Chen Wei, Chen Yue, Xu Bing-e, Juang Yu-Chi, Stippec Steve, Zhao Yingming, Cobb Melanie H
Department of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
J Biol Chem. 2009 Feb 6;284(6):3453-60. doi: 10.1074/jbc.M807502200. Epub 2008 Dec 9.
SGK1 (serum- and glucocorticoid-induced kinase 1) is a member of the AGC branch of the protein kinase family. Among well described functions of SGK1 is the regulation of epithelial transport through phosphorylation of the ubiquitin protein ligase Nedd4-2 (neuronal precursor cell expressed developmentally down-regulated 4-2). The activation of SGK1 has been widely accepted to be dependent on the phosphorylation of Thr256 in the activation loop and Ser422 in the hydrophobic motif near the C terminus. Here, we report the identification of two additional phosphorylation sites, Ser397 and Ser401. Both are required for maximum SGK1 activity induced by extracellular agents or by coexpression with other protein kinases, with the largest loss of activity from mutation of Ser397. Coexpression with active Akt1 increased the phosphorylation of Ser397 and thereby SGK1 kinase activity. SGK1 activation was further augmented by coexpression with the protein kinase WNK1 (with no lysine kinase 1). These findings reveal further complexity underlying the regulation of SGK1 activity.
血清和糖皮质激素诱导激酶1（SGK1）是蛋白激酶家族AGC分支的成员。SGK1的诸多已明确的功能之一是通过泛素蛋白连接酶Nedd4-2（神经元前体细胞发育性下调表达4-2）的磷酸化来调节上皮运输。人们普遍认为，SGK1的激活依赖于其激活环中苏氨酸256以及C末端附近疏水基序中丝氨酸422的磷酸化。在此，我们报告另外两个磷酸化位点丝氨酸397和丝氨酸401的鉴定结果。这两个位点都是细胞外因子或与其他蛋白激酶共表达诱导的SGK1最大活性所必需的，其中丝氨酸397突变导致的活性丧失最大。与活性Akt1共表达增加了丝氨酸397的磷酸化，从而增强了SGK1激酶活性。与蛋白激酶WNK1（无赖氨酸激酶1）共表达进一步增强了SGK1的激活。这些发现揭示了SGK1活性调控背后更深层次的复杂性。
