PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION IS REQUIRED FOR INSULIN STIMULATION OF PP70 S6 KINASE, DNA-SYNTHESIS, AND GLUCOSE-TRANSPORTER TRANSLOCATION
PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION IS REQUIRED FOR INSULIN STIMULATION OF PP70 S6 KINASE, DNA-SYNTHESIS, AND GLUCOSE-TRANSPORTER TRANSLOCATION
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DOI：
10.1128/mcb.14.7.4902
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发表时间：
1994-07-01
影响因子：
5.3
通讯作者：
KAHN, CR
中科院分区：
文献类型：
--
作者：
CHEATHAM, B;VLAHOS, CJ;KAHN, CR
磷脂酰肌醇3-激酶（PI 3-激酶）受胰岛素和多种生长因子的刺激，但其在信号转导中的确切作用尚不清楚。我们使用了一种新的，高度特异性的PI 3-激酶抑制剂来解剖这种酶在胰岛素作用中的作用。用LY294002处理完整的3T3-L1脂肪细胞，对胰岛素刺激的Pi - 3激酶产生剂量依赖性抑制（50%抑制浓度，6 PM），使磷脂酰肌醇3,4,5-三磷酸水平降低约95%，而磷脂酰肌醇-4-单磷酸或其衍生物的水平没有变化。与此同时，胰岛素刺激的pp70 S6激酶磷酸化和活化被完全抑制。抑制PI 3-激酶还通过抑制GLUT 4葡萄糖转运蛋白向质膜的易位，有效阻断胰岛素和血清刺激的DNA合成和胰岛素刺激的葡萄糖摄取。LY294002对胰岛素刺激丝裂原活化蛋白激酶和pp90s6激酶无影响。因此，PI 3激酶的激活在哺乳动物细胞中起着至关重要的作用，并且是pp70 S6激酶和DNA合成以及某些形式的细胞内囊泡运输的激活所必需的，但不是丝裂原激活的蛋白激酶或pp90 S6激酶的激活。这些数据表明，PI 3-激酶不仅是胰岛素信号网络的一个重要组成部分，而且是一个分歧点。
Phosphatidylinositol 3-kinase (PI 3-kinase) is stimulated by insulin and a variety of growth factors, but its exact role in signal transduction remains unclear. We have used a novel, highly specific inhibitor of PI 3-kinase to dissect the role of this enzyme in insulin action. Treatment of intact 3T3-L1 adipocytes with LY294002 produced a dose-dependent inhibition of insulin-stimulated Pi 3-kinase (50% inhibitory concentration, 6 PM) with > 95% reduction in the levels of phosphatidylinositol3,4,5-trisphosphate without changes in the levels of phosphatidylinositol-4-monophosphate or its derivatives. In parallel, there was a complete inhibition of insulin-stimulated phosphorylation and activation of pp70 S6 kinase. Inhibition of PI 3-kinase also effectively blocked insulin- and serum-stimulated DNA synthesis and insulin-stimulated glucose uptake by inhibiting translocation of GLUT 4 glucose transporters to the plasma membrane. By contrast, LY294002 had no effect on insulin stimulation of mitogen-activated protein kinase or pp90 S6 kinase. Thus, activation of PI 3-kinase plays a critical role in mammalian cells and is required for activation of pp70 S6 kinase and DNA synthesis and certain forms of intracellular vesicular trafficking but not mitogen-activated protein kinase or pp90 S6 kinase activation. These data suggest that PI 3-kinase is not only an important component but also a point of divergence in the insulin signaling network.