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FLASH GENE
Symbol PPM1D contributors: mct/pgu - updated : 09-05-2017
HGNC name protein phosphatase 1D magnesium-dependent, delta isoform
HGNC id 9277
Corresponding disease
IDDGIP intellectual developmental disorder with gastrointestinal difficulties and high pain threshold
Location 17q23.2      Physical location : 58.677.553 - 58.742.036
Synonym name
  • wild type p53,induced phosphatase 1
  • protein phosphatase 2C delta isoform
  • protein phosphatase Wip1
  • p53-induced protein phosphatase 1
  • Synonym symbol(s) WIP1, P2CD, PP2C-DELTA
    EC.number 3.1.3.16
    DNA
    TYPE like-sequence
    STRUCTURE 64.48 kb     6 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • CREB-regulated gene due to the presence of a cyclic AMP response element (CRE) in the promoter
  • a conserved TP53 response element located in the 5' untranslated region (UTR) required for the TP53-dependent induction of transcription from the promoter
  • MAPPING cloned Y linked N status provisional
    Physical map
    DHX40 17q23.2 DEAH (Asp-Glu-Ala-His) box polypeptide 40 CLTC 17q11-qter clathrin, heavy polypeptide (Hc) PRO0456 17q23.2 PRO0456 protein CGI-147 17q23.2 CGI-147 protein VMP1 17q23.2 likely ortholog of rat vacuole membrane protein 1 TUBD1 17q23.2 likely ortholog of mouse tubulin, delta 1 RPS6KB1 17q23.3 ribosomal protein S6 kinase, 70kDa, polypeptide 1 LOC51136 17q23.2 PTD016 protein LOC390805 17 similar to DEAH (Asp-Glu-Ala-His) box polypeptide 40 LOC388404 17 similar to TBC1 domain family member 3 (Rab GTPase-activating protein PRC17) (Prostate cancer gene 17 protein) (TRE17 alpha protein) LOC201201 17q23.2 hypothetical LOC201201 ABC1 17q23.2-q23.3 amplified in breast cancer 1 LOC388405 17 LOC388405 CA4 17q23 carbonic anhydrase IV USP32 17q23.3 ubiquitin specific protease 32 LOC124773 17q23.3 hypothetical protein LOC124773 LOC284166 17q23.3 similar to 60S ribosomal protein L12 APPBP2 17q23 amyloid beta precursor protein (cytoplasmic tail) binding protein 2 LOC388406 17 hypothetical gene supported by AK131012 PPM1D 17q23.1 protein phosphatase 1D magnesium-dependent, delta isoform BCAS3 17q23 breast carcinoma amplified sequence 3 TBX2 17q23 T-box 2 LOC388407 17 hypothetical gene supported by BC046200 TBX4 17q23 T-box 4
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 3163 - 605 - 2008 19015127
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
    Endocrinepancreas    
    Lymphoid/Immunethymus   highly
    Nervousbrain     Homo sapiensAdult
     brain     Homo sapiensFetal
    Reproductivemale systemtestis  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmature hematopoietic Homo sapiens
    Blood/Hematopoieticneutrophil Homo sapiens
    Blood/Hematopoieticprogenitor cell Homo sapiens
    Lymphoid/ImmuneB cell Homo sapiens
    Lymphoid/ImmuneT cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • catalytic domain
  • HOMOLOGY
    interspecies homolog to murine Ppm1d
    Homologene
    FAMILY
  • PP2C family
  • CATEGORY enzyme , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    text
  • associated with chromatin
  • basic FUNCTION
  • contributing to growth inhibitory pathways activated in response to DNA damage in a TP53-dependant manner
  • phosphatase acting as a direct negative regulator of NF-Kappa B signaling
  • may be a general regulator of apoptosis (loss of WIP1 sensitizes cell to stress- and DNA damage-induced apoptosis)
  • directly dephosphorylating gamma-H2AFX to silence the checkpoint and restore chromatin structure
  • important mammalian phosphatase for gamma-H2AFX with a role in the tumor surveillance network
  • may suppress NER (Nucleotide excision repair) kinetics by dephosphorylating and inactivating XPA and XPC and other NER proteins and regulators after UV-induced DNA damage is repaired
  • can act as an oncogene largely by turning off DNA damage checkpoint responses
  • can provide ample time for wild type TP53-containing cells to prepare entry into mitosis and avoid encountering mitotic catastrophe
  • may play important roles in cell/tissue homeostasis maintained by wild type TP53 under normal conditions, enhancing our understanding of how p53 makes cell-fate decisions
  • stress responsive PP2C phosphatase that plays a key role in stress signaling
  • functions to abrogate cell cycle checkpoints and inhibit senescence, apoptosis, DNA repair, and the production of inflammatory cytokines
  • play an important role in several physiological processes including adult neurogenesis and organismal aging
  • positive modulator of the HH signaling
  • role in modulating the activity of GLI1 and in sustaining cancer cell growth and cancer stem cell self-renewal induced by activation of the HH pathway
  • plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences
  • plays an important role in the regulation of global heterochromatin silencing and thus is critical in maintaining genome integrity
  • unrecognized function of PPM1D as an intrinsic negative regulator for neutrophil proinflammatory cytokine production and migration through multiple signal pathways
  • controls DKK3-dependent inhibition of neuronal differentiation during aging, suggesting that regulating PPM1D levels could prevent certain aspects of functional decline of the aging brain
  • plays a critical role in maintaining antigen-independent B-cell development in the bone marrow and preventing an aging-related decline in B-cell development
  • PPM1D-ULK1 axis plays a pivotal role in genotoxic stress-induced autophagy
  • type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of MAPK14-TP53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis
  • PP2C serine-threonine phosphatase, that is an important regulator of stress response
  • controls a number of critical cellular functions: proliferation, cell cycle arrest, senescence and programmed cell death, apoptosis or autophagy
  • CELLULAR PROCESS cell life, proliferation/growth
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule cofactor,
  • 2 ions of Mg2+ or Mn2+
  • protein
  • RAS (to transformation of primary cells)
  • NEU1
  • enhances the function of GLI1 by increasing its transcriptional activity, nuclear localization and protein stability, but not of GLI2 nor GLI3
  • NCOR2 is responsible for basal repression of PPM1D, a phosphatase that de-phosphorylates and inactivates CHEK2, thus affecting a feedback loop responsible for licensing the correct timing of CHEK2 activation and the proper execution of the DNA repair process
  • PPM1D regulates nucleolar formation by regulating NPM1 phosphorylation status through a novel signalling pathway, PPM1D-CDC25C-CDK1-PLK1
  • PPM1D interacts with and dephosphorylates ULK1 at Ser637 in a TP53-dependent manner and this dephosphorylation induces autophagy
  • CDK5RAP3 binds PPM1D and stimulates its phosphatase activity
  • CDK5RAP3 binding to the substrate is not required for potentiated PPM1D catalytic activity and directly binds PPM1D to augment its phosphatase activity
  • cell & other
    REGULATION
    activated by tp53
    induced by DNA-damaging treatments through a conserved TP53 response element coincides with a shift in the use of transcription initiation sites
    TP53 (can be induced by TP53 under not only stressed but also non-stressed conditions)
    ASSOCIATED DISORDERS
    corresponding disease(s) IDDGIP
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification    
    in breast cancer (in progression)
    tumoral     --over  
    in several types of cancers
    tumoral     --over  
    in cancer epithelial cells has significant value for tumor progression and the clinical prognosis of patients with primary lung adenocarcinoma
    tumoral somatic mutation     gain of function
    in breast and ovarian cancer
    constitutional     --low  
    plays an important role in Mn-induced neuronal death in the brain striatum via the modulation of TP53 signaling
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    PPM1D inhibitors should be viable anti-cancer agents
    cancerbrainglioma/neuroblstoma
    PPM1D inhibition represents a novel therapeutic approach to neuroblastoma that could be integrated with current chemotherapeutic approaches
    ANIMAL & CELL MODELS
  • Wip1-/- mice display immunodeficiency, abnormal lymphoid histopathology in thymus and spleen, defects in B- and T-cell differentiation, as well as susceptibility to viral infection
  • Wip1-deficient mice exhibit a significant reduction of B-cell numbers in the bone marrow, peripheral blood, and spleen