Jun N-terminal kinase mediates activation of skeletal muscle glycogen synthase by insulin in vivo.
Mitogen-activated protein kinases (MAPKs) represent a conserved family of Ser/Thr protein kinases with central roles in intracellular signaling. Activation of three prominent members of the MAPK family, i.e. extracellular response kinases (ERK), jun N-terminal kinase (JNK), and p38, was defined in vivo in order to establish their role, if any, in the cardinal response of skeletal muscle to insulin, the activation of glycogen synthesis. Insulin was found to activate ERK, JNK, and p38 in skeletal muscle. The time courses for activation of the three MAPKs by insulin, however, are distinctly different. Activation of JNK occurs most rapidly, within seconds. Activation of p38 by insulin follows that of JNK, within minutes. Activation of ERK occurs last, 4 min after administration of insulin. The temporal relationship between the activation of ERK, JNK, p38 and the downstream elements p90(rsk) and PP-1 in vivo suggest that JNK, but neither ERK nor p38 MAPKs, mediates insulin activation of glycogen synthase in vivo. Activation of JNK by anisomycin in vivo mimics activation of glycogen synthase by insulin. Challenge by anisomycin and insulin, in combination, are not additive, suggesting a common mode of glycogen synthase activation. The p90(rsk) isoform rapidly activated by insulin is identified as RSK3. In addition, RSK3 can be activated by JNK in vitro. Based upon these data a signal linkage map for activation of glycogen synthase in vivo in skeletal muscle can be constructed in which JNK mediates activation of glycogen synthase via RSK3.
Moxham
C M
CM
Department of Molecular Pharmacology, Diabetes and Metabolic Diseases Research Program, University Medical Center, State University of New York, Stony Brook, New York 11794-8651, USA.
Tabrizchi
A
A
Davis
R J
RJ
Malbon
C C
CC
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006006:Glycogen Synthase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D007328:Insulin / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018482:Muscle, Skeletal / Q000201:enzymology*; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007328:Insulin; D011090:Polyenes; D011500:Protein Synthesis Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D000841:Anisomycin; D006006:Glycogen Synthase; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus