Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras

作     者：Abe, JI Okuda, M Huang, QH Yoshizumi, M Berk, BC 

作者机构：Univ Rochester Sch Med & Dent Cardiol Unit Cardiovasc Res Ctr Rochester NY 14642 USA Kobe Univ Sch Med Dept Internal Med Div 1 Kobe Hyogo 6500017 Japan 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2000年第275卷第3期

页      面：1739-1748页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NHLBI NIH HHS [HL49192  HL44721] Funding Source: Medline 

主　　题：钙/代谢 细胞 培养的 剂量效应关系 药物 酶抑制剂/药理学 成纤维细胞/代谢 过氧化氢/代谢 Jurkat细胞 丝裂原活化蛋白激酶1/代谢 丝裂原活化蛋白激酶3 丝裂原激活蛋白激酶类/代谢 氧化性应激 磷酰化 原癌基因蛋白质类/代谢 原癌基因蛋白质c-fyn 活性氧/代谢 核糖体蛋白质S6激酶类/代谢 信号传导 ras蛋白质类/代谢 src族激酶类/拮抗剂和抑制剂 动物 人类 小鼠 

摘      要：Reactive oxygen species and growth factors stimulate similar intracellular signal transduction events including activation of Src kinase family members and extracellular signal-regulated kinases (ERK1/2), A potentially important downstream effector of Src and ERK1/2 is p90 ribosomal S6 kinase (p90RSK), which plays an important role in cell growth by activating several transcription factors as well as the Na+/H+ exchanger. In the present study, we determined whether H2O2 activates p90RSK to gain insight into signal transduction mechanisms activated by reactive oxygen species. H2O2 (200 mu M) Stimulated ERK1/2 and p90RSK activity in lymphocytes, endothelial cells, and fibroblasts. The MEK-1 inhibitor, PD98059 (30 mu M), inhibited H2O2-mediated activation of ERK1/2 but not of p90RSK, An essential role for Fyn and Ras in p90RSK activation was suggested by five findings. 1) The tyrosine kinase inhibitor, herbimycin A and the specific Src kinase family inhibitor, PP1, blocked p90RSK activation by H2O2 in a concentration-dependent manner. 2) p90RSK activation by H2O2 was significantly reduced in fibroblasts derived from transgenic mice deficient in Fyn, but not c-Src. 3) H2O2 rapidly activated Ras (peak at 2-5 min), which preceded p90RSK activation (peak at 20 min). 4) Dominant negative Res completely blocked H2O2-induced activation of p90RSK. 5) In Fyn-/- fibroblasts, activation of Ras by H2O2 was significantly attenuated. These results show essential roles for Fyn and Ras in H2O2-mediated activation of p90RSK and establish redox-sensitive regulation of Ras and p90RSK as a new function for Fyn.