The p38 MAP kinase (MAPK) signaling pathway is a key signal transduction cascade that cancer cells employ to sense and adapt to a plethora of environmental stimuli and has attracted much attention as a promising target for cancer therapy. Although the kinases that phosphorylate p38 have been extensively studied, the negative regulation of p38 phosphorylation remains to be elucidated. Here, we found that PPM1G was highly expressed in lung adenocarcinoma (LUAD) compared to normal tissues, and higher levels of PPM1G were observed in adverse staged LUAD. Furthermore, the higher levels of PPM1G were highly correlated with poor prognosis, according to the Cancer Genome Atlas cohort. Most importantly, we identified phospho-MEK6 as a direct substrate of PPM1G. PPM1G, a metal-dependent protein phosphatase family phosphatase, could reduce p38 phosphorylation via MEK6 dephosphorylation and contribute to the proliferation, invasion and metastasis of LUAD. Our study highlighted the essential role of PPM1G in LUAD and shed new light on unveiling the regulation of p38 activity via direct dephosphorylation of MEK6 in malignant transformation. Together, this study provides new insight into the complexity of regulating the versatile p38 signaling and suggests new directions in intervening in p38 MAPK signaling.

中文翻译：

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PPM1G 通过 MEK6 的去磷酸化抑制 p38 激活，从而促进肺腺癌的进展。

p38 MAP 激酶 (MAPK) 信号通路是癌细胞用来感知和适应过多环境刺激的关键信号转导级联，作为癌症治疗的有希望的靶点而备受关注。尽管磷酸化 p38 的激酶已被广泛研究，但 p38 磷酸化的负调控仍有待阐明。在这里，我们发现与正常组织相比，PPM1G 在肺腺癌 (LUAD) 中高表达，并且在不良分期的 LUAD 中观察到更高水平的 PPM1G。此外，根据癌症基因组图谱队列，较高水平的 PPM1G 与不良预后高度相关。最重要的是，我们将磷酸化 MEK6 鉴定为 PPM1G 的直接底物。PPM1G，一种金属依赖性蛋白磷酸酶家族磷酸酶，可通过 MEK6 去磷酸化降低 p38 磷酸化，并促进 LUAD 的增殖、侵袭和转移。我们的研究强调了 PPM1G 在 LUAD 中的重要作用，并揭示了通过 MEK6 在恶性转化中直接去磷酸化来揭示 p38 活性的调节。总之，这项研究提供了对调节多功能 p38 信号的复杂性的新见解，并提出了干预 p38 MAPK 信号的新方向。