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首页> 外文期刊>Molecular and Cellular Biology >The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance
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The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance

机译：磷酸肌醇3-激酶的p85α调节亚基增强c-Jun N末端激酶介导的胰岛素抵抗

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摘要

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.
机译：胰岛素抵抗是2型糖尿病和代谢综合征的主要特征。尽管胰岛素抵抗的分子机制是多种多样的，但最近的证据表明，c-Jun N末端激酶（JNK）减弱胰岛素信号传导可能是胰岛素抵抗病理生物学的重要组成部分。在这里，我们证明了磷酸肌醇3激酶（PI3K）的p85α调节亚基是胰岛素代谢作用的关键介质，在胰岛素抵抗状态（包括高脂饮食诱导的肥胖症和JNK1过表达）中也需要激活JNK。 。对JNK的p85α调节亚基的需求独立于其作为PI3K异二聚体的组成部分而起作用，并且仅在响应特定刺激（即胰岛素和衣霉素）时才发生，这是一种诱导内质网应激的化学物质。我们进一步表明，胰岛素和p85通过cdc42和MKK4激活JNK。此cdc42 / JNK途径的激活需要完整的N末端和p85α调节亚基C末端内的功能性SH2结构域。因此，p85α在调节胰岛素敏感性中起双重作用，并可能介导PI3K与应激激酶途径之间的串扰。

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