The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance.
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.
Taniguchi
Cullen M
CM
Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Aleman
José O
JO
Ueki
Kohjiro
K
Luo
Ji
J
Asano
Tomoichiro
T
Kaneto
Hideaki
H
Stephanopoulos
Gregory
G
Cantley
Lewis C
LC
Kahn
C Ronald
CR
D000818:Animals; D003921:Diabetes Mellitus, Experimental; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009765:Obesity / Q000139:chemically induced; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D007328:Insulin; D007527:Isoenzymes; D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein