A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1

Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-l) by the ins ulin receptor permits this docking protein to interact with signaling prote ins that promote insulin action. Serine phosphorylation uncouples IRS-l fro m 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 fa ctor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-l and activated the Akt/protein kinase B serine-threonine kinase, a downstream t arget for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-l was blocked by inhibiti on of PI 3-kinase and the PTEN tumor suppessor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Ak t impaired insulin-promoted IRS-l tyrosine phosphorylation. Conversely, TNF inhibition of IRS-l tyrosine phosphorylation was blocked by kinase dead Ak t. Inhibition of IRS-l tyrosine phosphorylation by TNF was blocked by rapam ycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstrea m target of Akt. mTOR induced the serine phosphorylation of IRS-l (Ser-636/ 639), and such phosphorylation was inhibited by rapamycin. These results su ggest that TNF impairs insulin signaling through IRS-1 by activation of a P i 3-kinase/Akt/ mTOR pathway, which is antagonized by PTEN.