Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation
Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation
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DOI：
10.1074/jbc.m509471200
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发表时间：
2006-02-17
影响因子：
4.8
通讯作者：
Yang, XJ
中科院分区：
文献类型：
--
作者：
Gregoire, S;Tremblay, AM;Yang, XJ
真核蛋白通常受到多种修饰的调控，如磷酸化、乙酰化、泛素化和聚合化。这些修饰如何在体内协调是一个重要的问题，人们对这个问题知之甚少，但它与许多生物过程有关。我们最近发现，人MEF2D（肌细胞增强因子2D）在Lys-439上被介导。与聚合基序相邻的是Ser-444，与Lys-439一样，它在不同物种的MEF2蛋白中高度保守。在这里，我们提出了几条证据来证明MEF2D的Ser-444是Lys-439的sumomylation所必需的。组蛋白去乙酰化酶4 （HDAC4）通过Ser-444激活这种修饰。此外，Ser-444被Cdk5（一种已知抑制MEF2转录活性的周期蛋白依赖性激酶）磷酸化，刺激了sumoylation。与HDAC4和Cdk5相反，钙调磷酸酶（也称为蛋白磷酸酶2B）使Ser-444去磷酸化并抑制Lys-439的sumo化。然而，这种磷酸酶对ERK5（一种已知激活MEF2D的细胞外信号调节激酶）催化的磷酸化作用很小。这些结果确定了Ser-444在MEF2D聚合化中的重要作用，并揭示了钙调磷酸酶选择性“编辑”不同位点磷酸化的新机制，从而重申了不同修饰之间的相互作用代表了体内真核蛋白功能协调调节的一般机制。
A eukaryotic protein is often subject to regulation by multiple modifications like phosphorylation, acetylation, ubiquitination, and sumoylation. How these modifications are coordinated in vivo is an important issue that is poorly understood but is relevant to many biological processes. We recently showed that human MEF2D (myocyte enhancer factor 2D) is sumoylated on Lys-439. Adjacent to the sumoylation motif is Ser-444, which like Lys-439 is highly conserved among MEF2 proteins from diverse species. Here we presented several lines of evidence to demonstrate that Ser-444 of MEF2D is required for sumoylation of Lys-439. Histone deacetylase 4 (HDAC4) stimulated this modification by acting through Ser-444. In addition, phosphorylation of Ser-444 by Cdk5, a cyclin-dependent kinase known to inhibit MEF2 transcriptional activity, stimulated sumoylation. Opposing the actions of HDAC4 and Cdk5, calcineurin (also known as protein phosphatase 2B) dephosphorylated Ser-444 and inhibited sumoylation of Lys-439. This phosphatase, however, exerted minimal effects on the phosphorylation catalyzed by ERK5, an extracellular signal-regulated kinase known to activate MEF2D. These results identified an essential role for Ser-444 in MEF2D sumoylation and revealed a novel mechanism by which calcineurin selectively "edits" phosphorylation at different sites, thereby reiterating that interplay between different modifications represents a general mechanism for coordinated regulation of eukaryotic protein functions in vivo.