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.
The NF-B family of transcription factors plays a fundamental role in development, maintenance of the immune system, and cell viability (1-3). NF-B is composed of heterodimers of DNA-binding subunits (p50 and p52) and subunits with transcriptional activity (p65 (RelA), RelB, or c-Rel). In unstimulated cells, binary complexes of these subunits are restricted to the cytoplasm by interaction with members of a family of inhibitory proteins, inhibitors of B (IBs) 1 (4, 5). In response to extracellular stimuli such as cytokines or UV radiation, IB proteins are phosphorylated, polyubiquitinated, and then degraded by the 26 S proteasome (6 -13). Dissociation from IBs unmasks the nuclear localization sequence of NF-B, permitting it to move into the nucleus, bind the promoters of target genes, and alter gene expression and cell function (10,13,14). The demonstration that phosphorylation of IB proteins initiates events necessary for activation of NF-B led to the discovery of IB kinase (IKK) complexes composed of IKK␣, IKK, and IKK␥ (NEMO) (15)(16)(17)(18)(19). IKK␣ and IKK are serine-threonine kinases, and IKK␥ is a scaffolding protein essential for the function of IKK␣ and IKK. IKK␣ and IKK share a high degree of amino acid homology and domain organization. The kinases are composed of an N-terminal kinase domain, a leucine zipper that facilitates homo-and heterodimerization, and a helix-loop-helix domain (20). IKK␣ and IKK can be activated by diverse kinases, among which are NF-B-inducing kinase (NIK), MEKK1, Cot, NF-Bactivating kinase (NAK/TBK), protein kinases C and C␦, and MEKK3 (21-28). However, interest remains sustained in identifying other kinases that affect IKK complexes and NF-B activity. One of these is the Akt serine-threonine kinase, a downstream target for activated phosphatidylinositol 3-kinase (PI 3-kinase) (29 -32). Akt is activated by mitogens and cytokines that function as survival factors. Akt mediates its functions by phosphorylating substrates that decrease the activity of pro-apoptotic proteins or increase the activity of anti-apoptotic proteins (32)(33)(34)(35)(36)(37)(38)(39)(40)(41).Akt may affect NF-B through multiple mechanisms. We demonstrated previously that TNF activates Akt, which phosphorylates and activates IKK␣, thus promoting NF-B function (42). TNF and interleukin-1 can also increase the transactivation potential of the RelA/p65 subunit of NF-B through a mechanism in which Akt has been implicated (43-45). PI 3-kinase activated by phorbol esters or lipopolysaccharide and PI 3-kinase/Akt signaling induced by signaling through CD40, interleukin-1, or G protein-coupled receptors activates [46][47][48]. However, PI 3-kinase/Akt signaling induced by TNF in human umbilical vein endothelial cells inhibits apoptosis without playing a significant role in activation of NF-B (49). Furthermore, Akt can activate a member of the mitogenactivated protein kinase kinase kinase (MAP3K) family, Cot, and indirectly affect IKK activity and NF-B (50). Thus, PI 3-kinase/Akt signaling is upstream of diver...
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