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

Abstract

Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-1 from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine͞threonine kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-1 and activated the Akt͞protein 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-1 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-1 tyrosine phosphorylation. Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-1 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-1 (Ser-636͞639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase͞Akt͞ mTOR pathway, which is antagonized by PTEN.

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…In this work we detected for the first time a significant enlargement of Ptpn1 mRNA and protein expression in brown adipocytes treated with TNFα, as well as an increase in phosphatase activity. Numerous sources of evidence suggest that phosphatases are used by TNFα to block insulin signalling at different levels [38][39][40]. Moreover, studies with obese rats have shown that expression of leucocyte common antigen-related protein tyrosine phosphatase in liver is downregulated after TNFα blockade [41], and in rat hepatoma cells TNFα increased SHIP2 production.…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…TNFa binds to its receptor and activates downstream inflammatory signaling pathways including IKK, mTORC or JNK. In turn, these effectors recruit downstream molecules, respectively nuclear factor-kappa B (NFkB), S6 kinase (S6K) and activator protein-1 (AP-1), which inhibit IRS phosphorylation, subsequently impairing insulin signaling in the liver (Kamada et al, 2008;Lumeng et al, 2008;Ozes et al, 2001) (Fig. 2).…”

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype‐specific mechanisms†

“…32,33 Therefore, to further investigate the mechanisms were subjected to immunoblot analysis with anti-SOCS-7 and anti-␤-actin antibodies (C). We quantified the signal of SOCS-7 by densitometry and normalized it using ␤-actin signal as reference protein.…”