Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 27, Issue 8, Pages 2830-2840Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00079-07
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Funding
- NCI NIH HHS [CA089021, P01 CA089021] Funding Source: Medline
- NIDDK NIH HHS [R01 DK055545, DK34834, DK33201, DK55545, R01 DK033201] Funding Source: Medline
- NIGMS NIH HHS [R37 GM041890, GM41890, R01 GM041890] Funding Source: Medline
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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 alpha 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 p85a 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 alpha regulatory subunit. Thus, p85 alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
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