The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance

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 p85α 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 p85α 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 p85α regulatory subunit. Thus, p85α plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.

SUPPLEMENTAL MATERIAL

We greatly appreciate the technical assistance of Laureen Mazzola, Will Wisdom, and Michael Rourk.

This work was supported by National Institutes of Health grants DK33201 and DK55545, Joslin Diabetes and Endocrinology Research Center grant DK34834 (to C.R.K.), and grants GM41890 and CA089021 to L.C.C. C.M.T. acknowledges support from the American Diabetes Association Medical Scholars Award and a Medical Scientist Training Program scholarship (Harvard Medical School). J.L. acknowledges support from an HHMI predoctoral fellowship.