cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells
cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells
复制标题
DOI：
10.1074/jbc.271.49.31166
复制
发表时间：
1996-12-06
影响因子：
4.8
通讯作者：
Ragolia, L
中科院分区：
文献类型：
--
作者：
Begum, N;Ragolia, L
在这项研究中，我们检查了最近报道的胰岛素使蛋白磷酸酶-2A (PP-2A) 失活的机制（Srinivasan, IM., 和 Begum, N, (1994) J. Biol. Chem, 269, 12514-12520）及其 cAMP 激动剂的反调节作用。L6 肌管暴露于胰岛素导致 PP-W 快速抑制，并伴有免疫沉淀的 PP-2A 催化亚基的磷酸酪氨酸含量增加了 3 倍，用 cAMP 激动剂 (S-p) cAMP 预处理，完全阻断了胰岛素介导的 PP-2A 活性抑制，并将 PP-2A 催化亚基的酪氨酸磷酸化降低至控制水平。为了了解 (S-p)-cAMP 反向调节 PP-2A 的机制，用磷酸酪氨酸磷酸酶抑制剂原钒酸钠预处理细胞。钒酸盐阻止了 (S-p)-cAMP 对 PP-2A 活性的影响，并将 PP-2A 催化亚基的磷酸化状态增加到用胰岛素、渥曼青霉素（一种磷脂酰肌醇 8-激酶抑制剂）和雷帕霉素（一种 70-kDa S6 激酶激活抑制剂）观察到的水平，阻止了胰岛素介导的 PP-2A 失活，表明这些途径可能参与胰岛素介导的磷酸化和PP-2A 失活 这些结果表明，胰岛素信号传导通过增加酪氨酸磷酸化导致 PP-PA 快速失活，而 cAMP 激动剂通过减少磷酸化（可能是通过活化的磷酸酶）来反调节胰岛素对 PP-2A 的作用。
In this study, we examined the mechanism of recently reported inactivation of protein phosphatase-2A (PP-2A) by insulin (Srinivasan, IM., and Begum, N, (1994) J. Biol. Chem, 269, 12514-12520) and its counter-regulation by cAMP agonists, Exposure of L6 myotubes to insulin resulted in a rapid inhibition of PP-W that was accompanied by a 3-fold increase in the phosphotyrosine content of the immunoprecipitated PP-2A catalytic subunit, Pretreatment with (S-p) cAMP, a cAMP agonist, completely blocked insulin-mediated inhibition of PP-2A activity and decreased the tyrosine phosphorylation of PP-2A catalytic subunit to control levels. To understand the mechanism of counter regulation of PP-2A by (S-p)-cAMP, cells were pretreated with sodium orthovanadate, an inhibitor of phosphotyrosine phosphatases. Vanadate prevented the effect of (S-p)-cAMP on PP-2A activity and increased the phosphorylation status of PP-2A catalytic subunit to the level observed with insulin, Wortmannin, a phosphatidylinositol 8-kinase inhibitor, and rapamycin, an inhibitor of 70-kDa S6 kinase activation, prevented insulin-mediated inactivation of PP-2A, suggesting that these pathways may participate in insulin mediated phosphorylation and inactivation of PP-2A These results show that insulin signaling results in a rapid inactivation of PP-PA by increased tyrosine phosphorylation and cAMP agonists counter-regulate insulin's effect on PP-2A by decreasing phosphorylation, presumably via an activated phosphatase.