Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4
Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4
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DOI：
10.1074/jbc.m606225200
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发表时间：
2006-11-17
影响因子：
4.8
通讯作者：
Seternes, Ole-Morten
中科院分区：
文献类型：
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作者：
Aberg, Espen;Perander, Maria;Seternes, Ole-Morten
MAPK活化蛋白激酶5 （MK5）最近被确定为非典型MAPK ERK3的生理底物。ERK3和MK5之间的复合物形成导致MK5的磷酸化和激活，ERK3的稳定，以及这两种蛋白的核排斥。然而，使用小干扰RNA或来源于ERK3缺失小鼠的成纤维细胞消融HeLa细胞中的ERK3仅能降低内源性MK5活性50%，提示MK5调控的其他机制。在这里，我们发现erk3相关激酶ERK4是MK5的真正相互作用伙伴。ERK4与MK5的结合伴随着MK5的磷酸化和激活。此外，复合体的形成也导致MK5从细胞核重新定位到细胞质。然而，与ERK3不同的是，ERK4是一种稳定的蛋白质，其半衰期不受MK5存在与否的影响。最后，尽管HeLa细胞中ERK4蛋白的敲除会使内源性MK5活性降低50%，但同时靶向ERK4和ERK3的小干扰rna的组合会使MK5活性进一步降低80%以上。我们得出结论，MK5的激活依赖于这些细胞中的ERK3和ERK4，并且这些非典型mapk都是MK5活性的生理调节因子。
MAPK-activated protein kinase 5 (MK5) was recently identified as a physiological substrate of the atypical MAPK ERK3. Complex formation between ERK3 and MK5 results in phosphorylation and activation of MK5, concomitant stabilization of ERK3, and the nuclear exclusion of both proteins. However, ablation of ERK3 in HeLa cells using small interfering RNA or in fibroblasts derived from ERK3 null mice reduces the activity of endogenous MK5 by only 50%, suggesting additional mechanisms of MK5 regulation. Here we identify the ERK3-related kinase ERK4 as a bona fide interaction partner of MK5. Binding of ERK4 to MK5 is accompanied by phosphorylation and activation of MK5. Furthermore, complex formation also results in the relocalization of MK5 from nucleus to cytoplasm. However unlike ERK3, ERK4 is a stable protein, and its half-life is not modified by the presence or absence of MK5. Finally, although knock-down of ERK4 protein in HeLa cells reduces endogenous MK5 activity by similar to 50%, a combination of small interfering RNAs targeting both ERK4 and ERK3 causes a further reduction in the MK5 activity by more than 80%. We conclude that MK5 activation is dependent on both ERK3 and ERK4 in these cells and that these atypical MAPKs are both physiological regulators of MK5 activity.