Nutrients Suppress Phosphatidylinositol 3-kinase/Akt Signaling Via Raptor-dependent Mtor-mediated Insulin Receptor Substrate 1 Phosphorylation.
From: Boston University School of Medicine, Massachusetts 02118, USA. atzatsos@tufts-nemc.org
Molecular and cellular biology
- Publish Date: Jan 2006
- ISSN: 0270-7306
- Volume: 26
- Issue: 1
- Pages: 63-76
- Medium: Print
- Language: English
- Citation (JAMA): Tzatsos Alexandros, Kandror Konstantin V, et al. Nutrients Suppress Phosphatidylinositol 3-kinase/Akt Signaling Via Raptor-dependent Mtor-mediated Insulin Receptor Substrate 1 Phosphorylation.. Mol. Cell. Biol. Jan 2006;26:63-76
Abstract
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.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Leucine, Mice, Monomeric GTP-Binding Proteins, Mutation, Neuropeptides, Phosphoproteins, Phosphorylation, Protein Kinases, Proteins, Proto-Oncogene Proteins c-akt, Rats, Serine, Signal Transduction, Sirolimus
Check for Full Text / PubMed Unique Identifier (PMID): 16354680
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