Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.
Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
Tzatsos
Alexandros
A
Boston University School of Medicine, Massachusetts 02118, USA. atzatsos@tufts-nemc.org
Kandror
Konstantin V
KV
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007930:Leucine / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D000076223:Regulatory-Associated Protein of mTOR; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007930:Leucine; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D000076205:Ras Homolog Enriched in Brain Protein; D000076223:Regulatory-Associated Protein of mTOR; D012694:Serine; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C490211:RHEB protein, human; C463659:RPTOR protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat