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Mol. Cell. Biol. doi:10.1128/MCB.00079-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The p85 Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates JNK-mediated Insulin Resistance

Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, 02215, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Systems Biology, Harvard Medical School, Boston, MA, 02215; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan; Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, Suita City, Japan

^* To whom correspondence should be addressed. Email: c.ronald.kahn{at}joslin.harvard.edu.

	Abstract

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high fat diet-induced obesity and JNK1 overexpression. The requirement of the p85 regulatory subunit for JNK occurs independent of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely insulin and tunicamycin, a chemical that induces endoplasmic reticulum (ER) stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N-terminus and functional SH2 domains within the C-terminus of the p85 regulatory subunit. Thus, p85 plays a dual role in regulating insulin sensitivity and may mediate crosstalk between the PI3K and stress kinase pathways.

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