ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain
ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain
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DOI：
10.1128/mcb.20.22.8382-8389.2000
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发表时间：
2000-11-01
影响因子：
5.3
通讯作者：
Winoto, A
中科院分区：
文献类型：
--
作者：
Kasler, HG;Victoria, J;Winoto, A
先前的研究已经表明，孤儿类固醇受体Nur 77的上调是响应于抗原受体信号的未成熟T细胞凋亡所必需的。响应于抗原受体信号传导的Nur 77的转录上调涉及位于Nur 77启动子中的MEF 2家族转录因子的两个结合位点。钙信号通过翻译后机制大大增加T细胞中MEF 2D的活性。使用MEF 2D的MADS-MEF 2结构域作为诱饵，在酵母双杂交筛选中分离促分裂原活化蛋白（MAP）激酶ERK 5。ERK 5在其N-末端的一半类似于其他MAP激酶家族成员，但它也包含一个400个氨基酸的C-末端结构域，以前未表征的功能。我们在这里报告说，ERK 5的C-末端区域包含一个MEF 2相互作用域，令人惊讶的是，也是一个有效的转录激活域。这些结构域都是ERK 5共激活MEF 2D所必需的。发现MEF 2-ERK 5相互作用在体内是活化依赖性的，并且在体外可通过钙敏感性MEF 2阻遏物Cabin 1来激活。ERK 5的转录激活结构域是响应T细胞中钙流的最大MEF 2活性所需的，并且当通过MEF 2位点组成性募集到Nur 77启动子时，它可以激活内源性Nur 77基因。这些研究提供了对MEF 2活性可以响应钙信号传导的机制的见解，并提出了一种新的、意想不到的MAP激酶功能机制。
Previous studies have shown that upregulation of the orphan steroid receptor Nur77 is required for the apoptosis of immature T cells in response to antigen receptor signals. Transcriptional upregulation of Nur77 in response to antigen receptor signaling involves two binding sites for the MEF2 family of transcription factors located in the Nur77 promoter. Calcium signals greatly increase the activity of MEF2D in T cells via a posttranslational mechanism. The mitogen-activated protein (MAP) kinase ERK5 was isolated in a yeast two-hybrid screen using the MADS-MEF2 domain of MEF2D as bait. ERK5 resembles the other MAP kinase family members in its N-terminal half, but it also contains a 400-amino-acid C-terminal domain of previously uncharacterized function. We report here that the C-terminal region of ERK5 contains a MEF2-interacting domain and, surprisingly, also a potent transcriptional activation domain. These domains are both required for coactivation of MEF2D by ERK5. The MEF2-ERK5 interaction was found to be activation dependent in vivo and inhibitable in vitro by the calcium-sensitive MEF2 repressor Cabin 1. The transcriptional activation domain of ERK5 is required for maximal MEF2 activity in response to calcium flux in T cells, and it can activate the endogenous Nur77 gene when constitutively recruited to the Nur77 promoter via MEF2 sites. These studies provide insights into a mechanism whereby MEF2 activity can respond to calcium signaling and suggest a novel, unexpected mechanism of MAP kinase function.