Phosphatase Subfamily PPM1D

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1D (WIP1)

Evolution

The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human genome. See internal gOrtholog database.

Domain

PPM1D has a single domain, the phosphatase domain of PPM (PP2C) fold.

Function

Cancer

Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types [1]:

• PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 [2].
• PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)[3]. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC [4].
• PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro [5].
• PPM1D is a frequent target of somatic mutation in brainstem gliomas [6].

Several inhibitors target PPM1D to suppress cancer (e.g. [7]).

Cell cell checkpoint and DNA damage response

Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome [8]. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including Atm, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK. Several substrate proteins are directly involved in sensing and repairing DNA damage, suchas Atm, p53, Chk2, XPA, XPC and UNG2 [1].

Other functions

PPM1D is highly expressed in haematopoietic stem cells (HSC)s but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity [9].

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner [10].

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB [11].

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 [12].

References

1. Emelyanov A and Bulavin DV. Wip1 phosphatase in breast cancer. Oncogene. 2015 Aug 20;34(34):4429-38. DOI:10.1038/onc.2014.375 |
2. Buss MC, Remke M, Lee J, Gandhi K, Schniederjan MJ, Kool M, Northcott PA, Pfister SM, Taylor MD, and Castellino RC. The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants. Oncogene. 2015 Feb 26;34(9):1126-40. DOI:10.1038/onc.2014.37 |
3. Fu Z, Sun G, and Gu T. Proto-oncogene Wip1, a member of a new family of proliferative genes in NSCLC and its clinical significance. Tumour Biol. 2014 Apr;35(4):2975-81. DOI:10.1007/s13277-013-1382-y |
4. Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwiński R, and Rusin M. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer. 2015 Mar 17;112(6):1114-20. DOI:10.1038/bjc.2015.79 |
5. Zhang Y, Sun H, He G, Liu A, Wang F, and Wang L. WIP1 regulates the proliferation and invasion of nasopharyngeal carcinoma in vitro. Tumour Biol. 2014 Aug;35(8):7651-7. DOI:10.1007/s13277-014-2034-6 |
6. Zhang L, Chen LH, Wan H, Yang R, Wang Z, Feng J, Yang S, Jones S, Wang S, Zhou W, Zhu H, Killela PJ, Zhang J, Wu Z, Li G, Hao S, Wang Y, Webb JB, Friedman HS, Friedman AH, McLendon RE, He Y, Reitman ZJ, Bigner DD, and Yan H. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet. 2014 Jul;46(7):726-30. DOI:10.1038/ng.2995 |
7. Ogasawara S, Kiyota Y, Chuman Y, Kowata A, Yoshimura F, Tanino K, Kamada R, and Sakaguchi K. Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorg Med Chem. 2015 Oct 1;23(19):6246-9. DOI:10.1016/j.bmc.2015.08.042 |
8. Filipponi D, Muller J, Emelyanov A, and Bulavin DV. Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation. Cancer Cell. 2013 Oct 14;24(4):528-41. DOI:10.1016/j.ccr.2013.08.022 |
9. Chen Z, Yi W, Morita Y, Wang H, Cong Y, Liu JP, Xiao Z, Rudolph KL, Cheng T, and Ju Z. Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways. Nat Commun. 2015 Apr 16;6:6808. DOI:10.1038/ncomms7808 |
10. Yi W, Hu X, Chen Z, Liu L, Tian Y, Chen H, Cong YS, Yang F, Zhang L, Rudolph KL, Zhang Z, Zhao Y, and Ju Z. Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner. Blood. 2015 Jul 30;126(5):620-8. DOI:10.1182/blood-2015-02-624114 |
11. Sun B, Hu X, Liu G, Ma B, Xu Y, Yang T, Shi J, Yang F, Li H, Zhang L, and Zhao Y. Phosphatase Wip1 negatively regulates neutrophil migration and inflammation. J Immunol. 2014 Feb 1;192(3):1184-95. DOI:10.4049/jimmunol.1300656 |
12. Pandolfi S, Montagnani V, Penachioni JY, Vinci MC, Olivito B, Borgognoni L, and Stecca B. WIP1 phosphatase modulates the Hedgehog signaling by enhancing GLI1 function. Oncogene. 2013 Oct;32(40):4737-47. DOI:10.1038/onc.2012.502 |