Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation (Retracted article. See vol. 38, 2018)
Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation (Retracted article. See vol. 38, 2018)
复制标题
DOI：
10.1128/mcb.05424-11
复制
发表时间：
2011-09-01
影响因子：
5.3
通讯作者：
Seger, Rony
中科院分区：
文献类型：
--
作者：
Plotnikov, Alexander;Chuderland, Dana;Seger, Rony
细胞外信号调节激酶（ERK）1和2（ERK 1/2）是丝裂原活化蛋白激酶（MAPK）家族的成员。在刺激时，这些激酶从细胞质易位到细胞核，在那里它们诱导生理过程，如增殖和分化。这种激酶的易位机制涉及核易位信号（NTS）内的两个Ser残基的磷酸化，其允许结合到重要蛋白7并随后通过核孔穿透。在这里，我们表明，这两个丝氨酸残基的磷酸化主要是介导的酪蛋白激酶2（CK 2）和活性ERK可能有助于N-末端丝氨酸的磷酸化。我们还表明，磷酸化依赖于释放ERK从细胞质锚定蛋白。磷酸化模拟ERK的晶体结构表明，NTS磷酸化在ERK中产生了酸性斑块。我们的模型是，在静息细胞中，ERK与细胞质锚结合，从而阻止其NTS磷酸化。在刺激后，ERK TEY结构域的磷酸化释放ERK，并允许其NTS被CK 2和活性ERK磷酸化，以在ERK中产生带负电荷的补丁，结合输入蛋白7和核转位。这些结果提供了CK 2在调节细胞核ERK活性中的重要作用。
The extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase [MAPK] family. Upon stimulation, these kinases translocate from the cytoplasm to the nucleus, where they induce physiological processes such as proliferation and differentiation. The mechanism of translocation of this kinase involves phosphorylation of two Ser residues within a nuclear translocation signal (NTS), which allows binding to importin7 and a subsequent penetration via nuclear pores. Here we show that the phosphorylation of both Ser residues is mediated mainly by casein kinase 2 (CK2) and that active ERK may assist in the phosphorylation of the N-terminal Ser. We also demonstrate that the phosphorylation is dependent on the release of ERK from cytoplasmic anchoring proteins. Crystal structure of the phosphomimetic ERK revealed that the NTS phosphorylation creates an acidic patch in ERK. Our model is that in resting cells ERK is bound to cytoplasmic anchors, which prevent its NTS phosphorylation. Upon stimulation, phosphorylation of the ERK TEY domain releases ERK and allows phosphorylation of its NTS by CK2 and active ERK to generate a negatively charged patch in ERK, binding to importin 7 and nuclear translocation. These results provide an important role of CK2 in regulating nuclear ERK activities.