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. 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 [1].

Other functions

PPM1D is highly expressed in haematopoietic stem cells (HSC) 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

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