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磷酸酶PPM1F是整合素活性的负调节因子，对胚胎发育至关重要，并控制肿瘤细胞的侵袭。

The phosphatase PPM1F, a negative regulator of integrin activity, is essential for embryonic development and controls tumor cell invasion.

作者信息

Grimm Tanja M, Dierdorf Nina I, Herbinger Marleen, Baumgärtner Sarah, Sontowski Erik, Paone Christoph, Baade Timo, Hauck Christof R

机构信息

Lehrstuhl Zellbiologie, Fachbereich Biologie, Maildrop 621, Universität Konstanz, Universitätsstrasse 10, Konstanz, Germany.

Konstanz Research School Chemical Biology, Universität Konstanz, Konstanz, Germany.

出版信息

BMC Biol. 2025 Jun 19;23(1):166. doi: 10.1186/s12915-025-02254-3.

DOI:10.1186/s12915-025-02254-3
PMID:40537771
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12180154/
Abstract

BACKGROUND

The Mn/Mg-dependent Ser/Thr phosphatase PPM1F was identified to control integrin activity. Furthermore, PPM1F regulates several protein kinases known to be involved in organizing the cytoskeleton and other cellular functions. Therefore, PPM1F appears critical for a multitude of physiological processes.

RESULTS

Here, we report the phenotype of ppm1f gene disruption in mice. While heterozygous ppm1f ± mice are viable and fertile, ppm1f-/- mice show severe defects and significant morphological abnormalities in the developing brain and vasculature and abort embryonic development at day E10.5. Isolated ppm1f-/- MEFs or PPM1F-depleted human neuro-epithelial cells display enhanced integrin-dependent cell adhesion, deregulated PAK phosphorylation, and perturbed cell migration. These phenotypes were reversed by re-expression of the wildtype enzyme, but not the phosphatase-inactive PPM1F. In different human tumor cell types, PPM1F expression levels directly correlated with invasive potential, while deletion of PPM1F abrogates tissue invasion.

CONCLUSIONS

These results highlight the non-redundant role of this enzyme in integrin and PAK regulation and identify PPM1F as a promising target to limit tumor metastasis.

摘要

背景

已确定锰/镁依赖性丝氨酸/苏氨酸磷酸酶PPM1F可控制整合素活性。此外，PPM1F调节几种已知参与细胞骨架组织和其他细胞功能的蛋白激酶。因此，PPM1F似乎对多种生理过程至关重要。

结果

在此，我们报告了小鼠ppm1f基因缺失的表型。虽然杂合子ppm1f±小鼠可存活且可育，但ppm1f-/-小鼠在发育中的大脑和血管系统中表现出严重缺陷和明显的形态异常，并在胚胎发育第10.5天流产。分离的ppm1f-/-小鼠胚胎成纤维细胞（MEFs）或PPM1F缺失的人神经上皮细胞表现出整合素依赖性细胞粘附增强、PAK磷酸化失调以及细胞迁移紊乱。这些表型可通过野生型酶的重新表达逆转，但磷酸酶失活的PPM1F则不能。在不同的人类肿瘤细胞类型中，PPM1F表达水平与侵袭潜能直接相关，而PPM1F的缺失则消除了组织侵袭。

结论

这些结果突出了该酶在整合素和PAK调节中的非冗余作用，并确定PPM1F是限制肿瘤转移的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/2bd09642d71b/12915_2025_2254_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/6d8b7e6ee43b/12915_2025_2254_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/ea46c6330e9b/12915_2025_2254_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/3a49b5a24e9a/12915_2025_2254_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/b4560cfb2241/12915_2025_2254_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/12db51069018/12915_2025_2254_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/40a7095a34ee/12915_2025_2254_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/2b9a29abb48d/12915_2025_2254_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/10167d858867/12915_2025_2254_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/2bd09642d71b/12915_2025_2254_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/6d8b7e6ee43b/12915_2025_2254_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/ea46c6330e9b/12915_2025_2254_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/3a49b5a24e9a/12915_2025_2254_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/b4560cfb2241/12915_2025_2254_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/12db51069018/12915_2025_2254_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/40a7095a34ee/12915_2025_2254_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/2b9a29abb48d/12915_2025_2254_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/10167d858867/12915_2025_2254_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/676d/12180154/2bd09642d71b/12915_2025_2254_Fig9_HTML.jpg

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