Cohen P, Alessi D R, Cross D A
Department of Biochemistry, University of Dundee, Scotland, UK.
FEBS Lett. 1997 Jun 23;410(1):3-10. doi: 10.1016/s0014-5793(97)00490-0.
The initial steps in insulin signal transduction occur at the plasma membrane and lead to the activation of phosphatidylinositide (PtdIns) 3-kinase and the formation of PtdIns(3,4,5,)P3 in the inner leaflet of the plasma membrane which is then converted to PtdIns(3,4)P2 by a specific phosphatase. Inhibitors of PtdIns 3-kinase suppress nearly all the metabolic actions of insulin indicating that PtdIns(3,4,5)P3 and/or PtdIns(3,4)P2 are key 'second messengers' for this hormone. A major effect of insulin is its ability to stimulate the synthesis of glycogen in skeletal muscle. By 'working backwards' from glycogen synthesis, we have dissected an insulin-stimulated protein kinase cascade which is triggered by the activation of PtdIns 3-kinase. The first enzyme in this cascade is termed 3-phosphoinositide-dependent protein kinase (PDK1), because it is only active in the presence of PtdIns(3,4,5)P3 or PtdIns(3,4)P2. PDK1 then activates protein kinase B (PKB) which, in turn, inactivates glycogen synthase kinase-3 (GSK3), leading to the dephosphorylation and activation of glycogen synthase and hence to an acceleration of glycogen synthesis. We review the evidence which indicates that the phosphorylation of other proteins by PKB and GSK3 is likely to mediate many of the intracellular actions of insulin.
胰岛素信号转导的起始步骤发生在质膜上，导致磷脂酰肌醇（PtdIns）3激酶的激活以及质膜内小叶中PtdIns(3,4,5)P3的形成，随后该物质被一种特异性磷酸酶转化为PtdIns(3,4)P2。PtdIns 3激酶抑制剂几乎能抑制胰岛素的所有代谢作用，这表明PtdIns(3,4,5)P3和/或PtdIns(3,4)P2是这种激素的关键“第二信使”。胰岛素的一个主要作用是其刺激骨骼肌中糖原合成的能力。通过从糖原合成“逆向推导”，我们剖析了一种由PtdIns 3激酶激活引发的胰岛素刺激的蛋白激酶级联反应。该级联反应中的第一种酶被称为3 - 磷酸肌醇依赖性蛋白激酶（PDK1），因为它仅在存在PtdIns(3,4,5)P3或PtdIns(3,4)P2时才具有活性。PDK1随后激活蛋白激酶B（PKB），而PKB又会使糖原合酶激酶 - 3（GSK3）失活，导致糖原合酶去磷酸化并激活，从而加速糖原合成。我们综述了相关证据，这些证据表明PKB和GSK3对其他蛋白质的磷酸化作用可能介导了胰岛素的许多细胞内作用。
