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The p85 Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance ^,

Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215,¹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,² Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,³ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02215,⁴ Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,⁵ Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan,⁶ Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, Suita City, Japan⁷

Received 15 January 2007/ Accepted 18 January 2007

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 independently 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 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 cross talk between the PI3K and stress kinase pathways.

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Published ahead of print on 5 February 2007.

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