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Molecular and Cellular Biology, January 2006, p. 63-76, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.63-76.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation{dagger}

Alexandros Tzatsos* and Konstantin V. Kandror*

Boston University School of Medicine, Boston, Massachusetts 02118

Received 3 December 2004/ Returned for modification 15 February 2005/ Accepted 3 October 2005

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 p85{alpha}/p110{alpha} 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.

* Corresponding author. Present address for Alexandros Tzatsos: Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington St., Box 5609, Boston, MA 02111. Phone: (617) 636-6153. Fax: (617) 636-6127. E-mail: atzatsos{at}tufts-nemc.org. Mailing address for Konstantin V. Kandror: Boston University School of Medicine, Department of Biochemistry, 715 Albany Street, Boston, MA 02118. Phone: (617) 638-5049. Fax: (617) 638-5339. kandror{at}biochem.bumc.bu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2006, p. 63-76, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.63-76.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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