Serine-Threonine Kinase 38 is regulated by Glycogen Synthase Kinase-3 and modulates oxidative stress-induced cell death
Serine-Threonine Kinase 38 is regulated by Glycogen Synthase Kinase-3 and modulates oxidative stress-induced cell death
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DOI：
10.1016/j.freeradbiomed.2011.11.006
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发表时间：
2012-01-15
影响因子：
7.4
通讯作者：
Miyagawa, Kiyoshi
中科院分区：
文献类型：
--
作者：
Enomoto, Atsushi;Kido, Naoki;Miyagawa, Kiyoshi
丝氨酸-苏氨酸激酶38(STK38)是蛋白激酶A(PKA)/PKG/PKC样家族的成员。在本研究中，我们研究了STK38的调控机制，并评估了它在细胞应激反应中的作用。在各种环境压力中。H(2)O(2)可特异性激活STK38，磷脂酰肌醇3-激酶抑制剂Wortmannin或AKT抑制剂IV可抑制这种激活。STK38也可被固有活性的AKT1或GSK-3β抑制剂VII激活。在不同的细胞系中，GSK-3β的磷酸化水平与STK38的活性相关。免疫共沉淀分析表明GSK-3β与STK38在细胞内存在物理相互作用。过表达GSK-3β可抑制H(2)O(2)刺激的STK38活性。GSK-3β在体外使S6和17残基上的STK38磷酸化，这在很大程度上依赖于PKA介导的STK38在S10和S11残基上的启动磷酸化。STK38‘S H(2)O(2)的活性可被其起始位点和(或)S6和17位的丙氨酸取代所增强，但可被S6或T7位的拟磷突变部分降低。STK38基因敲除可增强H(2)O(2)诱导的JNK磷酸化和细胞死亡。我们的结果表明，GSK-3β抑制STK38‘S的完全激活，提示STK38的激活是防止细胞因氧化应激而死亡所必需的。(C)2011 Elsevier Inc.保留所有权利。
Serine-threonine kinase 38 (STK38) is a member of the protein kinase A (PKA)/PKG/PKC-like family. In the present study, we investigated the regulatory mechanism of STK38 and assessed its role in the cellular stress response. Among various environmental stresses. STK38 was specifically activated by H(2)O(2), and the phosphatidylinositol 3-kinase inhibitor wortmannin or AKT inhibitor IV suppressed this activation. STK38 was also activated by a constitutively active AKT1 or by GSK-3 beta inhibitor VII. The phosphorylation level of GSK-3 beta was correlated with the STK38 activity, in response to various stimuli and in different cell lines. Co-immunoprecipitation analysis revealed that GSK-3 beta physically interacted with STK38 in cells. GSK-3 beta over-expression inhibited the H(2)O(2)-stimulated STK38 activity. GSK-3 beta phosphorylated STK38 on residues S6 and 17 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. STK38's H(2)O(2)-stimulated activity was enhanced by alanine substitution at its priming sites and/or at S6 and 17, and it was partially reduced by a phosphomimetic mutation at S6 or T7. STK38 knockdown enhanced the H(2)O(2)-induced JNK phosphorylation and cell death. Our results indicate that that GSK-3 beta inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. (C) 2011 Elsevier Inc. All rights reserved.