-promoted IRS-l tyrosine phosphorylation. Conversely, TNF inhibition of IRS-l tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-l tyrosine phosphorylation by TNF was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstream target of Akt. mTOR induced the serine phosphorylation of IRS-l (Ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a Pi 3-kinase/Akt/ mTOR pathway, which is antagonized by PTEN.
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