Ueki K, Yamamoto-Honda R, Kaburagi Y, Yamauchi T, Tobe K, Burgering B M, Coffer P J, Komuro I, Akanuma Y, Yazaki Y, Kadowaki T
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
J Biol Chem. 1998 Feb 27;273(9):5315-22. doi: 10.1074/jbc.273.9.5315.
Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinositol 3-kinase, including glucose transport, glycogen synthesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase and these biological responses has been poorly understood. Recently, it has been shown that protein kinase B (PKB/c-Akt/Rac) lies immediately downstream from phosphatidylinositol 3-kinase. Here, we show that expression of a constitutively active form of PKB induced glucose uptake, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation of rapamycin-sensitive serine/threonine kinase by PKB in L6 myotubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These results suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase activation to multiple biological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target tissue of insulin.
胰岛素刺激产生的多种生物学反应被认为是由磷脂酰肌醇3激酶调节的，这些反应包括葡萄糖转运、糖原合成和蛋白质合成。然而，磷脂酰肌醇3激酶与这些生物学反应之间的分子联系却鲜为人知。最近的研究表明，蛋白激酶B（PKB/c-Akt/Rac）直接位于磷脂酰肌醇3激酶的下游。在此，我们发现，组成型活性形式的PKB的表达在磷脂酰肌醇3激酶的下游，且不依赖于Ras和丝裂原活化蛋白激酶的激活，可诱导L6肌管中的葡萄糖摄取、糖原合成和蛋白质合成。组成型活性PKB的导入可诱导3T3L-1脂肪细胞中的葡萄糖摄取和蛋白质合成，但不能诱导糖原合成，3T3L-1脂肪细胞缺乏与L6肌管不同的糖原合酶激酶3的表达。此外，我们发现，在L6肌管中，PKB使糖原合酶激酶3失活以及使雷帕霉素敏感的丝氨酸/苏氨酸激酶激活，可能分别参与了糖原合成和蛋白质合成的增强。这些结果表明，PKB作为一种关键酶，通过调节骨骼肌（胰岛素的主要靶组织）中的下游激酶，将磷脂酰肌醇3激酶的激活与胰岛素的多种生物学功能联系起来。
