The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance

Mol Cell Biol. 2007 Apr;27(8):2830-40. doi: 10.1128/MCB.00079-07. Epub 2007 Feb 5.


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 p85alpha 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 p85alpha 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 p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / pathology
  • Enzyme Activation / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Insulin / pharmacology
  • Insulin Resistance / physiology*
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Liver / drug effects
  • Liver / enzymology
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Obesity / chemically induced
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism*
  • Signal Transduction / drug effects
  • cdc42 GTP-Binding Protein / metabolism


  • Insulin
  • Isoenzymes
  • Protein Subunits
  • Phosphatidylinositol 3-Kinases
  • JNK Mitogen-Activated Protein Kinases
  • cdc42 GTP-Binding Protein