Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras
Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras
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DOI：
10.1074/jbc.275.3.1739
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发表时间：
2000-01-21
影响因子：
4.8
通讯作者：
Berk, BC
中科院分区：
文献类型：
--
作者：
Abe, JI;Okuda, M;Berk, BC
活性氧和生长因子可激活类似的细胞内信号转导事件，包括激活Src激酶家族成员和细胞外信号调节蛋白激酶(ERK1/2)，Src和ERK1/2的一个潜在的重要下游效应因子是p90核糖体S6激酶(P90RSK)，它通过激活几个转录因子和Na+/H+交换器在细胞生长中发挥重要作用。在本研究中，我们确定了过氧化氢是否激活了p90RSK，以深入了解活性氧激活的信号转导机制。H_2O_2(200mM)刺激淋巴细胞、内皮细胞和成纤维细胞的ERK1/2和p90RSK活性。MEK-1抑制剂PD98059(30 MU M)可抑制H_2O_2介导的ERK1/2的激活，但不抑制p90RSK的激活。5个发现表明Fyn和RAS在p90RSK激活中起重要作用。1)酪氨酸激酶抑制剂除草霉素A和特异性的Src激酶家族抑制剂PP1以浓度依赖的方式阻断H_2O_2激活p90RSK。2)Fyn基因缺陷小鼠成纤维细胞经过氧化氢诱导的p90RSK活性显著降低，而c-Src基因缺陷小鼠成纤维细胞p90RSK活性无明显变化。3)H_2O_2迅速激活RAS(峰值在2-5min)，先于p90RSK激活(峰值在20min)。4)显性负性Res可完全阻断H_2O_2诱导的p90RSK的激活。5)在Fyn-/-成纤维细胞中，H_2O_2对RAS的激活作用明显减弱。这些结果表明Fyn和Ras在H_2O_2介导的p90RSK激活中起重要作用，并建立了对Ras和p90RSK的氧化还原敏感调节作为Fyn的新功能。
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.