c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1 (BMK1)
c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1 (BMK1)
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DOI：
10.1074/jbc.272.33.20389
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发表时间：
1997-08-15
影响因子：
4.8
通讯作者：
Berk, BC
中科院分区：
文献类型：
--
作者：
Abe, J;Takahashi, M;Berk, BC
大丝裂原活化激酶1 （BMK1）或细胞外信号调节激酶5 （ERK5）最近被确定为丝裂原活化蛋白激酶家族的新成员，我们已经证明BMK1比生长因子更容易被H2O2激活，这表明与其他丝裂原活化蛋白激酶家族成员相比，BMK1是一种氧化还原敏感激酶。先前的研究表明，酪氨酸激酶c-Src介导活性氧（包括H2O2）的信号转导。因此，我们研究了Src激酶家族成员（c-Src和Fyn）在H2O2激活小鼠成纤维细胞BMK1中的作用，通过四个实验表明c-Src的重要作用，首先，H2O2在成纤维细胞中快速刺激c-Src活性（峰值在5分钟），比BMK1活性峰值（20分钟）要早，其次，特异性Src家族酪氨酸激酶抑制剂（herbimycin A和CP-118,556）以浓度依赖性的方式阻断H2O2对BMK1的激活。第三，来自c-Src缺失小鼠的细胞对H2O2的反应中，BMK1的激活被完全抑制，而非Fyn。最后，在v- src转化的NIH-3T3细胞中，BMK1的活性远高于野生型细胞。这些结果表明c-Src在h2o2介导的BMK1激活中发挥了重要作用，并表明对BMK1的氧化还原敏感调节是c-Src的一项新功能。
Big mitogen-activated kinase 1 (BMK1) or extracellular signal-regulated kinase-5 (ERK5) has recently been identified as a new member of the mitogen-activated protein kinase family, We have shown that BMK1 is activated to a greater extent by H2O2 than growth factors, suggesting that in comparison with other mitogen-activated protein kinase family members, BMK1 is a redox-sensitive kinase, Previous investigations indicate that the tyrosine kinase c-Src mediates signal transduction by reactive oxygen species, including H2O2. Therefore, the role of Src kinase family members (c-Src and Fyn) in activation of the BMK1 by H2O2 in mouse fibroblasts was studied, An essential role for c-Src was suggested by four experiments, First, H2O2 stimulated c-Src activity rapidly in fibroblasts (peak at 5 min), which preceded peak activity of BMK1 (20 min), Second, specific Src family tyrosine kinase inhibitors (herbimycin A and CP-118,556) blocked BMK1 activation by H2O2 in a concentration-dependent manner. Third, BMK1 activation in the response to H2O2 was completely inhibited in cells derived from mice deficient in c-Src, but not Fyn, Finally, BMK1 activity was much greater in v-Src-transformed NIH-3T3 cells than wild type cells. These results demonstrate an essential role for c-Src in H2O2-mediated activation of BMK1 and suggest that redox-sensitive regulation of BMK1 is a new function for c-Src.