Affinage

PPM1D

Protein phosphatase 1D · UniProt O15297

Length
605 aa
Mass
66.7 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPM1D (Wip1) is a p53-inducible PP2C-family serine/threonine phosphatase that acts as a homeostatic brake on the DNA damage response, dephosphorylating ATM/ATR pathway substrates within the p(S/T)Q motif to reset checkpoint signaling once repair is complete (PMID:15870257, PMID:17939684). Its catalytic domain recognizes phospho-Ser/Thr in p(S/T)Q sequences, with flanking acidic/hydrophobic residues enhancing turnover (PMID:17939684), and it directly inactivates the core checkpoint machinery: ATM at Ser1981 (PMID:16949371), Chk1 at Ser345 (PMID:15870257), Chk2 at Thr68 (PMID:16936775, PMID:16798742), p53 at Ser15 (PMID:15870257), and γ-H2AX (PMID:20460517). PPM1D reinforces a negative feedback loop on p53 both by dephosphorylating Mdm2-Ser395 to promote Mdm2-mediated p53 degradation (PMID:18333294)—a process facilitated by a p53-p21-Wip1 trimeric complex (PMID:33503543)—and by inactivating p38 MAPK to attenuate p53 phosphorylation and apoptosis (PMID:12021785). Its own induction is driven by a p53 response element in the 5'UTR after genotoxic stress (PMID:19015127). Beyond canonical checkpoint control, PPM1D suppresses multiple repair pathways by dephosphorylating UNG2-Thr6 (base excision repair) (PMID:15327777), XPA/XPC (nucleotide excision repair) (PMID:20451471), and BRCA1 and 53BP1-Thr543 (homologous recombination) (PMID:31619012), and it extends to autophagy via Ulk1-Ser637 (PMID:27670885), TGF-β/BMP signaling via Smad4-Thr277 (PMID:32103600), and p53 mRNA translation via RBM38-Ser195 (PMID:25823026). Oncogenic activation occurs through amplification or C-terminal exon 6 truncating gain-of-function mutations that remove a degradation domain, elevating protein stability and activity and broadly suppressing p53 and DDR signaling (PMID:23242139, PMID:23649806, PMID:29954749, PMID:35773251). The allosteric inhibitor GSK2830371 binds a divergent 'flap' subdomain and shifts PPM1D toward an inactive flap-closed conformation, restoring substrate phosphorylation and selectively impairing growth of Wip1-amplified, TP53-wild-type tumors (PMID:24390428, PMID:35773251). PPM1D also has p53-independent physiological roles in hematopoietic stem cell homeostasis, neurogenesis, macrophage function, and atherosclerosis (PMID:25879755, PMID:22768840, PMID:24911145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    Established PPM1D as a phosphatase that closes a negative feedback loop on stress signaling, dephosphorylating p38 MAPK to limit p53 activation and apoptosis—defining its oncogenic potential.

    Evidence Retroviral overexpression with phosphorylation, apoptosis, and in vivo MEF transformation assays

    PMID:12021785

    Open questions at the time
    • Did not identify direct DDR kinase substrates
    • p38 dephosphorylation may be indirect
  2. 2004 High

    Extended PPM1D's reach beyond checkpoints to DNA repair itself by showing direct dephosphorylation of UNG2-Thr6 suppresses base excision repair.

    Evidence Co-IP, in vitro phosphatase assay with active-site mutants, BER activity readout

    PMID:15327777

    Open questions at the time
    • In vivo significance of BER suppression not established
    • Did not place UNG2 regulation in broader repair context
  3. 2005 High

    Identified PPM1D as a direct antagonist of the ATR-Chk1 and p53 checkpoint arms, dephosphorylating Chk1-Ser345 and p53-Ser15 to dampen intra-S and G2/M checkpoints.

    Evidence Co-IP, in vitro phosphatase assays, checkpoint readouts after UV/IR

    PMID:15870257

    Open questions at the time
    • Did not address upstream ATM/ATR directly
    • Relative contribution of each substrate to checkpoint output unquantified
  4. 2006 High

    Placed PPM1D at the apex of DDR reset by demonstrating it dephosphorylates ATM-Ser1981 and Chk2-Thr68, defining nuclear localization and N-terminal/SQ-TQ domain requirements for substrate binding.

    Evidence In vitro phosphatase assays, knockdown/overexpression, structure-function domain mapping

    PMID:16798742 PMID:16936775 PMID:16949371

    Open questions at the time
    • Kinetics of ATM reset relative to repair completion not resolved
    • Whether ATM dephosphorylation is direct or scaffold-dependent in cells
  5. 2007 High

    Defined the biochemical substrate logic of PPM1D as a p(S/T)Q-directed phosphatase, rationalizing its selectivity for ATM/ATR substrates and predicting new targets.

    Evidence In vitro phosphatase kinetics with peptide variants, mutagenesis, molecular modeling

    PMID:17939684

    Open questions at the time
    • Predicted substrates (HDM2, SMC1A, ATR) not all validated in cells
    • No experimental structure of substrate-bound enzyme
  6. 2008 Medium

    Connected PPM1D to p53 turnover and its own transcriptional induction, showing Mdm2-Ser395 dephosphorylation promotes p53 degradation and a p53 response element drives PPM1D expression.

    Evidence In vitro phosphatase, ubiquitination, p53 stability assays; ChIP and promoter reporters

    PMID:18333294 PMID:19015127

    Open questions at the time
    • Post-transcriptional induction mechanism after UV/IR undefined
    • Mdm2 stabilization mechanism single-lab
  7. 2010 High

    Showed PPM1D directly dephosphorylates γ-H2AX and suppresses nucleotide excision repair, establishing premature dephosphorylation as a means of disrupting repair-factor recruitment.

    Evidence In vitro phosphatase assays, ectopic expression, immunofluorescence, repair kinetics with phosphatase-dead controls

    PMID:20451471 PMID:20460517

    Open questions at the time
    • XPA/XPC identified as potential rather than confirmed in vivo substrates
    • Timing of γ-H2AX reset versus repair completion not fully resolved
  8. 2012 Medium

    Reframed PPM1D mutation from loss to gain of function, showing exon 6 truncating mutations encode hyperactive isoforms that enhance p53 suppression after irradiation.

    Evidence NGS plus functional p53 suppression assays in cells carrying exon 6 variants

    PMID:23242139

    Open questions at the time
    • Molecular basis of hyperactivity not yet defined at this stage
    • Clonal context of mosaic mutations unclear
  9. 2013 Medium

    Defined exon 6 truncating mutations as G1-checkpoint-impairing gain-of-function alleles and linked PPM1D to BRCA1/HP1-dependent heterochromatin silencing upstream of ATM.

    Evidence Mutant functional checkpoint assays; ChIP, DNA methylation, co-IP, and ATM epistasis

    PMID:23649806 PMID:24135283

    Open questions at the time
    • Heterochromatin role single-lab and mechanism of DNMT recruitment incomplete
    • Direct vs indirect BRCA1 effect on methylation unresolved
  10. 2014 High

    Identified the druggable allosteric flap subdomain and validated PPM1D as a selective therapeutic target, while expanding its oncogenic roles to brainstem glioma drivers, CXCR4/GRK5 invasion, and WNT-dependent neurogenesis.

    Evidence SAR and GSK2830371 binding/PD/xenograft studies; exome sequencing with functional CHK2/p53 assays; knockdown/xenograft invasion and neurogenesis mouse models

    PMID:24390428 PMID:24632620 PMID:24880341 PMID:24911145

    Open questions at the time
    • Detailed conformational mechanism of inhibition not yet defined at this stage
    • Tissue specificity of CXCR4 and WNT roles unclear
  11. 2015 High

    Broadened PPM1D's substrate repertoire to autophagy (Ulk1-Ser637), p53 mRNA translation (RBM38-Ser195), HR repair via BRCA1, and revealed a p53-dependent HSC differentiation axis distinct from mTORC1-driven HSC expansion.

    Evidence Co-IP, in vitro dephosphorylation, autophagy flux/apoptosis assays, RNA-binding/luciferase, conditional KO with p53-deletion rescue and transplantation

    PMID:25823026 PMID:25879755 PMID:27670885

    Open questions at the time
    • RBM38 feedback loop single-lab
    • Tissue-specific balance of these substrates unquantified
  12. 2016 Medium

    Revealed a p53-independent role in nucleolar biogenesis through a PPM1D-CDC25C-CDK1-PLK1 cascade controlling NPM phosphorylation.

    Evidence Overexpression/knockdown, nucleolar counting, phospho-NPM analysis, pathway epistasis

    PMID:27619510

    Open questions at the time
    • Direct vs indirect control of NPM phosphorylation unclear
    • Single-lab pathway placement
  13. 2017 Medium

    Defined p53-independent immune functions: Wip1 loss enhances macrophage migration via Rac1-PI3K/AKT and phagocytosis via AMPK-driven CD36 recruitment.

    Evidence Wip1 KO macrophage migration/phagocytosis assays with Rac1, PI3K/AKT, AMPK pathway readouts

    PMID:28822916

    Open questions at the time
    • Direct substrates in these pathways not identified
    • Single-lab
  14. 2018 High

    Provided the mechanistic basis for gain-of-function mutations—loss of a C-terminal degradation domain elevating PPM1D abundance and activity—and globally mapped the resulting DDR phosphoproteome changes.

    Evidence Phosphoproteomics, CRISPR mutational profiling, cell cycle/apoptosis and mitochondrial priming assays

    PMID:29954749

    Open questions at the time
    • Which phosphoproteomic changes are direct substrates unresolved
    • Chemoresistance mechanism only partially mapped
  15. 2019 Medium

    Established PPM1D as a regulator of HR repair through BRCA1 and 53BP1-Thr543 dephosphorylation and revealed a therapeutically exploitable epigenetic vulnerability (NAPRT silencing, NAMPT synthetic lethality) in mutant cells.

    Evidence Co-IP, in vitro dephosphorylation, 53BP1/BRCA1 foci imaging, olaparib sensitivity; isogenic lines with genome-wide methylation and NAMPT inhibitor assays

    PMID:31439867 PMID:31619012

    Open questions at the time
    • HR role single-lab
    • Mechanism linking mutant PPM1D to CpG hypermethylation incomplete
  16. 2020 Medium

    Extended PPM1D into developmental signaling control by showing Smad4-Thr277 dephosphorylation limits TGF-β/BMP signaling and mesoderm formation, and identified PGAM1 as a cytoplasmic sequestering regulator of PPM1D nuclear import.

    Evidence Co-IP, in vitro phosphatase, nuclear fractionation, Xenopus gain/loss-of-function; cytoplasmic co-IP with non-enzymatic PGAM1 mutant rescue

    PMID:32103600 PMID:32294440

    Open questions at the time
    • Physiological contexts of Smad4 regulation in mammals unclear
    • Signals controlling PGAM1-PPM1D binding undefined
  17. 2022 High

    Defined the conformational mechanism of allosteric inhibition—GSK2830371 locks a flap-domain equilibrium in the inactive state—and linked PPM1D inhibition to the integrated stress response, enabling MDM2-combination apoptosis.

    Evidence HDX-MS, analytical ultracentrifugation, modeling, biochemistry; eIF2α/ATF4/HRI pathway analysis, RNA-seq, in vivo tumor assays

    PMID:35773251 PMID:36456590

    Open questions at the time
    • No high-resolution crystal/cryo-EM structure of inhibitor-bound PPM1D
    • ISR linkage to heme depletion mechanism single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PPM1D's broad substrate set is spatiotemporally prioritized—and which downstream effects of gain-of-function mutants are direct catalytic events versus secondary consequences—remains unresolved.
  • No experimental structure of substrate- or full-length protein
  • Substrate prioritization across DDR, autophagy, translation, and developmental signaling not integrated
  • Direct vs indirect basis of mutant-driven epigenetic and metabolic phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 2
Partners
ATMBRCA1CHEK1CHEK2MDM2PGAM1TP53UNG
Complex memberships
p53-p21-Wip1 trimeric complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PPM1D (Wip1) dephosphorylates and inactivates p38 MAPK, creating a negative feedback loop on p53 activity. Retrovirus-mediated overexpression of PPM1D reduced p53 phosphorylation at Ser33 and Ser46 (p38 MAPK target sites), abrogated Ras-induced apoptosis, and partially rescued cells from cell-cycle arrest. Retroviral overexpression, phosphorylation analysis, apoptosis/cell-cycle assays, MEF transformation assay in nude mice Nature genetics High 12021785
2005 PPM1D binds Chk1 and dephosphorylates ATR-targeted phospho-Ser345, reducing Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser15. These dephosphorylations correlate with reduced intra-S and G2/M checkpoint activity after UV and ionizing radiation. Co-immunoprecipitation, in vitro phosphatase assay, checkpoint activity assays after UV/IR Genes & development High 15870257
2006 Wip1 (PPM1D) dephosphorylates ATM at Ser1981, a site critical for ATM monomerization and activation, thereby resetting ATM phosphorylation as cells complete DNA repair. Overexpression of Wip1 reduces ATM-dependent signaling cascade activation after DNA damage; Wip1 deficiency results in constitutive ATM activation. In vitro phosphatase assay, overexpression and knockdown experiments, immunoblotting for ATM-S1981 phosphorylation Molecular cell High 16949371
2004 PPM1D interacts with the nuclear isoform of uracil DNA glycosylase UNG2 and suppresses base excision repair (BER). PPM1D dephosphorylates UNG2 at phosphothreonine 6, reducing UNG2 activity. Point mutations inactivating PPM1D phosphatase activity abrogate BER suppression. Co-immunoprecipitation, in vitro phosphatase assay, active-site mutagenesis, BER activity assay Molecular cell High 15327777
2006 Wip1 binds Chk2 and dephosphorylates phospho-Thr68 (the ATM-targeted activation site), thereby antagonizing Chk2 activation after ionizing irradiation. Wip1 overexpression suppresses the G2/M DNA damage checkpoint contribution of Chk2. Co-immunoprecipitation, in vitro phosphatase assay, G2/M checkpoint assay Oncogene High 16798742 16936775
2006 Nuclear localization of both Chk2 and Wip1 is required for their association. The SQ/TQ domain of Chk2 (containing Thr68) and the N-terminal ~100 amino acids of Wip1 are necessary and sufficient for binding. Intrinsic kinase activity of Chk2 (but not phosphatase activity of Wip1) is required for their association when full-length proteins are used. Structure-function analysis with deletion and point mutants, co-immunoprecipitation, nuclear localization experiments The Journal of biological chemistry High 16798742
2007 Recombinant Wip1 catalytic domain dephosphorylates phosphoserine and phosphothreonine specifically in the p(S/T)Q motif (ATM/ATR substrate motif). Acidic, hydrophobic, or aromatic residues flanking the p(S/T)Q enhance dephosphorylation; basic residues have negative influence. New putative substrates identified include HDM2, SMC1A, ATR, and Wip1 itself. In vitro phosphatase kinetics with peptide variants, site-directed mutagenesis, 3D molecular modeling Biochemistry High 17939684
2008 PPM1D (Wip1) dephosphorylates Mdm2 at Ser395 (an ATM target site), stabilizing Mdm2, enhancing Mdm2-p53 binding, and promoting ubiquitination and degradation of p53. Wip1 thus facilitates Mdm2-mediated p53 degradation as part of a negative feedback loop. In vitro phosphatase assay, co-immunoprecipitation, ubiquitination assay, p53 stability measurements Cell cycle (Georgetown, Tex.) Medium 18333294
2010 Wip1 directly dephosphorylates γ-H2AX (phospho-H2AX) in vitro and in vivo. Ectopic Wip1 expression significantly reduces γ-H2AX levels after ionizing radiation and UV; forced premature dephosphorylation disrupts recruitment of DNA repair factors to damage sites and delays DNA damage repair. In vitro phosphatase assay, ectopic expression, immunofluorescence, DNA repair kinetics assay Cancer research High 20460517
2010 WIP1 overexpression inhibits nucleotide excision repair (NER) kinetics in a phosphatase-activity-dependent manner; phosphatase-dead WIP1 mutants fail to inhibit NER. XPA and XPC are identified as potential WIP1 dephosphorylation targets in the NER pathway. Overexpression and depletion experiments, CPD repair kinetics assay, in vitro phosphatase assay with XPA/XPC, phosphatase-dead mutant analysis DNA repair High 20451471
2012 Truncating gain-of-function mutations in exon 6 of PPM1D (carboxy-terminal to the phosphatase domain) result in enhanced suppression of p53 in response to ionizing radiation, without simple loss of function. These mosaic mutations encode hyperactive PPM1D isoforms. Next-generation sequencing, functional p53 suppression assay after IR in cells with exon 6 truncating variants Nature Medium 23242139
2013 Exon 6 truncating mutations in PPM1D result in C-terminally truncated Wip1 with gain-of-function activity that impairs the p53-dependent G1 checkpoint and affects the DNA damage response pathway. Identification and functional characterization of exon 6 mutations, cell cycle checkpoint assay, DDR pathway analysis The Journal of cell biology Medium 23649806
2013 Wip1 is required for epigenetic remodeling of heterochromatin through regulation of BRCA1 interaction with HP1, recruitment of DNA methyltransferases, and subsequent DNA methylation. ATM attenuation reverses heterochromatin methylation, placing Wip1 upstream of ATM in heterochromatin silencing. Chromatin immunoprecipitation, DNA methylation assays, co-immunoprecipitation (BRCA1-HP1), genetic epistasis with ATM Cancer cell Medium 24135283
2014 PPM1D exon 6 truncating mutations in brainstem gliomas enhance PPM1D's ability to suppress CHK2 activation and attenuate p53 activation in vitro, establishing these as gain-of-function somatic driver mutations. Exome sequencing, functional in vitro assays for CHK2 suppression and p53 activation Nature genetics Medium 24880341
2014 Allosteric small-molecule inhibitors of Wip1 bind a 'flap' subdomain near the catalytic site that is structurally divergent from other PP2C family members, conferring selectivity. GSK2830371 binding to this site increases phosphorylation of Wip1 substrates and inhibits growth of hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Structure-activity relationship, biochemical binding assay, pharmacodynamic studies, xenograft tumor model Nature chemical biology High 24390428
2014 Phosphoglycerate mutase 1 (PGAM1) binds WIP1 in the cytoplasm, preventing its nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway, thereby regulating DNA damage response efficiency. Co-immunoprecipitation (cytoplasmic fractionation), PGAM1 knockdown, γ-H2AX foci assay, kinase-dead mutant rescue Cell reports Medium 32294440
2015 PPM1D interacts with and dephosphorylates Ulk1 at Ser637 in a p53-dependent manner after genotoxic stress, triggering Ulk1 puncta formation and inducing autophagy. Genetic ablation of PPM1D reduces Ulk1 Ser637 dephosphorylation, inhibits autophagy, and accelerates apoptosis induced by X-ray irradiation by preventing autophagic degradation of proapoptotic Noxa. Co-immunoprecipitation, in vitro phosphatase assay, Ulk1 puncta imaging, genetic KO, autophagy flux assay, apoptosis assay EMBO reports High 27670885
2015 PPM1D dephosphorylates RBM38 at serine 195, modulating p53 mRNA translation. RBM38 directly binds PPM1D 3'-UTR and promotes PPM1D expression; PPM1D dephosphorylation of RBM38 reduces p53 mRNA translation and p53-dependent growth suppression. Co-immunoprecipitation, in vitro dephosphorylation assay, luciferase reporter (3'-UTR), RNA-binding assay Oncogene Medium 25823026
2015 Wip1 deficiency in HSCs leads to sustained p53 activation, impaired repopulating activity, and aging-like phenotypes. Deletion of p53 (but not p21) completely rescues the multilineage repopulation defect of Wip1-deficient HSCs, defining a Wip1-p53 axis in HSC differentiation. Separately, HSC pool expansion in Wip1-/- mice is mediated by mTORC1-dependent proliferation, distinct from the p53-dependent differentiation defect. Conditional knockout, bone marrow transplantation competition assay, genetic epistasis (p53 deletion rescue), flow cytometry, mTORC1 pathway analysis Nature communications High 25879755
2018 PPM1D truncating mutations (exon 6) encode a protein with elevated expression and activity due to loss of a C-terminal degradation domain. Global phosphoproteomic profiling in PPM1D-mutant cells reveals altered phosphorylation of DNA damage response targets. PPM1D-mutant cells show abrogated DDR, altered cell cycle progression, decreased apoptosis, and reduced mitochondrial priming in the presence of chemotherapy. Phosphoproteomics (mass spectrometry), CRISPR mutational profiling, cell cycle and apoptosis assays, mitochondrial priming assay Blood High 29954749
2019 WIP1 promotes homologous recombination (HR) DNA repair. WIP1 interacts with BRCA1 and dephosphorylates it; WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking DNA lesions. WIP1 also dephosphorylates 53BP1 at Threonine 543, previously implicated in mediating interaction with RIF1. Loss/inhibition of WIP1 delayed disappearance of IR-induced 53BP1 foci in S/G2 cells and increased sensitivity to PARP inhibitor olaparib. Co-immunoprecipitation, in vitro dephosphorylation assay, immunofluorescence (53BP1/BRCA1 foci), WIP1 inhibitor treatment, olaparib sensitivity assay Cells Medium 31619012
2019 Mutant PPM1D drives CpG island hypermethylation genome-wide and promotes epigenetic silencing of NAPRT (a NAD biosynthesis gene), creating a synthetic lethal interaction with NAMPT inhibitors. Isogenic cell lines, genome-wide methylation profiling, NAMPT inhibitor sensitivity assay in vitro and in vivo Nature communications Medium 31439867
2020 Wip1 selectively binds and dephosphorylates Smad4 at Thr277 (a key MAPK phosphorylation site in the linker region), regulating Smad4 nuclear accumulation and half-life. This inhibits TGF-β/BMP signaling; in Xenopus embryos, Wip1 limits mesoderm formation by inhibiting TGF-β/BMP signals. Co-immunoprecipitation, in vitro phosphatase assay, nuclear fractionation, Xenopus embryo gain/loss-of-function, cell migration/invasion assay EMBO reports High 32103600
2016 PPM1D regulates nucleolar formation by controlling phosphorylation of nucleophosmin (NPM). PPM1D overexpression induces increased nucleolar number independently of p53 status. PPM1D acts as an upstream regulator in a PPM1D-CDC25C-CDK1-PLK1 signaling pathway that controls sequential NPM phosphorylation required for nucleolar formation. Overexpression, knockdown, immunofluorescence (nucleolar counting), phospho-NPM analysis, pathway epistasis Scientific reports Medium 27619510
2022 GSK2830371 binds an allosteric site of PPM1D (the flap domain). Hydrogen-deuterium exchange mass spectrometry and analytical ultracentrifugation reveal PPM1D exists in equilibrium between two conformations defined by flap domain movement; GSK2830371 shifts the equilibrium to the inactive (flap-closed) form. C-terminal truncating mutations proximal to residue 400 destabilize the protein via loss of a stabilizing N- and C-terminal interaction. HDX-MS, sedimentation velocity analytical ultracentrifugation, computational modeling, biochemical binding assays, functional genetic studies Nature communications High 35773251
2022 PPM1D inhibition induces phosphorylation of eIF2α and ATF4 accumulation, linking PPM1D to the integrated stress response (ISR). PPM1D inhibition depletes heme and induces HRI-dependent eIF2α phosphorylation. Dual inhibition of PPM1D and MDM2 synergistically induces apoptosis via amplification of p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibitor treatment, eIF2α phosphorylation assay, ATF4 reporter, HRI pathway analysis, RNA-seq, in vivo tumor growth assay Nature communications Medium 36456590
2008 A conserved p53 response element in the 5' UTR of the PPM1D gene is required for p53-dependent transcriptional induction after genotoxic stress. CREB binding to a CRE element in the promoter regulates basal PPM1D expression. After UV/IR exposure, increased PPM1D protein levels can occur without increased mRNA, indicating post-transcriptional regulation. Transient transfection, chromatin immunoprecipitation, promoter reporter assay, mRNA/protein comparison after DNA damage Nucleic acids research Medium 19015127
2012 Wip1 deficiency prevents fat accumulation and atherosclerosis in mice. During atherosclerosis, Wip1 deletion suppresses macrophage conversion to foam cells by acting via a non-canonical ATM-mTOR signaling pathway and selective autophagy to regulate cholesterol efflux, in a p53-independent manner. Wip1 knockout mouse model, atherosclerosis model, macrophage foam cell assay, autophagy and cholesterol efflux assays, genetic epistasis with ATM/mTOR Cell metabolism Medium 22768840
2014 WIP1 promotes medulloblastoma cell growth and invasion through regulation of CXCR4 cell surface localization via suppression of GRK5 expression. GRK5 promotes Ser339 phosphorylation of CXCR4 and inhibits cell surface CXCR4; WIP1 knockdown reduces GRK5-dependent CXCR4 phosphorylation, decreasing surface CXCR4 and invasion. Stable knockdown/overexpression, xenograft mouse model, cell surface CXCR4 assay, GRK5 manipulation, invasion assay Oncogene Medium 24632620
2014 WIP1 regulates adult neurogenesis by controlling DKK3-dependent inhibition of WNT signaling. WIP1 is expressed in neural stem/progenitor cells (NPCs) of the mouse SVZ; WIP1 suppresses expression of the WNT pathway inhibitor DKK3. DKK3 inhibits neuroblast formation by suppressing WNT signaling, and Wip1-dependent control of DKK3 promotes neuronal differentiation. Transgenic mice with enhanced WIP1 expression, Dkk3 deletion, pharmacological WNT activation, SVZ reporter strain, olfactory behavioral testing The Journal of clinical investigation Medium 24911145
2009 Loss of Wip1 sensitizes mouse embryonic fibroblasts to stress-induced apoptosis via activation of both p38-ATF2 and JNK-c-Jun signaling. Wip1 negatively regulates MKK4-JNK-c-Jun signaling during stress-induced apoptosis, representing a dual role in regulating both p38/p53-dependent and JNK-dependent apoptotic pathways. Wip1 knockout MEFs, stress-induced apoptosis assays, kinase activity measurements (p38, JNK), phospho-ATF2/c-Jun analysis The Journal of biological chemistry Medium 19395378
2021 p21WAF1/CIP1 promotes the interaction between p53 and Wip1 by forming a trimeric complex (p53-p21-Wip1), facilitating Wip1-mediated dephosphorylation of p53-S15 and subsequent Mdm2-mediated p53 degradation. A p21 deletion mutant unable to bind p53 cannot facilitate p53-Wip1 interaction. Co-immunoprecipitation, deletion mutant analysis, p53 stability assay, phospho-S15 immunoblotting Biochemical and biophysical research communications Medium 33503543
2017 Wip1-deficient macrophages show enhanced migration mediated by Rac1-GTPase and PI3K/AKT signaling pathways. Enhanced phagocytic ability of Wip1-/- macrophages is linked to CD36 plasma membrane recruitment regulated by AMPK activity. Wip1 knockout macrophage migration and phagocytosis assays, Rac1-GTPase activity measurement, PI3K/AKT pathway analysis, AMPK activity, CD36 membrane recruitment assay Redox biology Medium 28822916
2014 Akt stabilizes PPM1D protein by inhibiting CDDP-induced proteasomal degradation. In chemoresistant gynecological cancer cells, CDDP induces PPM1D nuclear localization while sensitive cells show nuclear exclusion. Active Akt overexpression in sensitive cells stabilizes PPM1D and prevents degradation. Nuclear/cytoplasmic fractionation, proteasome inhibitor assay, Akt overexpression/inhibition, PPM1D stability measurements Molecular carcinogenesis Medium 25154814

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nature genetics 372 12021785
2018 PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy. Cell stem cell 344 30388424
2005 PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes & development 329 15870257
2006 Wip1 phosphatase modulates ATM-dependent signaling pathways. Molecular cell 291 16949371
2008 The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer metastasis reviews 208 18265945
2003 PPM1D is a potential target for 17q gain in neuroblastoma. Cancer research 203 12702577
2012 Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 202 23242139
2018 PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 195 29954749
2014 Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nature chemical biology 173 24390428
2014 Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nature genetics 144 24880341
2009 PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 141 19293255
2013 Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. The Journal of cell biology 140 23649806
2010 Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response. Cancer research 129 20460517
2010 Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway. Cancer research 128 20668064
2012 Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell metabolism 120 22768840
2009 WIP1 phosphatase at the crossroads of cancer and aging. Trends in biochemical sciences 112 19879149
2007 Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. Journal of neuro-oncology 111 17932621
2004 The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Molecular cell 108 15327777
2006 The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene 94 16936775
2010 Control of p53 and NF-κB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cellular signalling 90 20940041
2022 Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 84 35585670
2012 Regulation of the Wip1 phosphatase and its effects on the stress response. Frontiers in bioscience (Landmark edition) 82 22201816
2005 The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast cancer research and treatment 82 16254685
2007 A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene 79 17700519
2016 Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy. EMBO reports 76 27670885
2014 Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. The Journal of clinical investigation 67 24911145
2006 Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Molecular carcinogenesis 67 16652371
2014 Phosphatase Wip1 negatively regulates neutrophil migration and inflammation. Journal of immunology (Baltimore, Md. : 1950) 66 24395919
2013 Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation. Cancer cell 61 24135283
2019 PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nature communications 58 31439867
2011 The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation. Oncogene 58 21927021
2007 The Wip1 phosphatase PPM1D dephosphorylates SQ/TQ motifs in checkpoint substrates phosphorylated by PI3K-like kinases. Biochemistry 56 17939684
2015 WIP1 phosphatase as a potential therapeutic target in neuroblastoma. PloS one 55 25658463
2015 Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways. Nature communications 54 25879755
2010 PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 54 20543821
2006 Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. Breast cancer research and treatment 52 16897432
2007 Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma. Pathology international 51 17685927
2008 Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites. Nucleic acids research 50 19015127
2017 Phosphatase Wip1 in Immunity: An Overview and Update. Frontiers in immunology 49 28144241
2017 WIP1 phosphatase as pharmacological target in cancer therapy. Journal of molecular medicine (Berlin, Germany) 49 28439615
2020 WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC. Signal transduction and targeted therapy 47 32296033
2006 Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. The Journal of biological chemistry 46 16798742
2016 Wip1 phosphatase: between p53 and MAPK kinases pathways. Oncotarget 45 26883196
2015 Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. British journal of cancer 45 25742468
2012 Wip1-dependent signaling pathways in health and diseases. Progress in molecular biology and translational science 45 22340722
2022 PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. Nature communications 43 35105861
2014 The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants. Oncogene 43 24632620
2010 The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair. DNA repair 43 20451471
2020 The role of PPM1D in cancer and advances in studies of its inhibitors. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 32006900
2022 Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy. JCO precision oncology 40 35025619
2014 Wip1 phosphatase in breast cancer. Oncogene 40 25381821
2023 PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy. Blood 39 37595362
2013 Genetic variants and mutations of PPM1D control the response to DNA damage. Cell cycle (Georgetown, Tex.) 39 23907125
2008 The Wip1 phosphatase and Mdm2: cracking the "Wip" on p53 stability. Cell cycle (Georgetown, Tex.) 39 18333294
2016 Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity. Oncotarget 38 27183917
2015 Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner. Blood 37 26012568
2017 DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation. Cell death discovery 34 28417018
2021 Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses. Nature communications 32 34131120
2013 DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase. Nucleic acids research 32 23396447
2008 PPM1D silencing by RNA interference inhibits proliferation and induces apoptosis in breast cancer cell lines with wild-type p53. Cancer genetics and cytogenetics 31 18328948
2015 Involvement of dysregulated Wip1 in manganese-induced p53 signaling and neuronal apoptosis. Toxicology letters 29 25791630
2012 Wip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis. Retrovirology 29 23256545
2011 A small molecule inhibitor of p53-inducible protein phosphatase PPM1D. Bioorganic & medicinal chemistry letters 29 22115592
2009 Loss of Wip1 sensitizes cells to stress- and DNA damage-induced apoptosis. The Journal of biological chemistry 29 19395378
2015 DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase. Cell cycle (Georgetown, Tex.) 28 25659035
2022 Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state. Nature communications 27 35773251
2022 PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nature communications 27 36456590
2015 Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation. Bioorganic & medicinal chemistry 27 26358280
2014 Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability. Molecular carcinogenesis 27 25154814
2020 Wip1 regulates Smad4 phosphorylation and inhibits TGF-β signaling. EMBO reports 26 32103600
2020 Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity. Cell reports 26 32294440
2019 Inhibition of mutant PPM1D enhances DNA damage response and growth suppressive effects of ionizing radiation in diffuse intrinsic pontine glioma. Neuro-oncology 26 30852603
2019 WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors. Cells 25 31619012
2017 MicroRNA16 regulates glioma cell proliferation, apoptosis and invasion by targeting Wip1-ATM-p53 feedback loop. Oncotarget 25 28903382
2015 PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38. Oncogene 25 25823026
2023 Ppm1d truncating mutations promote the development of genotoxic stress-induced AML. Leukemia 24 37709843
2020 Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib. Molecular cancer research : MCR 23 32229503
2016 Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy. Cell death & disease 23 27077811
2015 WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C. Oncotarget 22 25797250
2016 WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma. Oncogene 21 27086929
2007 Identification of differentially expressed genes after PPM1D silencing in breast cancer. Cancer letters 21 17977650
2019 Wip1 cooperates with KPNA2 to modulate the cell proliferation and migration of colorectal cancer via a p53-dependent manner. Journal of cellular biochemistry 20 31127650
2014 Overexpression of wip1 is associated with biologic behavior in human clear cell renal cell carcinoma. PloS one 20 25334029
2012 HDM2 promotes WIP1-mediated medulloblastoma growth. Neuro-oncology 20 22379189
2008 Characterization of the active site and a unique uncompetitive inhibitor of the PPM1-type protein phosphatase PPM1D. Protein and peptide letters 20 18991770
2021 TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist. Acta neuropathologica communications 19 34732238
2019 Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon. Cell death & disease 19 31659152
2022 PPM1D in Solid and Hematologic Malignancies: Friend and Foe? Molecular cancer research : MCR 18 35657598
2017 Wip1 is associated with tumorigenity and metastasis through MMP-2 in human intrahepatic cholangiocarcinoma. Oncotarget 18 28915621
2016 PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms. Apoptosis : an international journal on programmed cell death 18 26714478
2015 Wip1-deficient neutrophils significantly promote intestinal ischemia/reperfusion injury in mice. Current molecular medicine 18 25601473
2023 Clonal hematopoiesis with DNMT3A and PPM1D mutations impairs regeneration in autologous stem cell transplant recipients. Haematologica 17 37381752
2007 PP2Cdelta (Ppm1d, WIP1), an endogenous inhibitor of p38 MAPK, is regulated along with Trp53 and Cdkn2a following p38 MAPK inhibition during mouse preimplantation development. Molecular reproduction and development 17 17219434
2021 Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia. Stroke and vascular neurology 16 33452162
2021 p21WAF1/CIP1 promotes p53 protein degradation by facilitating p53-Wip1 and p53-Mdm2 interaction. Biochemical and biophysical research communications 16 33503543
2020 Protein phosphatase, Mg2+/Mn2+-dependent 1D (PPM1D) mutations in haematological cancer. British journal of haematology 16 33616916
2017 Wip1-dependent modulation of macrophage migration and phagocytosis. Redox biology 16 28822916
2016 Truncating and missense PPM1D mutations in early-onset and/or familial/hereditary prostate cancer patients. Genes, chromosomes & cancer 16 27401275
2016 PPM1D controls nucleolar formation by up-regulating phosphorylation of nucleophosmin. Scientific reports 16 27619510
2020 Phosphatase magnesium-dependent 1 δ (PPM1D), serine/threonine protein phosphatase and novel pharmacological target in cancer. Biochemical pharmacology 15 33309518

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