Wip1 phosphatase modulates ATM-dependent signaling pathways
Wip1 phosphatase modulates ATM-dependent signaling pathways
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DOI：
10.1016/j.molcel.2006.07.010
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发表时间：
2006-09-01
期刊：
影响因子：
16
通讯作者：
Bulavin, Dmitry V.
中科院分区：
文献类型：
--
作者：
Shreeram, Sathyavageeswaran;Demidov, Oleg N.;Bulavin, Dmitry V.
Ppm1d（编码 Wip1 磷酸酶的基因）的缺失使细胞对转化产生抵抗力，并使小鼠对肿瘤发展产生抵抗力。在此，我们报告 Wip1 缺陷导致共济失调毛细血管扩张突变 (ATM) 激酶的激活。反过来，Wip1 的过度表达足以减少 DNA 损伤后 ATM 依赖性信号级联的激活。 Wip1 使 ATM Ser1981 去磷酸化，这是 ATM 单体化和激活的关键位点，并且对于细胞修复受损 DNA 时重置 ATM 磷酸化至关重要。我们认为 Wip1 磷酸酶是 ATM 依赖性信号通路的一个组成部分。
Deletion of Ppm1d, the gene encoding the Wip1 phosphatase, renders cells resistant to transformation and mice resistant to tumor development. Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation, and was critical for resetting ATM phosphorylation as cells repaired damaged DNA. We propose that the Wip1 phosphatase is an integral component of an ATM-dependent signaling pathway.