p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response
p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response
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DOI：
10.1074/jbc.m111.335794
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Chen, Guan
中科院分区：
文献类型：
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作者：
Hou, Songwang;Suresh, Padmanaban S.;Chen, Guan
磷酸酶通过使其底物激酶失活，在决定细胞命运方面发挥着至关重要的作用，但尚不清楚激酶是否可以反之亦然地磷酸化其磷酸酶以执行此功能。蛋白酪氨酸磷酸酶 H1 (PTPH1) 是 p38 γ 丝裂原激活蛋白激酶 (MAPK) 通过 PDZ 结合的特异性磷酸酶，在这里，我们证明 p38 γ 也是一种 PTPH1 激酶，通过它执行其致癌活性并调节应激反应。通过无偏蛋白质组学分析，PTPH1 被鉴定为 p38 γ 的底物，其在 Ser-459 处的磷酸化通过其复合物的形成在体外和体内发生。遗传和药理学分析进一步表明，Ser-459 磷酸化直接受 Ras 信号传导调节，对 Ras、p38 gamma 和 PTPH1 致癌活性很重要。此外，生理刺激实验揭示了从 p38 γ 到 PTPH1/Ser-459 磷酸化的新应激途径，通过依赖于细胞环境但独立于典型 MAPK 活性的机制来调节细胞生长和细胞死亡。因此，这些结果揭示了 MAPK 通过直接磷酸化其磷酸酶来调节 Ras 肿瘤发生和应激反应的新机制。
Phosphatase plays a crucial role in determining cellular fate by inactivating its substrate kinase, but it is not known whether a kinase can vice versa phosphorylate its phosphatase to execute this function. Protein-tyrosine phosphatase H1 (PTPH1) is a specific phosphatase of p38 gamma mitogen-activated protein kinase (MAPK) through PDZ binding, and here, we show that p38 gamma is also a PTPH1 kinase through which it executes its oncogenic activity and regulates stress response. PTPH1 was identified as a substrate of p38 gamma by unbiased proteomic analysis, and its resultant phosphorylation at Ser-459 occurs in vitro and in vivo through their complex formation. Genetic and pharmacological analyses showed further that Ser-459 phosphorylation is directly regulated by Ras signaling and is important for Ras, p38 gamma, and PTPH1 oncogenic activity. Moreover, experiments with physiological stimuli revealed a novel stress pathway from p38 gamma to PTPH1/Ser-459 phosphorylation in regulating cell growth and cell death by a mechanism dependent on cellular environments but independent of canonical MAPK activities. These results thus reveal a new mechanism by which a MAPK regulates Ras oncogenesis and stress response through directly phosphorylating its phosphatase.