Affinage

PPP5C

Serine/threonine-protein phosphatase 5 · UniProt P53041

Length
499 aa
Mass
56.9 kDa
Annotated
2026-06-10
26 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP5C is a monomeric serine/threonine protein phosphatase that operates across DNA damage signalling, Wnt signalling, and calcium homeostasis through targeted dephosphorylation of specific phospho-substrates (PMID:21921034, PMID:29426949, PMID:29283027). Its catalytic activity is held low in the basal state by an autoinhibitory conformation, with a TPR domain that engages HSP90 chaperone complexes, and is relieved by activating partners such as S100A6 (PMID:31916625, PMID:37054560). In the DNA damage response, PPP5C acts downstream of ATR to dephosphorylate Chk1 at Ser-345, limiting Chk1 and p53 activation after UV-induced damage (PMID:21921034). In Wnt signalling, PPP5C directly binds and dephosphorylates Dvl2 at S143 and other sites, and localizes to the basal body of cilia where phospho-Dvl2 resides (PMID:29426949). In pulmonary artery endothelium, catalytically active PPP5C is an obligate component of the ISOC channel heterocomplex, co-precipitating with the TRPC4 channel subunit and mediating FKBP51- and S100A6-dependent inhibition of store-operated calcium entry and calcium-induced barrier disruption (PMID:29283027, PMID:31916625). The enzyme is inhibited by the small molecule LB-100, which coordinates the active-site catalytic metals as resolved by a 1.65 Å co-crystal structure, and by natural toxins including okadaic acid, microcystin, and cantharidin (PMID:30679389, PMID:25383722). A de novo p.Ala47Thr missense variant behaves as a loss-of-function hypomorph consistent with haploinsufficiency as a disease mechanism, as shown by epistasis in the C. elegans pph-5 ortholog (PMID:35361529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Established PPP5C as a phosphatase acting within the ATR-driven DNA damage response, answering which phosphatase restrains Chk1 activation after genotoxic stress.

    Evidence Cre/loxP conditional knockout mice and PP5-deficient MEFs with siRNA confirmation in human cells, scored by phospho-Western for Chk1-Ser345 and p53-Ser18

    PMID:21921034

    Open questions at the time
    • Does not establish direct dephosphorylation of Chk1 by purified PPP5C in vitro
    • Recruitment mechanism to damage sites unresolved
  2. 2014 Medium

    Provided a validated in vitro catalytic assay for purified PPP5C and placed it within the okadaic acid/microcystin/cantharidin-sensitive phosphatase class, enabling inhibitor screening.

    Evidence Fluorescent phosphatase assay with purified PPP5C, Z'=0.93 validation

    PMID:25383722

    Open questions at the time
    • Single method, single lab
    • Does not address physiological substrates or regulation
  3. 2017 High

    Defined PPP5C as an obligatory catalytic subunit of the ISOC channel complex, answering how store-operated calcium entry is suppressed in pulmonary endothelium.

    Evidence siRNA/KO rescue with WT vs catalytically inactive PP5C, Co-IP with TRPC4, membrane fractionation, and electrophysiology in HEK293/endothelial cells

    PMID:29283027

    Open questions at the time
    • Direct phospho-substrate within the ISOC complex not identified
    • Structural basis of TRPC4 association unresolved
  4. 2018 Medium

    Identified Dvl2 as a direct PPP5C substrate in Wnt signalling and localized PPP5C to the ciliary basal body, connecting the phosphatase to developmental signalling.

    Evidence Co-IP, in vitro dephosphorylation assay, siRNA knockdown, and immunofluorescence in hTERT-RPE1 cells

    PMID:29426949

    Open questions at the time
    • Single lab; functional Wnt pathway output downstream of Dvl2 dephosphorylation not quantified
    • Degree of redundancy with PP2A not fully resolved
  5. 2018 Low

    Linked PPP5C loss to elevated JNK and ERK1/2 phosphorylation in prostate cancer cells, implicating it in suppression of MAPK signalling.

    Evidence Lentiviral shRNA knockdown and phospho-Western for JNK and ERK1/2

    PMID:30254472

    Open questions at the time
    • No direct dephosphorylation assay; effect may be indirect
    • Single method, single lab
  6. 2019 High

    Resolved how the inhibitor LB-100 engages PPP5C, defining the active-site coordination chemistry and confirming substrate overlap with PP2A.

    Evidence 1.65 Å co-crystal structure of PPP5C with LB-100, in vitro inhibition assays with purified enzymes, and cell-based PPP5C disruption

    PMID:30679389

    Open questions at the time
    • LB-100 selectivity between PPP5C and PP2A in cells not fully delineated
    • Effect of inhibitor on autoinhibited vs activated enzyme not addressed
  7. 2020 Medium

    Established S100A6 as a positive regulator that activates PPP5C and couples it to the ISOC/FKBP51 axis, explaining how the autoinhibited enzyme is switched on at the membrane.

    Evidence Co-IP of S100A6 with TRPC4, PPP5C activity assay (tau-T231 dephosphorylation), calcium imaging, ECIS barrier assay, and live-cell imaging of S100A6 translocation

    PMID:31916625

    Open questions at the time
    • Single lab
    • Structural basis of S100A6-mediated activation not resolved
  8. 2022 Medium

    Showed that a de novo PPP5C missense variant is a recessive loss-of-function allele, supporting haploinsufficiency as a disease mechanism via epistasis in an orthologous model.

    Evidence CRISPR knock-in of the variant into C. elegans pph-5, with mec-15 and sep-1 epistasis, neurite growth, GABA signalling, and embryonic lethality readouts

    PMID:35361529

    Open questions at the time
    • Human disease phenotype and penetrance not characterized in this study
    • Molecular consequence on PPP5C catalysis/structure not directly measured
  9. 2023 Low

    Synthesized the dual phosphatase/co-chaperone model in which TPR-mediated autoinhibition keeps PPP5C low-activity and HSP90 binding modulates the enzyme.

    Evidence Review synthesizing structural and biochemical structure-function data

    PMID:37054560

    Open questions at the time
    • Review without new primary data
    • Quantitative contribution of HSP90 binding to substrate selection not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse activating inputs (S100 proteins, HSP90, membrane recruitment) are integrated to direct PPP5C toward distinct substrate pools across DNA damage, Wnt, and calcium pathways remains unresolved.
  • No unifying model of substrate targeting across pathways
  • Tissue-specific partner repertoire largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 2 R-HSA-73894 DNA Repair 1
Partners
DVL2FKBP51HSP90S100A6TRPC4
Complex memberships
ISOC channel heterocomplex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 LB-100 is a catalytic inhibitor of PPP5C that coordinates with the active-site metal ions and key conserved residues; crystal structure of PPP5C co-crystallized with LB-100 resolved to 1.65 Å shows the 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety of LB-100 coordinating with the catalytic metals. The phosphopeptide K-R-pT-I-R-R used to assign LB-100 specificity to PP2A is also a substrate for PPP5C. X-ray crystallography (1.65 Å co-crystal structure), in vitro inhibition assays with purified enzymes, substrate phosphopeptide assays, cell-based genetic disruption of PPP5C Molecular cancer therapeutics High 30679389
2011 PP5 (PPP5C) acts downstream of ATR kinase activation to dephosphorylate Chk1 at Ser-345 following UV light-induced DNA damage; genetic disruption of PP5 in mouse embryonic fibroblasts leads to enhanced and prolonged phosphorylation of Chk1-Ser345, increased p53-Ser18 phosphorylation, and increased p53 protein levels. A comparable role was confirmed in human cells. Cre/loxP conditional knockout mice, PP5-deficient mouse embryonic fibroblasts, siRNA knockdown in human cells, western blot for phosphorylation states The Journal of biological chemistry High 21921034
2018 PP5 (PPP5C) directly interacts with and dephosphorylates Dvl2, a key mediator of Wnt signalling. PP5 dephosphorylates Dvl2 at S143, the 10B5 cluster, and other sites. Knockdown of PP5 causes elevated Dvl2 phosphorylation at basal levels and upon Wnt stimulation. PP5 was found at the basal body of cilia where S143-phosphorylated Dvl2 also resides. PP5 and PP2A are not fully redundant in regulating Dvl2 phosphorylation. Co-immunoprecipitation, in vitro dephosphorylation assay, siRNA knockdown, immunofluorescence/localization in hTERT-RPE1 cells Scientific reports Medium 29426949
2017 PPP5C is a required component of the ISOC channel heterocomplex in pulmonary artery endothelial cells and mediates FKBP51-dependent inhibition of the store-operated calcium entry current (ISOC). Catalytically active PPP5C (but not catalytically inactive mutant) is required for FKBP51-mediated inhibition of ISOC. PPP5C co-precipitates with TRPC4, an essential ISOC channel subunit, and co-fractionates with the ISOC heterocomplex in membrane fractions. siRNA knockdown, genetic disruption in HEK293 cells, reintroduction of WT vs. catalytically inactive PP5C, cell fractionation, co-immunoprecipitation with TRPC4, electrophysiology, microscopy/impedance assays Pulmonary circulation High 29283027
2020 S100A6 activates PPP5C catalytic activity in pulmonary endothelial cells (activating tau-T231 dephosphorylation), translocates to the plasma membrane following ISOC activation, and interacts with the TRPC4 subunit of the ISOC channel. FKBP51-mediated inhibition of ISOC and calcium entry-induced barrier disruption require S100A6 in a PPP5C-dependent manner, placing S100A6 as a positive regulator of the PPP5C-FKBP51 axis. Co-immunoprecipitation (S100A6 with TRPC4), PPP5C activity assay (tau-T231 dephosphorylation), calcium imaging, ECIS barrier assay, live-cell imaging of S100A6 translocation, siRNA/genetic knockdown FASEB journal Medium 31916625
2022 A de novo missense variant in PPP5C (p.Ala47Thr) behaves as a loss-of-function (strong hypomorph or null) in C. elegans pph-5. The Ala48Thr variant suppresses neurite growth phenotypes and GABA signaling defects of mec-15 mutants, and suppresses embryonic lethality of sep-1 mutants, establishing epistatic relationships. The variant is non-dominant, consistent with haploinsufficiency as the disease mechanism. CRISPR knock-in of variant into C. elegans pph-5 ortholog, genetic epistasis assays (mec-15, sep-1 double mutants), neurite growth assay, GABA signaling assay, embryonic lethality assay Molecular genetics and metabolism Medium 35361529
2023 PPP5C possesses dual function as a serine/threonine phosphatase and a co-chaperone. Free PPP5C adopts an autoinhibitory conformation with low basal catalytic activity, and the TPR domain mediates interaction with HSP90 chaperone complexes. This self-inhibition mechanism underlies its monomeric enzyme form and distinguishes it from other PPP family phosphatases. Review synthesizing structural and biochemical data (structure-function analysis) European journal of medicinal chemistry Low 37054560
2014 PP5 (PPP5C) and PP1α share a common catalytic mechanism, and both enzymes are inhibited by natural compounds okadaic acid, microcystin, and cantharidin; a validated fluorescent phosphatase assay was developed demonstrating catalytic activity of purified PPP5C (Z'=0.93) amenable to inhibitor screening. In vitro fluorescent phosphatase assay with purified PPP5C, Z'-factor validation Assay and drug development technologies Medium 25383722
2018 PPP5C knockdown in prostate cancer cells promotes phosphorylation of JNK and ERK1/2, indicating that PPP5C normally dephosphorylates or suppresses these kinase signaling pathways. Lentivirus-mediated shRNA knockdown, western blot for phospho-JNK and phospho-ERK1/2 OncoTargets and therapy Low 30254472

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1975 Reovirus messenger RNA contains a methylated, blocked 5'-terminal structure: m-7G(5')ppp(5')G-MpCp-. Proceedings of the National Academy of Sciences of the United States of America 361 1054511
1976 The 5' end of poliovirus mRNA is not capped with m7G(5')ppp(5')Np. Proceedings of the National Academy of Sciences of the United States of America 243 174106
1975 The 5' end group of tobacco mosaic virus RNA is m7G5' ppp5' Gp. Nucleic acids research 170 168558
1975 5'-Terminal m-7G(5')ppp(5')G-m-p in vivo: identification in reovirus genome RNA. Proceedings of the National Academy of Sciences of the United States of America 133 1054852
2019 The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C. Molecular cancer therapeutics 50 30679389
1976 5'-terminus of Moloney murine leukemia virus 35s RNA is m7G5' ppp5' GmpCp. Journal of virology 40 185415
2011 Disruption of serine/threonine protein phosphatase 5 (PP5:PPP5c) in mice reveals a novel role for PP5 in the regulation of ultraviolet light-induced phosphorylation of serine/threonine protein kinase Chk1 (CHEK1). The Journal of biological chemistry 33 21921034
1975 m7G5'ppp5'GmptcpUp at the 5' terminus of reovirus messenger RNA. Nucleic acids research 32 1178520
1975 Relationship of the first step in protein synthesis to ppGpp: formation of A(5')ppp(5')Gpp. Proceedings of the National Academy of Sciences of the United States of America 26 170611
1984 Synthesis and biological activity of tubercidin analogues of ppp5'A2'p(5'A2'p)n5'A. Biochemistry 21 6466631
2018 PPP5C promotes cell proliferation and survival in human prostate cancer by regulating of the JNK and ERK1/2 phosphorylation. OncoTargets and therapy 15 30254472
2014 Knockdown of PPP5C inhibits growth of hepatocellular carcinoma cells in vitro. Applied biochemistry and biotechnology 15 25326185
2018 PP5 (PPP5C) is a phosphatase of Dvl2. Scientific reports 14 29426949
2014 Development and validation of a robust and sensitive assay for the discovery of selective inhibitors for serine/threonine protein phosphatases PP1α (PPP1C) and PP5 (PPP5C). Assay and drug development technologies 12 25383722
2023 Dual function of protein phosphatase 5 (PPP5C): An emerging therapeutic target for drug discovery. European journal of medicinal chemistry 10 37054560
2022 Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay. Molecular genetics and metabolism 10 35361529
2020 S100A6 is a positive regulator of PPP5C-FKBP51-dependent regulation of endothelial calcium signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 31916625
2017 Serine/threonine phosphatase 5 (PP5C/PPP5C) regulates the ISOC channel through a PP5C-FKBP51 axis. Pulmonary circulation 10 29283027
1985 Cordycepin analogs of ppp5'A2'p5'A2'p5'A (2-5A) inhibit protein synthesis through activation of the 2-5A-dependent endonuclease. The Journal of biological chemistry 10 3972841
2022 MiR-520a-5p/PPP5C regulation pattern is identified as the key to gemcitabine resistance in pancreatic cancer. Frontiers in oncology 9 35957917
1990 Inhibition of the RNA polymerase of vesicular stomatitis virus by ppp5'A2'p5'A and related compounds. Antiviral research 6 2160797
2021 MicroRNA-365b-3p represses the proliferation and promotes the apoptosis of non-small cell lung cancer cells by targeting PPP5C. Oncology letters 5 33777212
2016 Knockdown of protein phosphatase 5 (PPP5C) suppresses the growth of leukemic cell line U937. Cellular and molecular biology (Noisy-le-Grand, France) 4 27755948
1985 Detection of human autoantibodies specific for 5'-m7GMP and m7G(5')ppp(5')N. Biochemical and biophysical research communications 4 3873239
2025 PPP5C pathogenic variant identified: a potential key to gaining insight into developmental and epileptic encephalopathy? Molecular and cellular pediatrics 0 40172746
2023 [Retracted] MicroRNA‑365b‑3p represses the proliferation and promotes the apoptosis of non‑small cell lung cancer cells by targeting PPP5C. Oncology letters 0 37664662

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