View source for Phosphatase Subfamily PPM1D

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview 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 <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. 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 <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== 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 <cite>Filipponi13</cite>. 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 <cite>Emelyanov14</cite>.

===== 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 <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

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 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>