{"gene":"PPP5C","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2019,"finding":"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.","method":"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","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, in vitro enzymatic assays with purified protein, and cell-based corroboration in a single rigorous study","pmids":["30679389"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Cre/loxP conditional knockout mice, PP5-deficient mouse embryonic fibroblasts, siRNA knockdown in human cells, western blot for phosphorylation states","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined phosphorylation readouts, replicated in both mouse and human cells","pmids":["21921034"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, in vitro dephosphorylation assay, siRNA knockdown, immunofluorescence/localization in hTERT-RPE1 cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct dephosphorylation assay plus Co-IP and knockdown phenotype, single lab","pmids":["29426949"],"is_preprint":false},{"year":2017,"finding":"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.","method":"siRNA knockdown, genetic disruption in HEK293 cells, reintroduction of WT vs. catalytically inactive PP5C, cell fractionation, co-immunoprecipitation with TRPC4, electrophysiology, microscopy/impedance assays","journal":"Pulmonary circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD/KO rescue with catalytic mutant, Co-IP, fractionation, functional electrophysiology) establishing catalytic requirement","pmids":["29283027"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphatase activity, functional barrier/calcium assays) in a single lab","pmids":["31916625"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in orthologous model system with multiple biological readouts, single lab","pmids":["35361529"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Review synthesizing structural and biochemical data (structure-function analysis)","journal":"European journal of medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review/synthesis paper, no primary experimental data presented","pmids":["37054560"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro fluorescent phosphatase assay with purified PPP5C, Z'-factor validation","journal":"Assay and drug development technologies","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with purified protein, single lab, single method","pmids":["25383722"],"is_preprint":false},{"year":2018,"finding":"PPP5C knockdown in prostate cancer cells promotes phosphorylation of JNK and ERK1/2, indicating that PPP5C normally dephosphorylates or suppresses these kinase signaling pathways.","method":"Lentivirus-mediated shRNA knockdown, western blot for phospho-JNK and phospho-ERK1/2","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (western blot after KD), no direct dephosphorylation assay","pmids":["30254472"],"is_preprint":false}],"current_model":"PPP5C is a monomeric serine/threonine protein phosphatase that adopts an autoinhibitory conformation (low basal activity) relieved by binding partners such as S100 proteins or HSP90 via its TPR domain; it dephosphorylates substrates including Chk1-Ser345 (downstream of ATR in the DNA damage response), Dvl2 (in Wnt signalling), and tau, and functions as a catalytic component of the ISOC channel heterocomplex where it is required, together with FKBP51 and S100A6, for inhibition of store-operated calcium entry in pulmonary endothelial cells; the drug LB-100 inhibits PPP5C by coordinating with its active-site metal ions, as revealed by a 1.65 Å co-crystal structure."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2011,"claim":"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","pmids":["21921034"],"confidence":"High","gaps":["Does not establish direct dephosphorylation of Chk1 by purified PPP5C in vitro","Recruitment mechanism to damage sites unresolved"]},{"year":2014,"claim":"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","pmids":["25383722"],"confidence":"Medium","gaps":["Single method, single lab","Does not address physiological substrates or regulation"]},{"year":2017,"claim":"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","pmids":["29283027"],"confidence":"High","gaps":["Direct phospho-substrate within the ISOC complex not identified","Structural basis of TRPC4 association unresolved"]},{"year":2018,"claim":"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","pmids":["29426949"],"confidence":"Medium","gaps":["Single lab; functional Wnt pathway output downstream of Dvl2 dephosphorylation not quantified","Degree of redundancy with PP2A not fully resolved"]},{"year":2018,"claim":"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","pmids":["30254472"],"confidence":"Low","gaps":["No direct dephosphorylation assay; effect may be indirect","Single method, single lab"]},{"year":2019,"claim":"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","pmids":["30679389"],"confidence":"High","gaps":["LB-100 selectivity between PPP5C and PP2A in cells not fully delineated","Effect of inhibitor on autoinhibited vs activated enzyme not addressed"]},{"year":2020,"claim":"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","pmids":["31916625"],"confidence":"Medium","gaps":["Single lab","Structural basis of S100A6-mediated activation not resolved"]},{"year":2022,"claim":"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","pmids":["35361529"],"confidence":"Medium","gaps":["Human disease phenotype and penetrance not characterized in this study","Molecular consequence on PPP5C catalysis/structure not directly measured"]},{"year":2023,"claim":"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","pmids":["37054560"],"confidence":"Low","gaps":["Review without new primary data","Quantitative contribution of HSP90 binding to substrate selection not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model of substrate targeting across pathways","Tissue-specific partner repertoire largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,4]}],"complexes":["ISOC channel heterocomplex"],"partners":["TRPC4","FKBP51","S100A6","HSP90","DVL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53041","full_name":"Serine/threonine-protein phosphatase 5","aliases":["Protein phosphatase T","PP-T","PPT"],"length_aa":499,"mass_kda":56.9,"function":"Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT (PubMed:14734805, PubMed:14764652, PubMed:14871926, PubMed:15383005, PubMed:15546861, PubMed:16260606, PubMed:16790549, PubMed:16892053, PubMed:19176521, PubMed:19948726, PubMed:21144835, PubMed:22399290, PubMed:22781750, PubMed:23102700, PubMed:30699359, PubMed:9000529). Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses (PubMed:14734805, PubMed:14764652, PubMed:14871926, PubMed:15383005, PubMed:15546861, PubMed:16260606, PubMed:16790549, PubMed:16892053, PubMed:19176521, PubMed:19948726, PubMed:21144835, PubMed:22399290, PubMed:22781750, PubMed:23102700, PubMed:30699359, PubMed:9000529). Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1 (PubMed:14871926, PubMed:16260606, PubMed:21144835). Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress (PubMed:23102700). Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function (By similarity). Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1 (By similarity). Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E (PubMed:16790549). May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels (PubMed:22781750). Dephosphorylates and may play a role in the regulation of TAU/MAPT (PubMed:15546861). Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2 (By similarity). Dephosphorylate FNIP1, disrupting interaction with HSP90AA1/Hsp90 (PubMed:30699359)","subcellular_location":"Nucleus; Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P53041/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP5C","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HSP90AA1","stoichiometry":0.2},{"gene":"HSP90AB1","stoichiometry":0.2},{"gene":"PIK3R1","stoichiometry":0.2},{"gene":"PLA2G4A","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP5C","total_profiled":1310},"omim":[{"mim_id":"615902","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B-DOUBLE PRIME, GAMMA; PPP2R3C","url":"https://www.omim.org/entry/615902"},{"mim_id":"615152","title":"KELCH DOMAIN-CONTAINING PROTEIN 10; KLHDC10","url":"https://www.omim.org/entry/615152"},{"mim_id":"611931","title":"PROTEIN PHOSPHATASE, MAGNESIUM/MANGANESE-DEPENDENT, 1L; PPM1L","url":"https://www.omim.org/entry/611931"},{"mim_id":"610302","title":"ENDOPLASMIC RETICULUM DEGRADATION-ENHANCING ALPHA-MANNOSIDASE-LIKE PROTEIN 2; EDEM2","url":"https://www.omim.org/entry/610302"},{"mim_id":"605065","title":"CELL DIVISION CYCLE 37, HSP90 COCHAPERONE; CDC37","url":"https://www.omim.org/entry/605065"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP5C"},"hgnc":{"alias_symbol":["PP5"],"prev_symbol":["PPP5"]},"alphafold":{"accession":"P53041","domains":[{"cath_id":"1.25.40.10","chopping":"21-150","consensus_level":"high","plddt":94.2268,"start":21,"end":150},{"cath_id":"3.60.21.10","chopping":"187-495","consensus_level":"high","plddt":96.602,"start":187,"end":495}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53041","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53041-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53041-F1-predicted_aligned_error_v6.png","plddt_mean":92.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP5C","jax_strain_url":"https://www.jax.org/strain/search?query=PPP5C"},"sequence":{"accession":"P53041","fasta_url":"https://rest.uniprot.org/uniprotkb/P53041.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53041/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53041"}},"corpus_meta":[{"pmid":"1054511","id":"PMC_1054511","title":"Reovirus messenger RNA contains a methylated, blocked 5'-terminal structure: m-7G(5')ppp(5')G-MpCp-.","date":"1975","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1054511","citation_count":361,"is_preprint":false},{"pmid":"174106","id":"PMC_174106","title":"The 5' end of poliovirus mRNA is not capped with m7G(5')ppp(5')Np.","date":"1976","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/174106","citation_count":243,"is_preprint":false},{"pmid":"168558","id":"PMC_168558","title":"The 5' end group of tobacco mosaic virus RNA is m7G5' ppp5' Gp.","date":"1975","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/168558","citation_count":170,"is_preprint":false},{"pmid":"1054852","id":"PMC_1054852","title":"5'-Terminal m-7G(5')ppp(5')G-m-p in vivo: identification in reovirus genome 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light-induced phosphorylation of serine/threonine protein kinase Chk1 (CHEK1).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21921034","citation_count":33,"is_preprint":false},{"pmid":"1178520","id":"PMC_1178520","title":"m7G5'ppp5'GmptcpUp at the 5' terminus of reovirus messenger RNA.","date":"1975","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1178520","citation_count":32,"is_preprint":false},{"pmid":"170611","id":"PMC_170611","title":"Relationship of the first step in protein synthesis to ppGpp: formation of A(5')ppp(5')Gpp.","date":"1975","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/170611","citation_count":26,"is_preprint":false},{"pmid":"6466631","id":"PMC_6466631","title":"Synthesis and biological activity of tubercidin analogues of ppp5'A2'p(5'A2'p)n5'A.","date":"1984","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6466631","citation_count":21,"is_preprint":false},{"pmid":"30254472","id":"PMC_30254472","title":"PPP5C promotes cell proliferation and survival in human prostate cancer by regulating of the JNK and ERK1/2 phosphorylation.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30254472","citation_count":15,"is_preprint":false},{"pmid":"25326185","id":"PMC_25326185","title":"Knockdown of PPP5C inhibits growth of hepatocellular carcinoma cells in vitro.","date":"2014","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/25326185","citation_count":15,"is_preprint":false},{"pmid":"29426949","id":"PMC_29426949","title":"PP5 (PPP5C) is a phosphatase of Dvl2.","date":"2018","source":"Scientific 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etiology","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.686570","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13570,"output_tokens":2631,"usd":0.040087,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9752,"output_tokens":3453,"usd":0.067543,"stage2_stop_reason":"end_turn"},"total_usd":0.10763,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, in vitro enzymatic assays with purified protein, and cell-based corroboration in a single rigorous study\",\n      \"pmids\": [\"30679389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Cre/loxP conditional knockout mice, PP5-deficient mouse embryonic fibroblasts, siRNA knockdown in human cells, western blot for phosphorylation states\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined phosphorylation readouts, replicated in both mouse and human cells\",\n      \"pmids\": [\"21921034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro dephosphorylation assay, siRNA knockdown, immunofluorescence/localization in hTERT-RPE1 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct dephosphorylation assay plus Co-IP and knockdown phenotype, single lab\",\n      \"pmids\": [\"29426949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, genetic disruption in HEK293 cells, reintroduction of WT vs. catalytically inactive PP5C, cell fractionation, co-immunoprecipitation with TRPC4, electrophysiology, microscopy/impedance assays\",\n      \"journal\": \"Pulmonary circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD/KO rescue with catalytic mutant, Co-IP, fractionation, functional electrophysiology) establishing catalytic requirement\",\n      \"pmids\": [\"29283027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphatase activity, functional barrier/calcium assays) in a single lab\",\n      \"pmids\": [\"31916625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in orthologous model system with multiple biological readouts, single lab\",\n      \"pmids\": [\"35361529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Review synthesizing structural and biochemical data (structure-function analysis)\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review/synthesis paper, no primary experimental data presented\",\n      \"pmids\": [\"37054560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro fluorescent phosphatase assay with purified PPP5C, Z'-factor validation\",\n      \"journal\": \"Assay and drug development technologies\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with purified protein, single lab, single method\",\n      \"pmids\": [\"25383722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPP5C knockdown in prostate cancer cells promotes phosphorylation of JNK and ERK1/2, indicating that PPP5C normally dephosphorylates or suppresses these kinase signaling pathways.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, western blot for phospho-JNK and phospho-ERK1/2\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (western blot after KD), no direct dephosphorylation assay\",\n      \"pmids\": [\"30254472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP5C is a monomeric serine/threonine protein phosphatase that adopts an autoinhibitory conformation (low basal activity) relieved by binding partners such as S100 proteins or HSP90 via its TPR domain; it dephosphorylates substrates including Chk1-Ser345 (downstream of ATR in the DNA damage response), Dvl2 (in Wnt signalling), and tau, and functions as a catalytic component of the ISOC channel heterocomplex where it is required, together with FKBP51 and S100A6, for inhibition of store-operated calcium entry in pulmonary endothelial cells; the drug LB-100 inhibits PPP5C by coordinating with its active-site metal ions, as revealed by a 1.65 Å co-crystal structure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #2, #3]. 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 [#4, #6]. 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 [#1]. 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 [#2]. 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 [#3, #4]. 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 [#0, #7]. 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 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established PPP5C as a phosphatase acting within the ATR-driven DNA damage response, answering which phosphatase restrains Chk1 activation after genotoxic stress.\",\n      \"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\",\n      \"pmids\": [\n        \"21921034\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not establish direct dephosphorylation of Chk1 by purified PPP5C in vitro\",\n        \"Recruitment mechanism to damage sites unresolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Fluorescent phosphatase assay with purified PPP5C, Z'=0.93 validation\",\n      \"pmids\": [\n        \"25383722\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single method, single lab\",\n        \"Does not address physiological substrates or regulation\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PPP5C as an obligatory catalytic subunit of the ISOC channel complex, answering how store-operated calcium entry is suppressed in pulmonary endothelium.\",\n      \"evidence\": \"siRNA/KO rescue with WT vs catalytically inactive PP5C, Co-IP with TRPC4, membrane fractionation, and electrophysiology in HEK293/endothelial cells\",\n      \"pmids\": [\n        \"29283027\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct phospho-substrate within the ISOC complex not identified\",\n        \"Structural basis of TRPC4 association unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Dvl2 as a direct PPP5C substrate in Wnt signalling and localized PPP5C to the ciliary basal body, connecting the phosphatase to developmental signalling.\",\n      \"evidence\": \"Co-IP, in vitro dephosphorylation assay, siRNA knockdown, and immunofluorescence in hTERT-RPE1 cells\",\n      \"pmids\": [\n        \"29426949\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; functional Wnt pathway output downstream of Dvl2 dephosphorylation not quantified\",\n        \"Degree of redundancy with PP2A not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked PPP5C loss to elevated JNK and ERK1/2 phosphorylation in prostate cancer cells, implicating it in suppression of MAPK signalling.\",\n      \"evidence\": \"Lentiviral shRNA knockdown and phospho-Western for JNK and ERK1/2\",\n      \"pmids\": [\n        \"30254472\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct dephosphorylation assay; effect may be indirect\",\n        \"Single method, single lab\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved how the inhibitor LB-100 engages PPP5C, defining the active-site coordination chemistry and confirming substrate overlap with PP2A.\",\n      \"evidence\": \"1.65 Å co-crystal structure of PPP5C with LB-100, in vitro inhibition assays with purified enzymes, and cell-based PPP5C disruption\",\n      \"pmids\": [\n        \"30679389\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"LB-100 selectivity between PPP5C and PP2A in cells not fully delineated\",\n        \"Effect of inhibitor on autoinhibited vs activated enzyme not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\n        \"31916625\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab\",\n        \"Structural basis of S100A6-mediated activation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\n        \"35361529\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Human disease phenotype and penetrance not characterized in this study\",\n        \"Molecular consequence on PPP5C catalysis/structure not directly measured\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Synthesized the dual phosphatase/co-chaperone model in which TPR-mediated autoinhibition keeps PPP5C low-activity and HSP90 binding modulates the enzyme.\",\n      \"evidence\": \"Review synthesizing structural and biochemical structure-function data\",\n      \"pmids\": [\n        \"37054560\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Review without new primary data\",\n        \"Quantitative contribution of HSP90 binding to substrate selection not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unifying model of substrate targeting across pathways\",\n        \"Tissue-specific partner repertoire largely uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          2,\n          3,\n          7\n        ]\n      },\n      {\n        \"term_id\": \"GO:0016787\",\n        \"supporting_discovery_ids\": [\n          0,\n          7\n        ]\n      },\n      {\n        \"term_id\": \"GO:0044183\",\n        \"supporting_discovery_ids\": [\n          6\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005929\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [\n          3,\n          4\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-73894\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [\n          2,\n          3,\n          4\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-382551\",\n        \"supporting_discovery_ids\": [\n          3,\n          4\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"ISOC channel heterocomplex\"\n    ],\n    \"partners\": [\n      \"TRPC4\",\n      \"FKBP51\",\n      \"S100A6\",\n      \"HSP90\",\n      \"DVL2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}