Alternative ERK5 regulation by phosphorylation during the cell cycle
Alternative ERK5 regulation by phosphorylation during the cell cycle
复制标题
DOI：
10.1016/j.cellsig.2010.07.010
复制
发表时间：
2010-12-01
影响因子：
4.8
通讯作者：
Cuenda, A.
中科院分区：
文献类型：
--
作者：
Inesta-Vaquera, Francisco A.;Campbell, David G.;Cuenda, A.
ERK 5是丝裂原活化蛋白激酶（MAPK）家族的成员，其在刺激后通过MAPK激酶5（MEK 5）在TEY基序中的双重磷酸化而选择性地活化。ERK 5在调节细胞增殖、存活、分化和应激反应中起重要作用。此外，它还参与G2/M进程和适时的有丝分裂进入。ERRS在有丝分裂过程中被磷酸化，但在此阶段调节ERRS的分子机制仍不清楚。在这里，我们表明，虽然ERK 5是磷酸化的有丝分裂，这并不发生在激活基序（TEY），但在其C-末端的一半。我们已经确定了有丝分裂中ERK 5磷酸化的五个位点，其中两个未知。此外，我们证明，ERK 5磷酸化在有丝分裂是不MEK 5依赖，而是，细胞周期蛋白依赖性激酶（CDK）依赖。使用诱变方法，我们分析了ERRS功能中磷酸化残基的重要性;我们的证据表明，在有丝分裂中鉴定的残基的磷酸化抑制ERK 5活性，并调节ERK 5从细胞质穿梭到细胞核。这些结果揭示了以前未报道的磷酸化ERK 5调节形式，并在有丝分裂期间建立了CDK和ERK 5通路之间的联系，这可能对细胞周期的正确进展至关重要。(C)2010年爱思唯尔公司All rights reserved.
ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 plays an important role in regulating cell proliferation, survival, differentiation and stress response. Moreover, it is involved in G2/M progression and timely mitotic entry. ERRS is phosphorylated during mitosis, but the molecular mechanism by which it is regulated during this phase is still unclear. Here we show that although ERK5 is phosphorylated in mitosis, this does not occur on the activation motif (TEY), but at its C-terminal half. We have identified five sites of ERK5 phosphorylation in mitosis, two of them unknown. Furthermore, we demonstrate that ERK5 phosphorylation in mitosis is not MEK5-dependent, but rather, cyclin-dependent kinase (CDK)-dependent. Using a mutagenesis approach, we analysed the importance of the phosphorylated residues in ERRS function; our evidence show that phosphorylation in mitosis of the residues identified inhibits ERK5 activity and regulates ERK5 shuttling from cytoplasm to the nucleus. These results reveal a previously unreported form of ERK5 regulation by phosphorylation and establish a link between CDK and ERK5 pathways during mitosis, which could be crucial for the correct progression of the cell cycle. (C) 2010 Elsevier Inc. All rights reserved.