Moxham C M, Tabrizchi A, Davis R J, Malbon C C
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.
J Biol Chem. 1996 Nov 29;271(48):30765-73. doi: 10.1074/jbc.271.48.30765.
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.
丝裂原活化蛋白激酶（MAPKs）是一类保守的丝氨酸/苏氨酸蛋白激酶家族，在细胞内信号传导中起核心作用。为了确定MAPK家族的三个主要成员，即细胞外信号调节激酶（ERK）、Jun氨基末端激酶（JNK）和p38，在骨骼肌对胰岛素的主要反应（糖原合成的激活）中是否发挥作用，对其在体内的激活情况进行了定义。研究发现胰岛素可激活骨骼肌中的ERK、JNK和p38。然而，胰岛素激活这三种MAPKs的时间进程明显不同。JNK的激活最为迅速，在数秒内即可发生。胰岛素对p38的激活紧随JNK之后，在数分钟内发生。ERK的激活发生在最后，在注射胰岛素后4分钟。体内ERK、JNK、p38的激活与下游元件p90（rsk）和PP-1之间的时间关系表明，在体内JNK而非ERK或p38 MAPKs介导胰岛素对糖原合酶的激活。茴香霉素在体内对JNK的激活模拟了胰岛素对糖原合酶的激活。茴香霉素和胰岛素联合刺激并不具有叠加性，提示存在糖原合酶激活的共同模式。胰岛素快速激活的p90（rsk）亚型被鉴定为RSK3。此外，RSK3在体外可被JNK激活。基于这些数据，可以构建骨骼肌中体内糖原合酶激活的信号连接图谱，其中JNK通过RSK3介导糖原合酶的激活。
