Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases - Identification and characterization of a signaling pathway to the nucleus
Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases - Identification and characterization of a signaling pathway to the nucleus
复制标题
DOI：
10.1074/jbc.274.37.26563
复制
发表时间：
1999-09-10
影响因子：
4.8
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Kamakura, S;Moriguchi, T;Nishida, E
ERK 5（也称为BMK 1）是丝裂原活化蛋白激酶（MAPK）超家族的成员，已知其被氧化和渗透胁迫强烈激活。我们发现ERK 5被表皮生长因子和神经生长因子强烈激活，它们的受体是酪氨酸激酶。在PC12细胞中，显性负性Has的表达可抑制ERK 5的激活，而活性Has的表达可诱导ERK 5的激活，表明ERK 5的激活需要Has。表皮生长因子诱导的ERK 5激活被PD98059和U0126抑制剂抑制，这些抑制剂以前被认为特异性作用于经典MAPK激酶（也称为MEK 1），并且容易被CL100和MKP-3双特异性磷酸酶逆转，经典MAPK以前被证明是首选底物。报告基因分析表明，血清诱导的增强转录从血清反应元件显着抑制由显性阴性形式的MEK 5，这是一个直接和特异性的激活ERK 5的表达和转录从血清反应元件介导的Ets结构域转录因子Sap1a，但不是由Elk1，刺激ERK 5和活性MEK 5的共表达。此外，Sap1a在体外被ERK 5磷酸化，并通过细胞中ERK 5通路的激活而磷酸化。此外，血清诱导的c-Fos的表达显着抑制显性阴性MEK5的表达。这些结果揭示了一种新的信号通路的细胞核介导的ERK 5的受体酪氨酸激酶的下游功能，以诱导立即早期基因，在平行于经典的MAPK级联反应。
ERK5 (also known as BMK1), a member of the mitogen-activated protein kinase (MAPK) superfamily, was known to be activated strongly by oxidant and osmotic stresses. Here we have found that ERK5 is strongly activated by epidermal growth factor and nerve growth factor, whose receptors are tyrosine kinases. The activation of ERK5 was inhibited by expression of dominant-negative Has and induced by expression of active Has in PC12 cells, indicating a requirement for Has in ERK5 activation. The epidermal growth factor-induced activation of ERK5 was found to be inhibited by PD98059 and U0126 inhibitors, which were previously thought to act specifically on classical MAPK kinase (also known as MEK1) and readily reversed by CL100 and MKP-3 dual-specificity phosphatases for which classical MAPKs were previously shown to serve as preferred substrates. The reporter assays demonstrated that the serum-induced enhancement of transcription from serum response element was significantly inhibited by expression of a dominant-negative form of MEK5, which was a direct and specific activator for ERK5 and that transcription from serum response element mediated by the Ets-domain transcription factor Sap1a, but not by Elk1, was stimulated by coexpression of ERK5 and active MEK5. In addition, Sap1a was shown to be phosphorylated by ERK5 in vitro and by the activation of the ERK5 pathway in cells. Moreover, the serum-induced c-Fos expression was markedly inhibited by expression of dominant-negative MEK5. These results reveal a novel signaling pathway to the nucleus mediated by ERK5 that functions downstream of receptor tyrosine kinases to induce immediate early genes, in parallel with the classical MAPK cascade.