Palmada Monica, Boehmer Christoph, Akel Ahmad, Rajamanickam Jeyaganesh, Jeyaraj Sankarganesh, Keller Konrad, Lang Florian
Institute of Physiology I, University of Tübingen, Germany.
Diabetes. 2006 Feb;55(2):421-7. doi: 10.2337/diabetes.55.02.06.db05-0720.
Phosphatidylinositol 3-kinase (PI3 kinase) inhibition disrupts the ability of insulin to stimulate GLUT1 and GLUT4 translocation into the cell membrane and thus glucose transport. The effect on GLUT4 but not on GLUT1 is mediated by activation of protein kinase B (PKB). The serum- and glucocorticoid-inducible kinase SGK1, a further kinase downstream of PI3 kinase, regulates several transporters by enhancing their plasma membrane abundance. GLUT1 contains a consensus site ((95)Ser) for phosphorylation by SGK1. Thus, the present study investigated whether GLUT1 is regulated by the kinase. Tracer-flux studies in Xenopus oocytes and HEK-293 cells demonstrated that GLUT1 transport is enhanced by constitutively active (S422D)SGK1. The effect requires the kinase catalytical activity since the inactive mutant (K127N)SGK1 failed to modulate GLUT1. GLUT1 stimulation by (S422D)SGK1 is not due to de novo protein synthesis but rather to an increase of the transporter's abundance in the plasma membrane. Kinetic analysis revealed that SGK1 enhances maximal transport rate without altering GLUT1 substrate affinity. These observations suggest that SGK1 regulates GLUT1 and may contribute to or account for the PI3 kinase-dependent but PKB-independent stimulation of GLUT1 by insulin.
磷脂酰肌醇3激酶（PI3激酶）的抑制作用会破坏胰岛素刺激葡萄糖转运蛋白1（GLUT1）和葡萄糖转运蛋白4（GLUT4）转位到细胞膜从而进行葡萄糖转运的能力。对GLUT4而非GLUT1的影响是由蛋白激酶B（PKB）的激活介导的。血清和糖皮质激素诱导激酶SGK1是PI3激酶下游的另一种激酶，它通过增加几种转运蛋白在质膜上的丰度来调节它们。GLUT1含有一个可被SGK1磷酸化的共有位点（（95）Ser）。因此，本研究调查了GLUT1是否受该激酶调节。在非洲爪蟾卵母细胞和人胚肾293细胞（HEK-293细胞）中进行的示踪通量研究表明，组成型活性（S422D）SGK1可增强GLUT1的转运。该作用需要激酶的催化活性，因为无活性突变体（K127N）SGK1无法调节GLUT1。（S422D）SGK1对GLUT1的刺激不是由于从头合成蛋白质，而是由于转运蛋白在质膜上的丰度增加。动力学分析表明，SGK1提高了最大转运速率，而不改变GLUT1对底物的亲和力。这些观察结果表明，SGK1调节GLUT1，可能有助于或解释胰岛素对GLUT1的PI3激酶依赖性但PKB非依赖性刺激。
