MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation
MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation
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DOI：
10.1016/j.molcel.2004.11.021
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发表时间：
2005-01-07
期刊：
影响因子：
16
通讯作者：
Yaffe, MB
中科院分区：
文献类型：
--
作者：
Manke, IA;Nguyen, A;Yaffe, MB
细胞对DNA损伤的反应由进化上保守的Ser/Thr激酶、Cdc 25蛋白磷酸酶的磷酸化、与14-3-3蛋白的结合以及退出细胞周期介导。为了研究p38/应激激活蛋白激酶（SAPK）信号传导轴介导的DNA损伤反应，确定了哺乳动物p38 alpha SAPK和MAPKAP激酶-2的最佳磷酸化基序。MAPKAP激酶-2的最佳底物基序与Cdc 25 B/C上的14-3-3结合位点紧密匹配，而p38 SAPK的最佳底物基序与Cdc 25 B/C上的14-3-3结合位点不匹配。我们表明，MAPKAP激酶-2是直接负责Cdc 25 B/C磷酸化和14-3-3结合在体外，并在哺乳动物细胞内的UV诱导的DNA损伤。MAPKAP激酶-2的下调消除了DNA损伤诱导的G（2）/M、G（1）和S期内检查点。我们认为MAPKAP激酶-2是DNA损伤检查点激酶家族的一个新成员，与Chk 1和Chk 2平行发挥作用，整合哺乳动物细胞中的DNA损伤信号应答和细胞周期阻滞。
The cellular response to DNA damage is mediated by evolutionarily conserved Ser/Thr kinases, phosphorylation of Cdc25 protein phosphatases, binding to 14-3-3 proteins, and exit from the cell cycle. To investigate DNA damage responses mediated by the p38/stress-activated protein kinase (SAPK) axis of signaling, the optimal phosphorylation motifs of mammalian p38alpha SAPK and MAPKAP kinase-2 were determined. The optimal substrate motif for MAPKAP kinase-2, but not for p38 SAPK, closely matches the 14-3-3 binding site on Cdc25B/C. We show that MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and 14-3-3 binding in vitro and in response to UV-induced DNA damage within mammalian cells. Downregulation of MAPKAP kinase-2 eliminates DNA damage-induced G(2)/M, G(1), and intra S phase checkpoints. We propose that MAPKAP kinase-2 is a new member of the DNA damage checkpoint kinase family that functions in parallel with Chk1 and Chk2 to integrate DNA damage signaling responses and cell cycle arrest in mammalian cells.