ERK1/2, but not ERK5, is necessary and sufficient for phosphorylation and activation of c-Fos
ERK1/2, but not ERK5, is necessary and sufficient for phosphorylation and activation of c-Fos
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DOI：
10.1016/j.cellsig.2009.02.006
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发表时间：
2009-06-01
影响因子：
4.8
通讯作者：
Cook, Simon J.
中科院分区：
文献类型：
--
作者：
Gilley, Rebecca;March, H. Nikki;Cook, Simon J.
生长因子刺激的c-Fos的表达和激活受ERK1/2信号通路的调控。然而，最近的报道也表明，密切相关的ERK5通路在调节c-Fos的表达、转录激活和核定位方面发挥着重要作用。在这里，我们比较了ERK1/2和ERK5在使用条件蛋白激酶、选择性生化抑制剂和ERK5缺失的成纤维细胞调节c-Fos中的作用。我们证明ERK1/2通路的激活，而不是ERK5的激活，足以实现c-Fos的磷酸化和转录激活。此外，低剂量的PD184352选择性地抑制ERK1/2通路，但在ERK5-/-3T9细胞中正常进行；此外，c-Fos的核定位在ERK5-/-细胞中是正常的。然而，ERK5-/-细胞缺乏c-jun的表达，但ERK5的重新表达逆转了这一点。除ERK5外，JNK和p38信号通路都不能替代ERK1/2对c-Fos转录活性的调控。这些结果表明，c-Fos的转录活性不受ERK5途径的调节；相反，在所有的MAPK和SAPKs中，c-Fos的激活似乎主要与ERK1/2途径有关。(C)2009 Elsevier Inc.保留所有权利。
Growth factor-stimulated expression and activation of c-Fos is regulated by the ERK1/2 pathway. However, recent reports have also suggested a prominent role for the closely related ERK5 pathway in regulating the expression, transcriptional activation and nuclear localization of c-Fos. Here we have compared the role of ERK1/2 and ERK5 in regulating c-Fos using a combination of conditional protein kinases, selective biochemical inhibitors and ERK5 null fibroblasts. We demonstrate that activation of the ERK1/2 pathway, but not ERK5, is sufficient for c-Fos phosphorylation and transcriptional activation. Furthermore, growth factor-dependent expression of c-Fos is blocked by low doses of PD184352 that selectively inhibit the ERK1/2 pathway but proceeds normally in ERK5-/- 3T9 cells; in addition, nuclear localization of c-Fos is normal in ERK5-/- cells. ERK5-/- cells are, however, defective for c-Jun expression but this is reversed by re-expression of ERK5. In addition to ERK5, neither the JNK nor p38 pathways can substitute for ERK1/2 in the regulation of c-Fos transcriptional activity. These results demonstrate that c-Fos transcriptional activity is not regulated by the ERK5 pathway; rather, of all the MAPKs and SAPKs, c-Fos activation appears to be predominantly linked to the ERK1/2 pathway. (C) 2009 Elsevier Inc All rights reserved.