Affinage

PPP4C

Serine/threonine-protein phosphatase 4 catalytic subunit · UniProt P60510

Length
307 aa
Mass
35.1 kDa
Annotated
2026-06-10
78 papers in source corpus 36 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP4C (PP4, PPX) is an evolutionarily conserved okadaic-acid/microcystin-sensitive serine/threonine phosphatase, distinct from PP2A in that it does not bind the PP2A 65 kDa regulatory subunit, that acts as the catalytic core of multimeric holoenzymes to control the DNA damage response, innate immune signaling, and cell-cycle/developmental processes (PMID:8384557). Holoenzyme assembly and substrate selection are coupled: C-terminal leucine methylation of the catalytic subunit by LCMT-1 is required to build PP4R1- and PP4R3β-containing complexes (PMID:27507813, PMID:34845248), and the R3-type regulatory subunits recognize substrates through FxxP/MxPP short linear motifs that dock into a conserved pocket of the regulatory subunit's EVH1/WH1 domain (PMID:31585692, PMID:33352067). As a master phosphatase in the DNA damage response, PP4 dephosphorylates γ-H2AX within nucleosomes via a PP4C–PP4R2–PP4R3β complex to permit checkpoint recovery (PMID:18614045, PMID:18758438), dephosphorylates RPA2 to license RAD51 loading and homologous recombination (PMID:20154705), removes ATM/CHK2 marks from KAP-1 (S824/S473) to enable NHEJ and heterochromatic repair (PMID:22491012, PMID:22732494), and dephosphorylates PLK1-S137 to coordinate the DSB response in early embryos (PMID:35546066). In innate immunity PP4 acts as a negative regulator, directly dephosphorylating TBK1-Ser172 to limit IRF3/type I IFN output (PMID:26363053, PMID:41723906) and inactivating the IKK complex and TRAF/NF-κB signaling through its PP4R1 subunit (PMID:23084358, PMID:25134449). PP4 additionally functions at centrosomes (PMID:8384557), represses RNA Pol III transcription by dephosphorylating Maf1 (PMID:22333918), controls cohesin release via FxxP-dependent dephosphorylation of WAPL/Rad21 (PMID:31585692, PMID:28438891), and regulates metabolic and chromatin signaling through dephosphorylation of AMPK (PMID:30917323) and HDAC3 (PMID:27507813, PMID:31268609). PP4 activity is held in check by multiple inputs: LCMT-1 methylation and CDK5 phosphorylation of PP4R3β gate holoenzyme function (PMID:31534152, PMID:34845248), FBXO42-mediated ubiquitination restrains complex assembly (PMID:41484364), SIRT1 deacetylation of the R3 WH1 domain inhibits the phosphatase after DNA damage (PMID:37309898), and CCDC6 sequesters the complex (PMID:35964058). Loss of PPP4C causes male-specific oligoasthenoteratospermia in mice and is required for B-cell V(D)J and class-switch recombination (PMID:33543287, PMID:23874770, PMID:25215539).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1993 High

    Established PPP4C as a distinct catalytic phosphatase: it shares PP2A-like substrate and inhibitor profiles yet does not bind the PP2A regulatory subunit, defining it as a separate enzyme, and localized it to centrosomes throughout mitosis.

    Evidence Baculovirus expression with in vitro phosphatase and inhibitor assays, plus dual-antibody immunofluorescence

    PMID:8384557

    Open questions at the time
    • No regulatory subunits or physiological substrates identified at this stage
    • Functional role of centrosomal localization not defined
  2. 2008 High

    Resolved how PP4 acts in the DNA damage response by showing a defined PP4C–PP4R2–PP4R3β complex dephosphorylates γ-H2AX in nucleosomes to drive checkpoint recovery.

    Evidence Reciprocal Co-IP, siRNA knockdown, in vitro mononucleosome dephosphorylation, and γ-H2AX/MDC1 foci and checkpoint assays in human cells

    PMID:18614045 PMID:18758438

    Open questions at the time
    • Did not establish how the complex is targeted to specific chromatin sites
    • Other DDR substrates not yet defined
  3. 2010 High

    Expanded PP4's DDR role to homologous recombination and uncovered conserved substrate logic across kingdoms, including RPA2, yeast Zip1, and the NCC cotransporter.

    Evidence In vitro dephosphorylation, HR reporter and RAD51 foci assays, genetic epistasis in yeast meiosis, and Xenopus oocyte transport assays

    PMID:20154705 PMID:20951350 PMID:20962898

    Open questions at the time
    • NCC regulation rests on a single lab and oocyte system
    • How PP4R2 confers damage-dependent RPA2 recognition not structurally defined
  4. 2012 High

    Defined PP4 as both a DDR effector on KAP-1 and a negative regulator of innate immune/NF-κB signaling, showing regulatory subunits direct catalytic activity to distinct pathways.

    Evidence Phosphoproteomic substrate screen, in vitro dephosphorylation, NHEJ reporter epistasis, and PP4R1-bridged IKK/TRAF NF-κB assays in T and other cells; plus yeast Maf1/Pol III repression

    PMID:22333918 PMID:22491012 PMID:22732494 PMID:23084358 PMID:25134449

    Open questions at the time
    • TRAF2/TRAF6 axis from single lab
    • How a single catalytic subunit is partitioned between immune and DDR roles not resolved
  5. 2014 Medium

    Connected PP4 directly to the apical ATR/Mec1 machinery and to lymphocyte development, showing PP4 governs both the kinase signal and the biological programs that depend on it.

    Evidence FRET and biochemical interaction with Mec1-Ddc2 plus phosphoproteomics in yeast; B-cell-specific knockouts with V(D)J/CSR and germinal center phenotypes

    PMID:23874770 PMID:25215539 PMID:25533186

    Open questions at the time
    • Mammalian PP4–ATR physical interaction not directly demonstrated
    • B-cell phenotypes not tied to a single PP4 substrate
  6. 2015 High

    Pinpointed TBK1-Ser172 as a direct PP4C substrate, mechanistically explaining PP4's suppression of type I IFN during viral infection.

    Evidence Co-IP, in vitro/cellular dephosphorylation, phosphatase-dead mutant, and viral infection assays in macrophages/DCs with in vivo validation

    PMID:26363053

    Open questions at the time
    • Which regulatory subunit recruits PP4C to TBK1 not defined here
  7. 2016 High

    Identified LCMT-1 carboxyl methylation as the switch controlling PP4 holoenzyme composition and revealed HDAC3 as a methylation-dependent PP4R1 substrate.

    Evidence LCMT-1 knockout MEFs, methylation-specific antibodies, BN-PAGE holoenzyme analysis, and HDAC3 phosphorylation readout

    PMID:27507813

    Open questions at the time
    • Quantitative contribution of methylation to each holoenzyme not fully mapped
  8. 2019 High

    Established the structural basis of PP4 substrate selectivity (FxxP/MxPP SLiM recognition by the R3 EVH1 domain) and added cohesin regulation, AMPK/metabolism, HDAC3-driven axon regeneration, and CDK5-gated 53BP1 recruitment to its functional repertoire.

    Evidence X-ray crystallography and proteomics of FxxP recognition; WAPL/cohesin, AMPK (MCU knockout mice/zebrafish), HDAC3 ChIP-seq in nerve injury, and CDK5 kinase/phosphomimetic 53BP1 assays

    PMID:30917323 PMID:31268609 PMID:31534152 PMID:31544936 PMID:31585692 PMID:33352067

    Open questions at the time
    • How a single SLiM pocket discriminates among hundreds of FxxP-bearing proteins unclear
    • Drosophila EVH1 leucine-substitution finding is Medium confidence/single lab
  9. 2021 High

    Confirmed the C-terminal leucine as the methylation site governing PP4R1/PP4R3β holoenzyme assembly and added sNASP-directed termination of TLR4/TRAF6 signaling and a spermiogenesis requirement.

    Evidence MS proteomics with C-terminal leucine deletion mutants and BN-PAGE; sNASP Co-IP with in vivo sepsis model; conditional knockout mouse spermiogenesis analysis

    PMID:33543287 PMID:34789577 PMID:34845248

    Open questions at the time
    • Direct PP4 substrate underlying the infertility phenotype not identified
    • sNASP recruitment mechanism rests on single lab
  10. 2022 High

    Identified PLK1-Ser137 as a PP4C substrate coordinating the embryonic DSB response and revealed CCDC6 as a sequestering inhibitor whose loss confers BRCAness.

    Evidence Conditional knockout in oocytes/embryos with in vitro PLK1 dephosphorylation and CHK2/CDK1 readouts; CCDC6 Co-IP, phosphomimetics, and PARP-inhibitor sensitivity assays

    PMID:35546066 PMID:35964058

    Open questions at the time
    • CCDC6 sequestration mechanism from single lab
    • Whether PLK1-S137 regulation generalizes beyond early embryos untested
  11. 2023 Medium

    Added a post-translational inhibitory input by showing SIRT1 deacetylates the R3 WH1 domain to restrain PP4 activity on γ-H2AX and RPA2 after DNA damage.

    Evidence Co-IP, deacetylation assays, and γ-H2AX/RPA2 phosphorylation analysis in SIRT1-deficient cells

    PMID:37309898

    Open questions at the time
    • Single lab; specific acetyl-lysines and their direct effect on substrate docking not fully defined
  12. 2026 Medium

    Established FBXO42 ubiquitination as a regulator of PP4 holoenzyme assembly and extended PP4's roles to YAP1/Hippo signaling in cancer and macrophage/neutrophil control during sepsis.

    Evidence MS proteomics and ubiquitination assays (glioma); PPP4C–MST4 Co-IP and YAP1 assays with syngeneic tumors; myeloid-specific PP4 knockout sepsis models with TBK1 dephosphorylation

    PMID:41484364 PMID:41690452 PMID:41723906

    Open questions at the time
    • MST4/YAP1 and FBXO42 axes each from single labs
    • Direct vs indirect PP4 effects on YAP1 not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single catalytic subunit achieves pathway-specific substrate selection across DDR, immune, metabolic, and developmental programs in vivo, and how the converging regulatory inputs (methylation, ubiquitination, deacetylation, metal-ion reduction, sequestration) are integrated, remains unresolved.
  • No unified structural model linking SLiM recognition to substrate-specific outcomes
  • CYB5R4 metal-ion activation and FBXO42/CCDC6 regulation captured largely in preprints
  • Mendelian disease association in humans not established in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-1430728 Metabolism 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
CCDC6FBXO42KAP1PPP4R1PPP4R2PPP4R3BSMEK1TBK1
Complex memberships
PP4 holoenzyme (PP4C-PP4R2-PP4R3β)PP4:SMEK1 complexPP4C-PP4R1 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 PPX (PPP4C) was identified as a novel mammalian protein serine/threonine phosphatase with substrate specificity and sensitivity to okadaic acid and microcystin similar (but not identical) to PP2A catalytic subunit; unlike PP2A, PPX did not bind the 65 kDa regulatory subunit of PP2A. Baculovirus expression, in vitro phosphatase assays, inhibitor sensitivity assays, co-immunoprecipitation The EMBO journal High 8384557
1993 PPX (PPP4C) localizes intensely to centrosomes at all stages of mitosis except telophase, while also distributed throughout cytoplasm and nucleus; centrosomal staining colocalizes with the human autoantibody #5051 marking pericentriolar material. Immunofluorescence microscopy with two independent antibodies (anti-bacterially expressed PPX and anti-PPX peptide) The EMBO journal High 8384557
2008 A three-protein PP4 complex containing PP4C, PP4R2, and PP4R3beta specifically dephosphorylates ATR-mediated gamma-H2AX generated during DNA replication; PP4 efficiently dephosphorylates gamma-H2AX within mononucleosomes in vitro without directly altering ATR or checkpoint kinase activity. Co-immunoprecipitation, siRNA knockdown, in vitro dephosphorylation assay with mononucleosomes, cell hypersensitivity assays Molecular cell High 18614045
2008 PP4C contributes to dephosphorylation of gamma-H2AX both at sites of DNA damage and in undamaged chromatin in human cells; depletion of PP4C results in prolonged checkpoint arrest due to persistence of MDC1 at DNA lesion sites. siRNA knockdown, immunofluorescence, checkpoint assays, gamma-H2AX foci analysis EMBO reports High 18758438
2008 Drosophila PP4 (ortholog of PPP4C) dephosphorylates Smoothened (Smo) to regulate Hedgehog signaling; RNAi knockdown of PP4 elevates Smo phosphorylation and accumulation, leading to increased Hh signaling. PP4 interaction with Smo is mediated by Cos2, and Hh signaling downregulates the Smo-PP4 interaction. In vivo RNAi screen, epistasis analysis, Co-IP, phosphorylation assays, deletion mapping (aa 626-678 of Smo) Development (Cambridge, England) High 19088085
2010 A PP4 phosphatase complex dephosphorylates RPA2 (replication protein A subunit 2) to regulate its role in DSB response; PP4R2 mediates the DNA damage-dependent association between RPA2 and PP4C; PP4 efficiently dephosphorylates phospho-RPA2 in vitro; PP4-mediated dephosphorylation of RPA2 is required for efficient RAD51 loading and homologous recombination. Co-immunoprecipitation, in vitro dephosphorylation assay, siRNA knockdown, HR reporter assay, RAD51 foci analysis, phosphomimetic mutant analysis Nature structural & molecular biology High 20154705
2010 Yeast PP4 (Pph3/Psy2) mediates centromere pairing during meiotic prophase by dephosphorylating Zip1 at serine 75, a consensus Mec1 (ATR) site; loss of PP4 leads to persistent Zip1-S75 phosphorylation and blocked centromere pairing; centromere pairing is restored in mec1 mutants, establishing genetic epistasis between Mec1 and PP4 at this step. Genetic epistasis (double mutant analysis), phosphorylation site mutagenesis, chromatin immunofluorescence for centromere pairing Developmental cell High 20951350
2010 PP4C dephosphorylates the NCC (Na+-Cl- cotransporter) to inhibit its intrinsic transport activity (but not surface trafficking) through a mechanism requiring phosphatase activity and the conserved N-terminal threonine 58 of NCC; PP4 is selectively expressed in the distal nephron including distal convoluted tubule cells. Xenopus oocyte expression system, transport activity assays, phosphatase-dead mutant, NCC Thr58 mutagenesis, immunofluorescence of mouse kidney sections Canadian journal of physiology and pharmacology Medium 20962898
2012 PP4C/R3beta complex dephosphorylates KAP-1 at S824 (phosphorylated by ATM) and S473 (phosphorylated by CHK2) after ionizing radiation; a PP4C/R3beta complex interacts with KAP-1; phosphorylation of KAP-1 S473 by CHK2 impacts the G2/M checkpoint; PP4-mediated dephosphorylation of KAP-1 S824 is required for repair of heterochromatic DNA lesions. Phosphoproteomic substrate identification screen, Co-IP, siRNA knockdown, phosphomimetic mutants, G2/M checkpoint assays, chromatin remodeling analysis The EMBO journal High 22491012
2012 PP4C and regulatory subunit PP4R2 physically interact with KAP1 and dephosphorylate pKAP1-S824 in vitro; PP4C depletion compromises NHEJ-mediated DSB repair; PP4C and KAP1 function in the same epistasis group for NHEJ. Co-IP, in vitro dephosphorylation assay, siRNA knockdown, I-SceI NHEJ reporter assay, epistasis analysis (co-depletion) Cell cycle (Georgetown, Tex.) High 22732494
2012 PP4 complex (catalytic subunit Pph3, scaffold Psy2, regulatory subunits Rrd1 and Tip41) is the main Maf1 phosphatase in yeast, required for Maf1 dephosphorylation, nuclear localization, and rapid repression of RNA Pol III; purified PP4 dephosphorylates Maf1 in vitro and PP4 co-precipitates with Maf1. In vitro dephosphorylation assay, co-precipitation, genetic analysis of PP4 subunit mutants, nuclear localization assays, Pol III transcription assays The EMBO journal High 22333918
2012 PP4 (via PP4R1 regulatory subunit) forms a holoenzyme that bridges the IKK complex and PP4c, directing PP4c to dephosphorylate and inactivate the IKK complex, thereby negatively regulating NF-κB signaling in T lymphocytes. RNAi screen, Co-IP, kinase activity assays, NF-κB reporter assays, T cell activation assays Immunity High 23084358
2014 Yeast PP4 (Pph3) physically interacts with the ATR homolog Mec1-Ddc2 complex, mediated by cofactors Psy2 and Ddc2; this interaction was demonstrated biochemically and by FRET in subnuclear repair foci; phosphoproteomic analysis showed 94% of mec1-100-compromised phosphorylation targets on HU are PP4 regulated; PP4 also dephosphorylates a phosphoacceptor site within Mec1 itself. Genetic suppressor screen, E-MAP screen, biochemical interaction assays, FRET microscopy in living cells, phosphoproteomic analysis Molecular cell High 25533186
2014 PP4R1 subunit of PP4 interacts with TRAF2 and TRAF6 in a RING finger domain-dependent manner (identified by yeast two-hybrid with TRAF2 as bait); PP4R1 mediates dephosphorylation of TRAF2 Ser11 and inhibits TRAF6 polyubiquitination, thereby inhibiting NF-κB activation. Yeast two-hybrid screen, Co-IP, phosphorylation assays, ubiquitination assays, NF-κB reporter assays, siRNA knockdown Cellular signalling Medium 25134449
2015 PP4C dephosphorylates TBK1 at Ser172 upon RNA virus infection, inhibiting TBK1 activation and subsequent IRF3 activation, thereby suppressing type I IFN production; a phosphatase-dead PP4C mutant abolished inhibitory effects; PP4C directly binds TBK1 upon virus infection. Co-IP, in vitro/cellular dephosphorylation assays, phosphatase-dead mutant, siRNA knockdown in macrophages and DCs, viral infection assays, in vivo peritoneal macrophage assays Journal of immunology High 26363053
2016 LCMT-1 is the major carboxyl methyltransferase for PP4C (as well as PP2A and PP6) in mouse embryonic fibroblasts; LCMT-1-dependent methylation differentially regulates PP4 holoenzyme formation, with the PP4R1-containing complex being most dramatically affected by LCMT-1 loss; LCMT-1 knockout MEFs show hyperphosphorylation of HDAC3, a target of the methylation-dependent PP4R1-PP4c complex. Methylation-specific antibodies, BN-PAGE holoenzyme analysis, LCMT-1 knockout MEFs, HDAC3 phosphorylation assays The Journal of biological chemistry High 27507813
2019 PP4 (via regulatory subunit PPP4R3) recognizes substrates through a conserved FxxP consensus binding motif; X-ray crystallography revealed that FxxP motifs bind to a conserved pocket in PPP4R3; the FxxP motif in cohesin release factor WAPL regulates WAPL phosphorylation and is required for efficient cohesin release. X-ray crystallography, proteomic analysis of PP4 interacting proteins, in silico FxxP motif searches, functional WAPL phosphorylation and cohesin release assays Molecular cell High 31585692
2019 PP4C dephosphorylates AMPK in a Ca2+-dependent manner downstream of mitochondrial Ca2+ (MCU); elevated cytosolic Ca2+ (when MCU is deleted) activates PP4 activity, which dephosphorylates AMPK, leading to increased hepatic lipid accumulation; PP4 knockdown or AMPK reconstitution restores lipid clearance in MCU-deleted hepatocytes. Mcu liver-specific knockout mice, CRISPR/Cas9 zebrafish knockout, Ca2+ measurements, PP4 activity assays, AMPK phosphorylation assays, siRNA knockdown, lipid accumulation measurements Cell reports High 30917323
2019 PP4C dephosphorylates HDAC3 following peripheral nerve injury, impairing HDAC3 activity and enhancing histone acetylation to promote a regenerative gene expression program; this PP4 activation is calcium-dependent (triggered by peripheral but not central injury); PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration competence and failure. Pharmacological screen, in vivo injury models (DRG), calcium imaging, ChIP-seq (H3K9ac), RNA-seq, genetic and pharmacological HDAC3 inhibition, PP4 activity assays The EMBO journal High 31268609
2019 CDK5 directly phosphorylates PP4R3β (the PP4 regulatory subunit that recognizes 53BP1) in late mitotic phases in non-neuronal cells; CDK5-mediated phosphorylation of PP4R3β is required for PP4R3β to recognize and dephosphorylate 53BP1; without CDK5 activity in mitosis, 53BP1 fails to localize to damaged chromatin in G1. In vitro kinase assays, specific CDK5 inhibition in mitosis, Co-IP of PP4R3β-53BP1, 53BP1 foci assays in G1, phosphomimetic/phosphodeficient mutants Nature communications High 31534152
2019 Drosophila PP4 (Falafel/R3 subunit) EVH1 domain recognizes FxxP and MxPP short linear motifs through a conserved leucine residue (replacing the invariant phenylalanine of canonical EVH1 domains) rather than canonical proline-rich sequences; the Smk-1 domain of Falafel also participates in target-binding. Binding studies, mass spectrometry identification of interactors, site-directed mutagenesis of EVH1 domain residues, structural analysis Open biology Medium 33352067
2021 C-terminal leucine methylation of PP4C (catalytic subunit) by LCMT-1 is required for PP4R1-containing and PP4R3β-containing holoenzyme assembly; deletion of the C-terminal leucine faithfully recapitulates loss of methylation; loss of methylation reduces PP4R1 and PP4R3β binding. Mass spectrometry-based proteomics, C-terminal leucine deletion mutants, genome editing, BN-PAGE holoenzyme analysis Scientific reports High 34845248
2021 PP4C dephosphorylates the sNASP phosphoprotein to terminate TLR4-induced TRAF6 activation; PP4 is directly recruited by phosphorylated sNASP; this PP4-mediated negative regulation reduces pro-inflammatory cytokine production; in vivo PP4 overexpression improves survival in a sepsis model. Co-IP, ectopic expression of PP4, siRNA knockdown, cytokine production assays, in vivo adenovirus-mediated PP4 expression in sepsis model Proceedings of the National Academy of Sciences of the United States of America High 34789577
2021 Deletion of PPP4C in mouse causes male-specific infertility characterized by oligoasthenoteratospermia (OAT): sperm tail bending, low sperm count, poor motility, and defective cytoplasm removal during spermiogenesis. Conditional knockout mouse model, light microscopy, transmission electron microscopy of spermiogenesis Molecular human reproduction Medium 33543287
2022 PPP4C dephosphorylates PLK1 at Ser137, negatively regulating PLK1 activity during DNA DSB response in early embryos; PPP4C depletion causes sustained PLK1 activity, inhibits CHK2, upregulates CDK1 activation, and results in inefficient RAD51 loading, impairing homologous recombination. PPP4C conditional knockout in oocytes/embryos, in vitro dephosphorylation assay, PLK1 inhibition experiments, RAD51 foci analysis, CDK1/CHK2 activity assays Development (Cambridge, England) High 35546066
2022 CCDC6 (when un-phosphorylated at T427) forms a complex with PP4c that sequesters PP4c activity; the CCDC6-PP4 interaction and PP4 regulation of gamma-H2AX is mediated via PP4R3α; functional or physical loss of CCDC6 enhances PP4c complex activity, causing BRCAness and PARP inhibitor sensitivity in ovarian cancer cells. Co-IP, phosphomimetic mutants (T427D), siRNA knockdown of CCDC6 and PP4R3α, gamma-H2AX assays, HR reporter assays, PARP inhibitor sensitivity assays Journal of experimental & clinical cancer research Medium 35964058
2023 SIRT1 interacts with PP4c and promotes its inhibition by deacetylating the WH1 domain of regulatory subunits PP4R3α/β upon DNA damage; SIRT1-mediated inhibition of PP4 regulates gamma-H2AX and RPA2 phosphorylation; SIRT1-deficient cells show decreased gamma-H2AX levels consistent with unopposed PP4 activity. Co-IP of SIRT1 with PP4c, deacetylation assays, gamma-H2AX and RPA2 phosphorylation analysis in SIRT1-deficient cells Nucleic acids research Medium 37309898
2026 FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits, with the net effect of restraining PP4 phosphatase activity; FBXO42 depletion unleashes PP4 activity with broad cellular effects on cell cycle, DNA damage response, and glioma stem cell survival. Mass spectrometry proteomics, ubiquitination assays, PP4 complex assembly analysis, FBXO42 depletion functional assays The EMBO journal High 41484364
2026 PP4 directly dephosphorylates TBK1 in macrophages, inactivating IRF3 and suppressing macrophage-derived CCL5 production during sepsis; wild-type PP4 (but not phosphatase-dead mutant) reduces LPS-mediated CCR5 expression in neutrophils, limiting ROS production and NETs formation; myeloid-specific PP4 KO mice show increased sepsis susceptibility. Myeloid-specific PP4 knockout mice (CLP model), in vitro dephosphorylation assay (TBK1), phosphatase-dead mutant, cytokine assays, NETosis assays Redox biology Medium 41723906
2026 PPP4C interacts with MST4 kinase and reduces its activity, thereby enabling YAP1 dephosphorylation and nuclear accumulation; PPP4C-mediated MST4 degradation promotes NSCLC cell growth and immunosuppression by restoring YAP1 activity through the MAP4K2-LATS1/2 cascade. Co-IP of PPP4C with MST4, gain/loss-of-function experiments, YAP1 phosphorylation assays, NK cell co-culture assays, in vivo syngeneic tumor models Cancer letters Medium 41690452
2026 AAV Rep proteins engage the SMEK1 regulatory subunit of the PP4:SMEK1 complex to interfere with substrate recruitment, preventing KAP1-S824 and RPA2-S4/8/33 dephosphorylation; KAP1 interaction with SMEK1 is mediated by a MAPP short linear motif binding the SMEK1 EVH1 domain. Binding studies, Co-IP, substrate phosphorylation assays (KAP1-S824, RPA2), SLiM motif mapping, AAV replication assays PLoS pathogens Medium 41805761
2013 Targeted suppression of PP4C (but not PP1C, PP2AC, or PP5C) alone is sufficient to mimic many cellular actions of fostriecin, inducing apoptosis in tetraploid cells following mitotic slippage; PP4C is specifically required to prevent mitotic slippage/apoptosis. Antisense oligonucleotides specifically targeting PP4C, high-content time-lapse live imaging, comparison with fostriecin treatment Molecular cancer research Medium 23671329
2014 PP4 is required for pro-B cell development and immunoglobulin VDJ recombination; PP4-deficient pro-B cells show impaired Ig DJ(H) recombination, increased DNA double-strand breaks at Ig loci, and accumulate in G1 with excessive DNA damage; normal B cell development is rescued by transgenic Ig expression. B cell-specific pp4 knockout mice, flow cytometry, V(D)J recombination analysis, gamma-H2AX foci, cell cycle analysis, transgenic rescue PloS one Medium 23874770
2014 PP4 is required for germinal center formation and class switch recombination in B cells; PP4-deficient mature B cells show impaired proliferation, reduced Ig class switching efficiency, failure to form germinal centers in vivo, impaired CD40-mediated MAPK activation, and abnormal IgM-mediated NF-κB activation. CD23-cre conditional PP4 knockout mice, antigen immunization, flow cytometry for GC B cells, CSR assays in vitro, MAPK/NF-κB activation assays PloS one Medium 25215539
2005 Co-transfection of PP4 with JNK-1 in prostate cancer cell lines PC-3 and LNCaP significantly increases JNK-1 activity following EGF or cisplatin stimulation, and this is associated with increased c-Jun/AP-1 and EGR-1 activities; PP4 appears to positively regulate JNK-1 stability/activity. Co-transfection assays, JNK-1 activity assays, AP-1/EGR-1 reporter assays Biological research Low 16238095
2017 Fission yeast PP4 co-immunoprecipitates with Wpl1 and cohesin; PP4-dependent dephosphorylation of Rad21 (cohesin kleisin) promotes cohesin release from DNA by Wpl1; phosphomimetic alleles of Rad21 at the identified PP4-regulated sites dampen Wpl1 anti-cohesion activity. Genetic screen, Co-IP of PP4 with Wpl1 and cohesin, phosphomimetic/alanine Rad21 mutants, cohesion assays The EMBO journal Medium 28438891
2019 PP4 phosphatase (via Psy2 subunit) dephosphorylates Rad53 during DSB repair to relieve Rad9-mediated inhibition of the Sgs1/Dna2 exonuclease complex, thereby stimulating DNA end resection; PP4-dependent Rad53 dephosphorylation is required for efficient single-strand annealing repair. Yeast genetics, Rad53 phosphorylation assays, resection assays, SSA repair assay, epistasis via Rad53 hyperphosphorylation mutants Nucleic acids research Medium 31544936
2025 CYB5R4 is an evolutionarily conserved activator of PP4 (and PP6 but not PP2A); heme binding is essential for CYB5R4 function; CYB5R4 activates PP4 by reducing the metal ions in the PP4 active site; CYB5R4-mediated activation of PP4 is critical for cell viability during DNA damage-inducing oxidative stress conditions. Genome-wide CRISPR KO and base editor screens, biochemical PP4 activity assays, heme-binding mutant analysis, cell viability assays under DNA damage/oxidative stress bioRxivpreprint Medium
2025 FBXO42 binds PPP4C, promotes its ubiquitination, and negatively regulates PPP4C expression; aberrant PPP4C expression is a major driver of cell death in FBXO42-essential neuroblastoma cells; CCDC6 independently interacts with PPP4C without affecting its ubiquitination; PPP4C knockdown reduces FBXO42-CCDC6 interactions. Mass spectrometry proteomics, ubiquitination assays, CRISPR KO screen (synthetic lethality), gene knockdown rescue experiments, Co-IP bioRxivpreprint Medium
2025 Drosophila PP4 (Pp4) is required for centrosome asymmetry establishment in neural stem cells; Pp4 loss causes two inactive centrioles in interphase and failure to correctly transfer Centrobin (Cnb) from mother to daughter centriole in mitosis; phosphomimetic Centrobin fails to relocalize correctly; PP4 may dephosphorylate both Centrobin and gamma-Tubulin. In vivo live cell imaging, superresolution imaging, Pp4 mutant analysis, phosphomimetic Centrobin constructs, centrosome asymmetry assays bioRxivpreprint Medium

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 An exopolyphosphatase of Escherichia coli. The enzyme and its ppx gene in a polyphosphate operon. The Journal of biological chemistry 227 8380170
2008 A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication. Molecular cell 201 18614045
1993 PPX, a novel protein serine/threonine phosphatase localized to centrosomes. The EMBO journal 201 8384557
2008 PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint. EMBO reports 169 18758438
2008 Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 142 18520802
2010 A PP4 phosphatase complex dephosphorylates RPA2 to facilitate DNA repair via homologous recombination. Nature structural & molecular biology 126 20154705
2012 Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response. The EMBO journal 96 22491012
1988 Characterization of cDNA encoding human placental anticoagulant protein (PP4): homology with the lipocortin family. Proceedings of the National Academy of Sciences of the United States of America 95 2967495
2008 Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 92 18594318
2010 A Mec1- and PP4-dependent checkpoint couples centromere pairing to meiotic recombination. Developmental cell 89 20951350
2019 Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation. Cell reports 80 30917323
2023 ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. American journal of human genetics 71 38103548
2014 Protein phosphatases PP2A, PP4 and PP6: mediators and regulators in development and responses to environmental cues. Plant, cell & environment 69 24810976
2008 PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development (Cambridge, England) 69 19088085
2003 Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein. Protein expression and purification 60 12963337
2019 A Consensus Binding Motif for the PP4 Protein Phosphatase. Molecular cell 59 31585692
2014 Yeast PP4 interacts with ATR homolog Ddc2-Mec1 and regulates checkpoint signaling. Molecular cell 51 25533186
2012 A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes. Immunity 50 23084358
2006 The structure of the exopolyphosphatase (PPX) from Escherichia coli O157:H7 suggests a binding mode for long polyphosphate chains. Journal of molecular biology 49 16678853
2019 Role of protein phosphatases PP1, PP2A, PP4 and Cdc14 in the DNA damage response. Cell stress 46 31225502
2010 The activity of the thiazide-sensitive Na(+)-Cl(-) cotransporter is regulated by protein phosphatase PP4. Canadian journal of physiology and pharmacology 46 20962898
2012 Protein phosphatase PP4 is involved in NHEJ-mediated repair of DNA double-strand breaks. Cell cycle (Georgetown, Tex.) 44 22732494
2016 Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. The Journal of biological chemistry 43 27507813
2024 Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial. Blood 42 38452197
2006 Biodegradation of phthalate isomers by Pseudomonas aeruginosa PP4, Pseudomonas sp. PPD and Acinetobacter lwoffii ISP4. Applied microbiology and biotechnology 42 16607524
2019 PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure. The EMBO journal 40 31268609
2003 Concurrent transcriptional activation of ppa and ppx genes by phosphate deprivation in the cyanobacterium Synechocystis sp. strain PCC 6803. Biochemical and biophysical research communications 40 12615077
2012 PP4 dephosphorylates Maf1 to couple multiple stress conditions to RNA polymerase III repression. The EMBO journal 38 22333918
2017 Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 28467989
2017 The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen. Oncotarget 34 28445980
2010 The role of the exopolyphosphatase PPX in avoidance by Neisseria meningitidis of complement-mediated killing. The Journal of biological chemistry 34 20736171
2022 PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling. Journal for immunotherapy of cancer 32 36564125
2015 Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1. Journal of immunology (Baltimore, Md. : 1950) 32 26363053
2007 Structure of the PPX/GPPA phosphatase from Aquifex aeolicus in complex with the alarmone ppGpp. Journal of molecular biology 30 18155044
2007 Paclitaxel poliglumex (PPX, CT-2103): macromolecular medicine for advanced non-small-cell lung cancer. Expert review of anticancer therapy 29 17428162
2014 Functional characterization of exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GPPA) of Campylobacter jejuni. Virulence 27 24569519
2015 Protein phosphatase 4 (PP4) functions as a critical regulator in tumor necrosis factor (TNF)-α-induced hepatic insulin resistance. Scientific reports 26 26666849
1997 Genomic organization of the human PP4 gene encoding a serine/threonine protein phosphatase (PP4) suggests a common ancestry with PP2A. Genomics 26 9325055
1990 Annexin proteins PP4 and PP4-X. Comparative characterization of biological activities of placental and recombinant proteins. The Biochemical journal 26 2148260
2023 SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex. Nucleic acids research 25 37309898
2022 Comprehensive analysis of PPPCs family reveals the clinical significance of PPP1CA and PPP4C in breast cancer. Bioengineered 25 34964699
2019 Structure and activity of PPX/GppA homologs from Escherichia coli and Helicobacter pylori. The FEBS journal 23 31679177
2021 Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation. Scientific reports 22 34845248
2019 A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. Nature communications 22 31534152
2014 The PP4R1 subunit of protein phosphatase PP4 targets TRAF2 and TRAF6 to mediate inhibition of NF-κB activation. Cellular signalling 22 25134449
2019 PP4 phosphatase cooperates in recombinational DNA repair by enhancing double-strand break end resection. Nucleic acids research 20 31544936
2005 Role of the phosphatase PP4 in the activation of JNK-1 in prostate carcinoma cell lines PC-3 and LNCaP resulting in increased AP-1 and EGR-1 activity. Biological research 18 16238095
2015 Termination of Replication Stress Signaling via Concerted Action of the Slx4 Scaffold and the PP4 Phosphatase. Genetics 17 26362319
2020 Novel perspectives of target-binding by the evolutionarily conserved PP4 phosphatase. Open biology 15 33352067
2018 PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244. American journal of clinical oncology 14 26658237
2017 A second Wpl1 anti-cohesion pathway requires dephosphorylation of fission yeast kleisin Rad21 by PP4. The EMBO journal 14 28438891
2021 Oligoasthenoteratospermia and sperm tail bending in PPP4C-deficient mice. Molecular human reproduction 13 33543287
2001 Genomic structure of the mouse PP4 gene: a developmentally regulated protein phosphatase. Gene 13 11707325
1994 The Saccharomyces cerevisiae gene PPH3 encodes a protein phosphatase with properties different from PPX, PP1 and PP2A. Yeast (Chichester, England) 13 7941742
2021 Regulation of TLR4 signaling through the TRAF6/sNASP axis by reversible phosphorylation mediated by CK2 and PP4. Proceedings of the National Academy of Sciences of the United States of America 12 34789577
2022 The disruption of the CCDC6 - PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma. Journal of experimental & clinical cancer research : CR 11 35964058
2013 Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death. Molecular cancer research : MCR 10 23671329
2014 PP4 is essential for germinal center formation and class switch recombination in mice. PloS one 9 25215539
2018 PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency. Cell death and differentiation 8 30237510
2013 The serine/threonine phosphatase PP4 is required for pro-B cell development through its promotion of immunoglobulin VDJ recombination. PloS one 8 23874770
2012 Protein phosphatase PP4: role in dephosphorylation of KAP1 and DNA strand break repair. Cell cycle (Georgetown, Tex.) 8 22751432
2022 PPP4C facilitates homologous recombination DNA repair by dephosphorylating PLK1 during early embryo development. Development (Cambridge, England) 7 35546066
1990 Enzyme immunoassay for placental protein 4 (PP4) and its possible diagnostic significance in patients with genital tract cancer. Archives of gynecology and obstetrics 6 2142405
2015 Biochemical Characterization of Inducible 'Reductase' Component of Benzoate Dioxygenase and Phthalate Isomer Dioxygenases from Pseudomonas aeruginosa strain PP4. Applied biochemistry and biotechnology 5 26201480
2019 Genetic interaction between Ptc2 and protein phosphatase 4 (PP4) in the regulation of DNA damage response and virulence in Candida albicans. FEMS yeast research 4 31644792
2009 Bypassing isophthalate inhibition by modulating glutamate dehydrogenase (GDH): purification and kinetic characterization of NADP-GDHs from isophthalate-degrading Pseudomonas aeruginosa strain PP4 and Acinetobacter lwoffii strain ISP4. Journal of bacteriology 4 19933355
2024 Maf1 phosphorylation is regulated through the action of prefoldin-like Bud27 on PP4 phosphatase in Saccharomyces cerevisiae. Nucleic acids research 3 38864693
2021 The structure of exopolyphosphatase (PPX) from Porphyromonas gingivalis in complex with substrate analogs and magnesium ions reveals the basis for polyphosphate processivity. Journal of structural biology 3 34214602
2022 Expressions of the Protein Phosphatases PP1 and PP4 during the Embryonic Diapause Process of the Silkworm Bombyx mori. Zoological studies 2 37007811
2022 Study on the nasal drug delivery system of PPX microcapsules in situ thermosensitive gel. Pakistan journal of pharmaceutical sciences 1 36451573
2026 Pervasive phenotypic effects of FBXO42 are promoted by regulation of PP4 phosphatase. The EMBO journal 0 41484364
2026 PPP4C restores YAP1 activity by modulating MST4 phosphorylation to enhance immunosuppression and augment tumor growth in non-small cell lung cancer. Cancer letters 0 41690452
2026 PP4 modulates macrophage-neutrophil crosstalk to restrict CCL5 -driven NETosis in sepsis. Redox biology 0 41723906
2026 The adeno-associated virus Rep proteins target PP4:SMEK1 by preventing substrate recruitment. PLoS pathogens 0 41805761
2026 PPP4C: a potential molecular marker and therapeutic target in thyroid cancer and triple-negative breast cancer. BMC cancer 0 42082953
2026 Roles for Phosphatase PP4 in Rhythmicity and Compensation in the Neurospora Circadian System. bioRxiv : the preprint server for biology 0 42244607
2025 Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer. Genetics in medicine : official journal of the American College of Medical Genetics 0 40916913
1984 TheUbx syndrome ofDrosophila: the prothoracic transformation (ppx) is independent ofbx, bxd andpbx. Wilhelm Roux's archives of developmental biology 0 28305224

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