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(Received for publication, June 24, 1996, and in revised form, September 4, 1996)
From the 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 p90rsk
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 p90rsk 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.
Volume 271, Number 48,
Issue of November 29, 1996
pp. 30765-30773
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Department of Molecular Pharmacology,
Diabetes and Metabolic Diseases Research Program, University Medical
Center, State University of New York, Stony Brook,
New York 11794-8651 and the ¶ Program in Molecular Medicine and
Howard Hughes Medical Institute, University of Massachusetts Medical
Center, Worcester, Massachusetts 01605
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