Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation

A Tzatsos, KV Kandror - Molecular and cellular biology, 2006 - Taylor & Francis
A Tzatsos, KV Kandror
Molecular and cellular biology, 2006Taylor & Francis
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 …
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 Y632MPM motif that is implicated in the binding of p85α/p110α 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.
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