Ppm1h, a metal-dependent protein phosphatase belonging to the PPM family [7], counteracts Leucine-Rich Repeat Kinase 2 (LRRK2) signaling by selectively dephosphorylating Rab GTPases [2,3]. It is also involved in pathways related to ciliogenesis, membrane trafficking, and axonal transport of autophagosomes [1,6]. In addition, it may play a role in the progression of hepatocellular carcinoma, non-small cell lung cancer, and colorectal cancer [4,5,8].

Knockout of Ppm1h in iPSC-derived human neurons phenocopies the effect of hyperactive LRRK2, disrupting the axonal transport of autophagosomes, which may contribute to Parkinson's disease pathogenesis [6]. In human A549 cells, Ppm1h knockout increased endogenous Rab phosphorylation, highlighting its role in regulating Rab GTPase phosphorylation [2].

In conclusion, Ppm1h is a key regulator in multiple biological processes. Its function in dephosphorylating Rab GTPases is crucial for normal cellular function, and its dysregulation may contribute to Parkinson's disease and several types of cancer. The use of gene knockout models, such as in iPSC-derived neurons, has been instrumental in uncovering these roles in disease-related processes [2,6].

References:

1. Yeshaw, Wondwossen M, Adhikari, Ayan, Chiang, Claire Y, Wawro, Paulina S, Pfeffer, Suzanne R. 2023. Localization of PPM1H phosphatase tunes Parkinson's disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2315171120. doi:10.1073/pnas.2315171120. https://pubmed.ncbi.nlm.nih.gov/37889931/

2. Berndsen, Kerryn, Lis, Pawel, Yeshaw, Wondwossen M, Pfeffer, Suzanne R, Alessi, Dario R. 2019. PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. In eLife, 8, . doi:10.7554/eLife.50416. https://pubmed.ncbi.nlm.nih.gov/31663853/

3. Alessi, Dario R, Pfeffer, Suzanne R. 2024. Leucine-Rich Repeat Kinases. In Annual review of biochemistry, 93, 261-287. doi:10.1146/annurev-biochem-030122-051144. https://pubmed.ncbi.nlm.nih.gov/38621236/

4. Yang, Xiaoshuang, Guo, Jianting, Li, Wei, Liu, Ying, Wu, Xiaopan. 2023. PPM1H is down-regulated by ATF6 and dephosphorylates p-RPS6KB1 to inhibit progression of hepatocellular carcinoma. In Molecular therapy. Nucleic acids, 33, 164-179. doi:10.1016/j.omtn.2023.06.013. https://pubmed.ncbi.nlm.nih.gov/37456776/

5. Zhang, Wen-Qi, Gao, Jian-Nan, Chen, Xiang-Lei, Yang, Xi-Feng. 2021. PPM1H is an independent prognostic biomarker of non-small cell lung cancer. In Neoplasma, 68, 917-923. doi:10.4149/neo_2021_201117N1238. https://pubmed.ncbi.nlm.nih.gov/33847131/

6. Dou, Dan, Smith, Erin M, Evans, Chantell S, Boecker, C Alexander, Holzbaur, Erika L F. 2023. Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes. In Cell reports, 42, 112448. doi:10.1016/j.celrep.2023.112448. https://pubmed.ncbi.nlm.nih.gov/37133994/

7. Kamada, Rui, Kudoh, Fuki, Ito, Shogo, Omichinski, James G, Sakaguchi, Kazuyasu. 2020. Metal-dependent Ser/Thr protein phosphatase PPM family: Evolution, structures, diseases and inhibitors. In Pharmacology & therapeutics, 215, 107622. doi:10.1016/j.pharmthera.2020.107622. https://pubmed.ncbi.nlm.nih.gov/32650009/

8. Xu, Xiaowen, Zhu, Li, Yang, Yun, Sui, Jinke, Cao, Fuao. 2019. Low tumour PPM1H indicates poor prognosis in colorectal cancer via activation of cancer-associated fibroblasts. In British journal of cancer, 120, 987-995. doi:10.1038/s41416-019-0450-5. https://pubmed.ncbi.nlm.nih.gov/30988394/