{"gene":"PPP1CB","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1994,"finding":"PPP1CB (PP1β) was cloned from a human teratocarcinoma cDNA library and shown to encode a catalytic subunit of protein phosphatase 1. The gene was mapped to human chromosome 2q23 by FISH, and three distinct mRNAs (3.1 kb, 4.0 kb, 5.4 kb) arise from alternative splicing of the 3' noncoding region, with the 5.4 kb form enriched in skeletal muscle.","method":"cDNA cloning, Northern blotting, somatic cell hybrid analysis, fluorescence in situ hybridization (FISH)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 — direct molecular characterization and chromosomal mapping with multiple orthogonal methods","pmids":["8312365"],"is_preprint":false},{"year":1994,"finding":"PPP1CB chromosomal loci are conserved across human (2p23), rat (6q21-q23), and mouse (12D), indicating syntenic conservation. Despite high sequence identity, the three PP1 catalytic subunit genes (PPP1CA, PPP1CB, PPP1CG) are located on different chromosomes in each species.","method":"Fluorescence in situ hybridization (FISH) in human, rat, and mouse","journal":"Idengaku zasshi","confidence":"Medium","confidence_rationale":"Tier 2 — direct FISH mapping, single method, replicates findings of contemporaneous study","pmids":["7857673"],"is_preprint":false},{"year":2000,"finding":"PP1 (including PPP1CB) is part of a macromolecular complex on the ryanodine receptor 2 (RyR2) in cardiac muscle, co-assembling with FKBP12.6, PKA, PP2A, and the anchoring protein mAKAP. PKA hyperphosphorylation of RyR2 in failing human hearts dissociates FKBP12.6 and dysregulates channel function.","method":"Cosedimentation, co-immunoprecipitation, functional channel recording","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, cosedimentation, functional assay in native cardiac tissue; highly cited foundational study","pmids":["10830164"],"is_preprint":false},{"year":2005,"finding":"PP1 (including the β isoform, PPP1CB) dephosphorylates tau at multiple sites (Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404, Ser409) in vitro, with a Km of 8–12 µM similar to intraneuronal tau concentration. PP1 accounts for approximately 11% of total tau phosphatase activity in human brain.","method":"In vitro phosphatase assay with purified enzymes, quantitative phosphorylation site analysis","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro assay with site-specific quantification of substrate dephosphorylation","pmids":["16262633"],"is_preprint":false},{"year":2013,"finding":"A recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB is detected in >95% of CLL samples. The YPEL5/PPP1CB chimeric transcript encodes a truncated PPP1CB protein with diminished phosphatase activity. Silencing of PPP1CB in MEC1 and JVM3 cells enhanced proliferation and colony formation, indicating a role for PPP1CB as a negative regulator of B-cell leukemia cell growth.","method":"Paired-end transcriptome sequencing, qRT-PCR, Southern blotting, whole-genome sequencing, phosphatase activity assay, siRNA knockdown with proliferation/colony formation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphatase assay plus functional KD with cellular phenotype; multiple orthogonal methods","pmids":["23382248"],"is_preprint":false},{"year":2015,"finding":"PPP1CB acts as an adipogenic activator in 3T3-L1 cells. PPP1CB expression increases during early adipogenesis and in high-fat-diet-induced obesity. Knockdown of PPP1CB suppresses clonal expansion, inhibits C/EBPδ expression, and consequently reduces PPARγ, C/EBPα, adiponectin, and aP2 levels. PPP1CB links p38 MAPK activation to C/EBPδ expression in early adipogenesis.","method":"siRNA knockdown, Western blotting, qRT-PCR, oil red O staining, adipocyte differentiation assay, p38 pathway analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD with defined cellular phenotype and pathway placement, single lab","pmids":["26449462"],"is_preprint":false},{"year":2016,"finding":"De novo missense mutations in PPP1CB (e.g., p.Pro49Arg, p.Ala56Pro) cause a novel RASopathy resembling Noonan syndrome with loose anagen hair. These mutations affect highly conserved residues predicted to disrupt PP1 subunit binding and impair dephosphorylation of RAF1 within the RAS/MAPK pathway.","method":"Whole-exome sequencing, Sanger sequencing, bioinformatic conservation analysis, clinical phenotyping","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 — genetic identification with pathway inference; mechanistic impact on dephosphorylation predicted but not directly demonstrated in this paper","pmids":["27264673","27681385"],"is_preprint":false},{"year":2018,"finding":"LZTR1 binds to the RAF1-PPP1CB complex, as demonstrated by immunoprecipitation of endogenous LZTR1 followed by western blotting. siRNA knockdown of LZTR1 decreased levels of RAF1 phosphorylated at Ser259, implicating the RAF1-PPP1CB complex in dephosphorylation of RAF1 at Ser259 within the RAS/MAPK pathway.","method":"Endogenous immunoprecipitation, western blotting, siRNA knockdown","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP of endogenous proteins plus functional knockdown; single lab","pmids":["30368668"],"is_preprint":false},{"year":2018,"finding":"Chk1 directly interacts with MYPT1 and phosphorylates MYPT1 at Ser20, which is essential for MYPT1 interaction with PP1cβ (PPP1CB). The MYPT1-PP1cβ complex dephosphorylates and inactivates Plk1 during mitotic damage; Chk1 inhibition abolishes Ser20 phosphorylation and prevents MYPT1-PP1cβ-mediated Plk1 dephosphorylation.","method":"Proteomic screen, co-immunoprecipitation, in vitro kinase assay, mutagenesis (Ser20), cell biology assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay plus mutagenesis plus reciprocal Co-IP defining functional interaction","pmids":["29262732"],"is_preprint":false},{"year":2018,"finding":"PPP1CB (PP1cβ) is the dominant PP1 isoform (>90% of total PP1c) in mouse smooth muscle. Smooth muscle-specific conditional knockout of PPP1CB, but not PPP1CA or PPP1CG, decreased contractile force in bladder, ileal, and aortic tissues and reduced mouse survival. Both MYPT1-bound and unbound (soluble) pools of PP1cβ contribute to dephosphorylation of the myosin regulatory light chain (RLC).","method":"Isoelectric focusing, isoform-specific immunoblotting, conditional knockout (Cre-lox), ex vivo contractility assays, selective permeabilization with α-toxin and Triton X-100","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — conditional KO with specific phenotypic readout plus biochemical dissection of bound vs. unbound pools; multiple orthogonal methods","pmids":["30185619"],"is_preprint":false},{"year":2019,"finding":"TIMAP inhibits myosin phosphatase in endothelial cells by competing with MYPT1 for binding to PP1cβ (PPP1CB) and blocking the PP1cβ active site. TIMAP overexpression enhanced MLC2 phosphorylation in a manner requiring TIMAP-PP1cβ interaction; excess TIMAP reduced MYPT1-PP1cβ association and caused proteasomal MYPT1 degradation. Active-site inhibitor (microcystin-LR) binding confirmed that PP1cβ's catalytic site is occluded when bound to TIMAP.","method":"Co-immunoprecipitation, recombinant protein pulldown (GST-TIMAP + His-MLC2), TIMAP overexpression/silencing, TIMAP-PP1cβ binding mutant, microcystin-LR active-site binding assay, mouse TIMAP-KO tissue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted direct interaction, active-site inhibitor competition assay, mutagenesis of TIMAP-PP1cβ interface, KO mouse validation; multiple orthogonal methods","pmids":["31315927"],"is_preprint":false},{"year":2019,"finding":"Classical swine fever virus structural glycoprotein E2 specifically binds PPP1CB (identified by yeast two-hybrid) and this interaction was confirmed in CSFV-infected swine cells by co-immunoprecipitation and Proximity Ligation Assay. Pharmacological activation of the PP1 pathway decreased CSFV replication, while PPP1CB siRNA knockdown had no observed effect on viral replication.","method":"Yeast two-hybrid, co-immunoprecipitation, Proximity Ligation Assay, siRNA knockdown, pharmacological PP1 activation, viral replication assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction confirmed by two independent methods in infected cells; functional significance partially characterized","pmids":["30934875"],"is_preprint":false},{"year":2022,"finding":"Chebulinic acid inhibits PPP1CB phosphatase activity in vitro (IC50 = 300 nM against hydrolysis of 6,8-difluoro-4-methylumbelliferyl phosphate) and suppresses adipogenesis of 3T3-L1 preadipocytes by downregulating key transcription factors controlling differentiation.","method":"In vitro phosphatase activity assay, 3T3-L1 adipogenesis assay, natural product screen (1033 compounds)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct in vitro enzymatic assay plus cellular phenotype; single lab","pmids":["35055051"],"is_preprint":false},{"year":2024,"finding":"NSD3 binds to PPP1CB and p-STAT3 at the protein level, forming a trimeric complex. Within this complex, PPP1CB dephosphorylates p-STAT3, leading to suppression of HK2 transcription and inhibition of glycolysis in lung adenocarcinoma. The phosphatase activity of PPP1CB in this context is sensitive to CO2 concentration and pH.","method":"Co-immunoprecipitation, western blotting, in vivo tumor models, glucose uptake/lactate production assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP demonstrating trimeric complex with functional dephosphorylation of STAT3; single lab","pmids":["39119928"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase TRIP12 is recruited by OIP5 to bind and degrade PPP1CB via ubiquitination. PPP1CB degradation enhances YBX1 transcription factor activity (by reducing dephosphorylation of YBX1's regulatory targets) and increases IKKβ phosphorylation activity, triggering NF-κB signaling and contributing to chemoresistance in bladder cancer.","method":"Co-immunoprecipitation, western blotting, siRNA/CRISPR knockdown, in vivo tumor models, NF-κB reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP demonstrating TRIP12-PPP1CB interaction and ubiquitin-mediated degradation; functional consequence established in cell and animal models; single lab","pmids":["39155295"],"is_preprint":false}],"current_model":"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that dephosphorylates substrates including myosin regulatory light chain (RLC), RAF1 (at Ser259), PLK1, p-STAT3, and tau; it assembles into distinct holoenzyme complexes via regulatory subunits such as MYPT1 and SHOC2, and is essential for smooth muscle contraction, cell cycle progression, RAS/MAPK pathway regulation, and adipogenesis, with gain-of-function missense mutations causing a Noonan-like RASopathy and loss of function promoting leukemic cell proliferation."},"narrative":{"teleology":[{"year":1994,"claim":"Molecular cloning and chromosomal mapping established PPP1CB as a distinct PP1 catalytic subunit gene on human 2p23, with tissue-regulated alternative polyadenylation generating multiple transcripts enriched in skeletal muscle.","evidence":"cDNA cloning from human teratocarcinoma library, Northern blotting, FISH mapping in human/rat/mouse","pmids":["8312365","7857673"],"confidence":"High","gaps":["Functional distinction from PPP1CA and PPP1CG isoforms was not resolved","No information on regulatory subunit specificity for PP1cβ versus other isoforms"]},{"year":2000,"claim":"Identification of PP1 (including PP1cβ) as a resident phosphatase in a macromolecular signaling complex on ryanodine receptor 2 revealed how PP1 is physically targeted to ion channel substrates in cardiac muscle.","evidence":"Cosedimentation, co-immunoprecipitation, and functional channel recording on native cardiac RyR2 complexes","pmids":["10830164"],"confidence":"High","gaps":["PP1 isoform specificity within the RyR2 complex was not distinguished (PP1cα vs PP1cβ)","Direct phospho-site on RyR2 dephosphorylated by PP1cβ was not mapped"]},{"year":2005,"claim":"Reconstituted enzyme–substrate assays demonstrated that PP1 dephosphorylates tau at ten distinct phospho-sites with physiologically relevant kinetics, placing PP1cβ among the phosphatases maintaining neuronal tau phosphorylation balance.","evidence":"In vitro phosphatase assay with purified PP1 and site-specific phospho-tau quantification","pmids":["16262633"],"confidence":"High","gaps":["Relative contribution of PP1cβ versus PP1cα or PP1cγ to tau dephosphorylation in vivo was not determined","Regulatory subunit directing PP1 to tau was not identified"]},{"year":2013,"claim":"Discovery of a recurrent YPEL5–PPP1CB chimeric transcript in >95% of CLL patients, encoding a truncated protein with diminished phosphatase activity, combined with functional knockdown studies, established PP1cβ as a negative regulator of leukemic B-cell proliferation.","evidence":"Paired-end RNA-seq, phosphatase activity assay on chimeric protein, siRNA knockdown with proliferation and colony formation readouts in MEC1/JVM3 cells","pmids":["23382248"],"confidence":"High","gaps":["Direct substrate whose dephosphorylation suppresses CLL cell growth was not identified","Whether full-length PPP1CB re-expression rescues the proliferative phenotype was not tested"]},{"year":2016,"claim":"Identification of de novo missense mutations in PPP1CB as the cause of a Noonan-like RASopathy linked PP1cβ dysfunction to RAS/MAPK pathway hyperactivation in a developmental disorder context.","evidence":"Whole-exome sequencing of affected individuals, Sanger validation, clinical phenotyping","pmids":["27264673","27681385"],"confidence":"Medium","gaps":["Biochemical impact of Pro49Arg and Ala56Pro on phosphatase activity and regulatory subunit binding was predicted but not directly measured","No patient-derived cellular models or animal models reported","Gain-of-function versus loss-of-function mechanism was inferred, not demonstrated"]},{"year":2018,"claim":"Three contemporaneous studies defined PP1cβ holoenzyme biochemistry in specific tissues: MYPT1-PP1cβ dephosphorylates PLK1 during DNA damage (controlled by Chk1-mediated MYPT1 Ser20 phosphorylation), LZTR1 scaffolds RAF1-PP1cβ for RAF1 Ser259 dephosphorylation in RAS signaling, and conditional knockout showed PP1cβ is the dominant PP1 isoform (>90%) controlling myosin RLC dephosphorylation and smooth muscle contractility.","evidence":"In vitro kinase assay and Ser20 mutagenesis (Chk1–MYPT1–PP1cβ); endogenous IP and siRNA (LZTR1–RAF1–PP1cβ); smooth-muscle-specific Cre-lox KO with ex vivo contractility and isoform quantification","pmids":["29262732","30368668","30185619"],"confidence":"High","gaps":["Whether MYPT1-PP1cβ is the sole PLK1 phosphatase during mitotic damage or acts redundantly was not resolved","Structural basis for PP1cβ isoform preference of MYPT1 over PP1cα/γ was not determined"]},{"year":2019,"claim":"TIMAP was shown to inhibit the MYPT1-PP1cβ myosin phosphatase by competitively binding PP1cβ and occluding its active site, establishing regulatory subunit competition as a mechanism controlling PP1cβ holoenzyme identity and output in endothelial cells.","evidence":"Recombinant pulldown, TIMAP-PP1cβ binding mutant, microcystin-LR active-site competition, TIMAP-KO mouse tissue","pmids":["31315927"],"confidence":"High","gaps":["Quantitative binding affinities for TIMAP vs MYPT1 for PP1cβ were not determined","In vivo endothelial phenotype of TIMAP-PP1cβ disruption was not fully characterized"]},{"year":2015,"claim":"PPP1CB was identified as an adipogenic activator that links p38 MAPK signaling to C/EBPδ expression during early clonal expansion of preadipocytes, extending PP1cβ function to metabolic differentiation.","evidence":"siRNA knockdown in 3T3-L1 cells, oil red O staining, qRT-PCR and western blotting for adipogenic markers","pmids":["26449462"],"confidence":"Medium","gaps":["Direct substrate of PP1cβ in the p38–C/EBPδ axis was not identified","In vivo adipose tissue phenotype upon PPP1CB loss was not tested"]},{"year":2024,"claim":"Two studies expanded the substrate and regulatory landscape of PP1cβ: NSD3 scaffolds PP1cβ to dephosphorylate p-STAT3 and suppress glycolysis in lung adenocarcinoma, while TRIP12-mediated ubiquitination degrades PP1cβ to activate NF-κB signaling and promote chemoresistance in bladder cancer.","evidence":"Co-IP of NSD3–PPP1CB–p-STAT3 trimeric complex with in vivo tumor models; Co-IP and CRISPR/siRNA defining TRIP12–OIP5-mediated PPP1CB ubiquitination with NF-κB reporter assays","pmids":["39119928","39155295"],"confidence":"Medium","gaps":["NSD3-directed dephosphorylation of STAT3 by PP1cβ has not been reconstituted with purified components","Whether TRIP12-mediated degradation is PP1cβ-isoform-specific is unknown","CO2/pH sensitivity of PP1cβ phosphatase activity reported in the NSD3 study awaits independent replication"]},{"year":null,"claim":"Key unresolved questions include the structural basis for PP1cβ isoform-selective regulatory subunit binding, the direct biochemical mechanism of RASopathy-causing mutations, and the identity of the PP1cβ substrate(s) mediating its growth-suppressive role in CLL.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of a PP1cβ-specific holoenzyme distinguishing it from PP1cα or PP1cγ complexes","Biochemical characterization of Noonan-associated PPP1CB missense mutants is lacking","CLL-relevant PP1cβ substrates remain unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,8,9,10,12,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,14]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,13,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14]}],"complexes":["MYPT1-PP1cβ myosin phosphatase","RyR2 macromolecular signaling complex","LZTR1-RAF1-PP1cβ complex","NSD3-PPP1CB-STAT3 complex"],"partners":["MYPT1","TIMAP","LZTR1","RAF1","NSD3","TRIP12","OIP5","RYR2"],"other_free_text":[]},"mechanistic_narrative":"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that assembles into substrate-specific holoenzymes through regulatory subunits and dephosphorylates diverse targets including myosin regulatory light chain, PLK1, RAF1 (Ser259), p-STAT3, and tau, thereby controlling smooth muscle contraction, mitotic checkpoint signaling, RAS/MAPK pathway output, and neuronal phospho-tau homeostasis [PMID:30185619, PMID:29262732, PMID:30368668, PMID:39119928, PMID:16262633]. Regulatory subunit competition governs holoenzyme composition: MYPT1 targets PP1cβ to myosin for contractile regulation, while TIMAP competitively displaces MYPT1 and occludes the PP1cβ active site to inhibit myosin phosphatase activity in endothelial cells, and TRIP12-mediated ubiquitination degrades PP1cβ to relieve dephosphorylation of NF-κB pathway components [PMID:31315927, PMID:39155295]. De novo gain-of-function missense mutations in PPP1CB (e.g., Pro49Arg, Ala56Pro) cause a Noonan syndrome–like RASopathy with loose anagen hair [PMID:27264673, PMID:27681385]. Loss of PPP1CB phosphatase activity—via a recurrent YPEL5–PPP1CB chimeric transcript in chronic lymphocytic leukemia or via siRNA silencing—promotes leukemic cell proliferation, establishing PP1cβ as a growth-suppressive phosphatase in B-cell malignancy [PMID:23382248]."},"prefetch_data":{"uniprot":{"accession":"P62140","full_name":"Serine/threonine-protein phosphatase PP1-beta catalytic subunit","aliases":[],"length_aa":327,"mass_kda":37.2,"function":"Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase (PP1) is essential for cell division, it participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates the MAPK pathway activation (PubMed:35768504, PubMed:35831509, PubMed:36175670). The SMP complex specifically dephosphorylates the inhibitory phosphorylation at 'Ser-259' of RAF1 kinase, 'Ser-365' of BRAF kinase and 'Ser-214' of ARAF kinase, stimulating their kinase activities (PubMed:35768504, PubMed:35831509, PubMed:36175670). The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c (PubMed:35768504, PubMed:36175670)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P62140/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP1CB","classification":"Common Essential","n_dependent_lines":1094,"n_total_lines":1208,"dependency_fraction":0.9056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP1CB","total_profiled":1310},"omim":[{"mim_id":"617506","title":"NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 2; NSLH2","url":"https://www.omim.org/entry/617506"},{"mim_id":"616564","title":"NOONAN SYNDROME 10; NS10","url":"https://www.omim.org/entry/616564"},{"mim_id":"614032","title":"TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 4; TOX4","url":"https://www.omim.org/entry/614032"},{"mim_id":"613275","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 16B; PPP1R16B","url":"https://www.omim.org/entry/613275"},{"mim_id":"613245","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 12C; PPP1R12C","url":"https://www.omim.org/entry/613245"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP1CB"},"hgnc":{"alias_symbol":["PP1Cbeta","PPP1CD","PP1Cdelta","PP1B","PP-1B","PP1beta","PP1c","MP","PPP1beta"],"prev_symbol":[]},"alphafold":{"accession":"P62140","domains":[{"cath_id":"3.60.21.10","chopping":"49-294","consensus_level":"high","plddt":97.6766,"start":49,"end":294}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62140","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62140-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62140-F1-predicted_aligned_error_v6.png","plddt_mean":91.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP1CB","jax_strain_url":"https://www.jax.org/strain/search?query=PPP1CB"},"sequence":{"accession":"P62140","fasta_url":"https://rest.uniprot.org/uniprotkb/P62140.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62140/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62140"}},"corpus_meta":[{"pmid":"27264673","id":"PMC_27264673","title":"A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.","date":"2016","source":"American journal of medical genetics. 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\"pmids\": [\"8312365\", \"7857673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PPP1CB participates in the RAS/MAPK pathway by dephosphorylating RAF; de novo missense mutations (p.Pro49Arg, p.Ala56Pro) in PPP1CB cause a Noonan-like rasopathy, placing PPP1CB as a regulator of RAF dephosphorylation in this signaling cascade.\",\n      \"method\": \"Whole-exome sequencing of patients, functional inference from known SHOC2-PP1C complex role in RAF dephosphorylation, pathogenicity criteria assessment\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement inferred from genetic evidence and known biochemistry of the SHOC2-PP1C complex; direct RAF dephosphorylation assay not performed in this paper\",\n      \"pmids\": [\"27264673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LZTR1 binds to the RAF1-PPP1CB complex as demonstrated by co-immunoprecipitation of endogenous proteins; siRNA knockdown of LZTR1 decreased phosphorylation of RAF1 at Ser259, indicating that the RAF1-PPP1CB complex (with LZTR1) dephosphorylates RAF1 at Ser259 within the RAS/MAPK pathway.\",\n      \"method\": \"Immunoprecipitation of endogenous LZTR1 followed by western blotting; siRNA knockdown of LZTR1 with phospho-RAF1(Ser259) readout\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional siRNA knockdown with specific phosphorylation readout in single study\",\n      \"pmids\": [\"30368668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PP1cβ (PPP1CB) is the dominant PP1 catalytic isoform (>90% of total PP1c) in smooth muscle and is essential for myosin regulatory light chain (RLC) dephosphorylation and smooth muscle contraction; conditional smooth muscle-specific PP1cβ knockout reduced contractile force in bladder, ileum, and aorta. Both MYPT1-bound and soluble (MYPT1-unbound) forms of PP1cβ contribute to RLC dephosphorylation.\",\n      \"method\": \"Isoform-specific immunoblotting with isoelectric focusing; conditional smooth muscle-specific PP1cβ knockout mice; selective permeabilization with α-toxin vs. Triton X-100; ex vivo contractility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific contractile phenotype, biochemical fractionation of MYPT1-bound vs. unbound PP1cβ, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30185619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Chk1 phosphorylates MYPT1 at Ser20, which is required for MYPT1 to recruit PP1cβ (PPP1CB) to form a complex that dephosphorylates and inactivates Plk1 during mitotic damage; Chk1 inhibition abolishes this phosphorylation and disrupts MYPT1-PP1cβ interaction.\",\n      \"method\": \"Proteomic screen (co-immunoprecipitation), in vitro kinase assay (Chk1 phosphorylation of MYPT1 at Ser20), mutagenesis of MYPT1 Ser20, co-IP of MYPT1-PP1cβ complex, Plk1 phosphorylation readout\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay plus mutagenesis plus reciprocal Co-IP with defined functional readout (Plk1 dephosphorylation)\",\n      \"pmids\": [\"29262732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIMAP competes with MYPT1 for binding to PP1cβ (PPP1CB) in endothelial cells, blocking the PP1cβ active site and inhibiting myosin light chain (MLC2) phosphatase activity; TIMAP overexpression enhanced MLC2 phosphorylation, an effect dependent on TIMAP's ability to bind PP1cβ, while TIMAP silencing reduced MLC2 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins; recombinant GST-TIMAP pulldown with His-MLC2; TIMAP overexpression/silencing with MLC2 phosphorylation readout; microcystin-LR active-site binding assay; TIMAP mutant unable to bind PP1cβ as control\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstituted direct interaction, active-site inhibitor assay, reciprocal Co-IP, gain/loss-of-function with specific phosphorylation readout, and mutagenesis controls in single study\",\n      \"pmids\": [\"31315927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPP1CB promotes adipogenesis in 3T3-L1 preadipocytes; PPP1CB depletion suppressed clonal expansion and differentiation into mature adipocytes, decreased C/EBPδ expression, and attenuated downstream PPARγ, C/EBPα, adiponectin, and aP2. PPP1CB links p38 activation to C/EBPδ expression in early adipogenesis.\",\n      \"method\": \"PPP1CB knockdown in 3T3-L1 cells with adipogenic differentiation assay, RT-PCR and western blotting of adipogenic markers, p38 activation assessment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — clean KD with defined differentiation phenotype and marker readouts, but limited mechanistic depth (no direct substrate assay or interaction confirmed)\",\n      \"pmids\": [\"26449462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A YPEL5/PPP1CB RNA chimera encodes a truncated PPP1CB protein with diminished phosphatase activity; PPP1CB silencing enhanced proliferation and colony formation of CLL cells (MEC1 and JVM3), suggesting a tumor-suppressive phosphatase role in B-cell leukemia.\",\n      \"method\": \"Paired-end transcriptome sequencing, qRT-PCR, whole-genome sequencing, Southern blotting, expression of chimeric protein in mammalian cells with phosphatase activity assay, siRNA knockdown with proliferation/colony formation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro phosphatase activity assay of truncated protein plus loss-of-function proliferation assay, multiple orthogonal methods\",\n      \"pmids\": [\"23382248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PPP1CB is recruited by the E3 ubiquitin ligase TRIP12 (brought to TRIP12 via OIP5) for proteasomal degradation; PPP1CB degradation enhances IKKβ phosphorylation activity and promotes NF-κB signaling, and PPP1CB dephosphorylates YBX1 (reducing its transcriptional activity) in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of OIP5-TRIP12-PPP1CB complex, ubiquitination assay, siRNA/CRISPR KO of components, IKKβ phosphorylation and NF-κB reporter assays, in vivo xenograft with CRISPR gene circuit\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of multiprotein complex, functional KO with specific downstream phosphorylation readouts, but YBX1 dephosphorylation by PPP1CB not directly reconstituted\",\n      \"pmids\": [\"39155295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSD3 acts as an intermediary that binds both PPP1CB and phospho-STAT3 (p-STAT3), forming a trimeric complex; PPP1CB within this complex dephosphorylates p-STAT3, suppressing HK2 transcription and glycolysis in lung adenocarcinoma cells. The phosphatase function of PPP1CB in this context is sensitive to CO2 concentration and pH.\",\n      \"method\": \"Co-immunoprecipitation of NSD3-PPP1CB-p-STAT3 complex, western blotting of p-STAT3 levels upon NSD3 overexpression/knockdown, HK2 transcription and glycolysis assays, in vivo tumor models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of trimeric complex with functional dephosphorylation readout and metabolic assays, but STAT3 dephosphorylation by PPP1CB not reconstituted in vitro\",\n      \"pmids\": [\"39119928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Classical swine fever virus structural glycoprotein E2 specifically interacts with host PPP1CB; this interaction was demonstrated in infected swine cells and pharmacological activation of the PP1 pathway (via PPP1CB) negatively affects CSFV replication.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in CSFV-infected cells, proximity ligation assay, pharmacological PP1 activation/inhibition and siRNA knockdown with viral replication readout\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent interaction methods plus functional PP1 pathway manipulation with viral replication readout\",\n      \"pmids\": [\"30934875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PPP1CB::ALK fusion oncoprotein (PPP1CB exons 1-5 fused to ALK kinase domain) activates non-canonical STAT3 signaling and interacts with SHC1/SHC3 (but not SHP2, unlike ROS1 fusions); phosphoproteomic and transcriptomic analyses demonstrated fusion-specific oncogenic functions in infant-type hemispheric glioma cells.\",\n      \"method\": \"Affinity purification mass spectrometry, phosphoproteomics, transcriptomics, cell motility assays in cells expressing PPP1CB::ALK fusion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity purification MS identifying interactors plus phosphoproteomics with functional readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.27.656302\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that dephosphorylates substrates including RAF1 (at Ser259, within the SHOC2/LZTR1-RAF1-PP1cβ complex in the RAS/MAPK pathway), myosin regulatory light chain (as the catalytic component of myosin light chain phosphatase holoenzyme with MYPT1/TIMAP in smooth muscle and endothelial cells), Plk1 (recruited via MYPT1 phosphorylated by Chk1 at Ser20), and p-STAT3 (within an NSD3-bridged trimeric complex); PP1cβ activity is regulated by competing regulatory subunits (MYPT1, TIMAP) that control substrate access and active-site availability, and gain-of-function mutations in its catalytic domain cause a RASopathy (NSLH2) by dysregulating RAS/MAPK signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"PPP1CB (PP1β) was cloned from a human teratocarcinoma cDNA library and shown to encode a catalytic subunit of protein phosphatase 1. The gene was mapped to human chromosome 2q23 by FISH, and three distinct mRNAs (3.1 kb, 4.0 kb, 5.4 kb) arise from alternative splicing of the 3' noncoding region, with the 5.4 kb form enriched in skeletal muscle.\",\n      \"method\": \"cDNA cloning, Northern blotting, somatic cell hybrid analysis, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct molecular characterization and chromosomal mapping with multiple orthogonal methods\",\n      \"pmids\": [\"8312365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PPP1CB chromosomal loci are conserved across human (2p23), rat (6q21-q23), and mouse (12D), indicating syntenic conservation. Despite high sequence identity, the three PP1 catalytic subunit genes (PPP1CA, PPP1CB, PPP1CG) are located on different chromosomes in each species.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) in human, rat, and mouse\",\n      \"journal\": \"Idengaku zasshi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct FISH mapping, single method, replicates findings of contemporaneous study\",\n      \"pmids\": [\"7857673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PP1 (including PPP1CB) is part of a macromolecular complex on the ryanodine receptor 2 (RyR2) in cardiac muscle, co-assembling with FKBP12.6, PKA, PP2A, and the anchoring protein mAKAP. PKA hyperphosphorylation of RyR2 in failing human hearts dissociates FKBP12.6 and dysregulates channel function.\",\n      \"method\": \"Cosedimentation, co-immunoprecipitation, functional channel recording\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, cosedimentation, functional assay in native cardiac tissue; highly cited foundational study\",\n      \"pmids\": [\"10830164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PP1 (including the β isoform, PPP1CB) dephosphorylates tau at multiple sites (Ser199, Ser202, Thr205, Thr212, Ser214, Ser235, Ser262, Ser396, Ser404, Ser409) in vitro, with a Km of 8–12 µM similar to intraneuronal tau concentration. PP1 accounts for approximately 11% of total tau phosphatase activity in human brain.\",\n      \"method\": \"In vitro phosphatase assay with purified enzymes, quantitative phosphorylation site analysis\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro assay with site-specific quantification of substrate dephosphorylation\",\n      \"pmids\": [\"16262633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB is detected in >95% of CLL samples. The YPEL5/PPP1CB chimeric transcript encodes a truncated PPP1CB protein with diminished phosphatase activity. Silencing of PPP1CB in MEC1 and JVM3 cells enhanced proliferation and colony formation, indicating a role for PPP1CB as a negative regulator of B-cell leukemia cell growth.\",\n      \"method\": \"Paired-end transcriptome sequencing, qRT-PCR, Southern blotting, whole-genome sequencing, phosphatase activity assay, siRNA knockdown with proliferation/colony formation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphatase assay plus functional KD with cellular phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"23382248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPP1CB acts as an adipogenic activator in 3T3-L1 cells. PPP1CB expression increases during early adipogenesis and in high-fat-diet-induced obesity. Knockdown of PPP1CB suppresses clonal expansion, inhibits C/EBPδ expression, and consequently reduces PPARγ, C/EBPα, adiponectin, and aP2 levels. PPP1CB links p38 MAPK activation to C/EBPδ expression in early adipogenesis.\",\n      \"method\": \"siRNA knockdown, Western blotting, qRT-PCR, oil red O staining, adipocyte differentiation assay, p38 pathway analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"26449462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo missense mutations in PPP1CB (e.g., p.Pro49Arg, p.Ala56Pro) cause a novel RASopathy resembling Noonan syndrome with loose anagen hair. These mutations affect highly conserved residues predicted to disrupt PP1 subunit binding and impair dephosphorylation of RAF1 within the RAS/MAPK pathway.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, bioinformatic conservation analysis, clinical phenotyping\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic identification with pathway inference; mechanistic impact on dephosphorylation predicted but not directly demonstrated in this paper\",\n      \"pmids\": [\"27264673\", \"27681385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LZTR1 binds to the RAF1-PPP1CB complex, as demonstrated by immunoprecipitation of endogenous LZTR1 followed by western blotting. siRNA knockdown of LZTR1 decreased levels of RAF1 phosphorylated at Ser259, implicating the RAF1-PPP1CB complex in dephosphorylation of RAF1 at Ser259 within the RAS/MAPK pathway.\",\n      \"method\": \"Endogenous immunoprecipitation, western blotting, siRNA knockdown\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP of endogenous proteins plus functional knockdown; single lab\",\n      \"pmids\": [\"30368668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Chk1 directly interacts with MYPT1 and phosphorylates MYPT1 at Ser20, which is essential for MYPT1 interaction with PP1cβ (PPP1CB). The MYPT1-PP1cβ complex dephosphorylates and inactivates Plk1 during mitotic damage; Chk1 inhibition abolishes Ser20 phosphorylation and prevents MYPT1-PP1cβ-mediated Plk1 dephosphorylation.\",\n      \"method\": \"Proteomic screen, co-immunoprecipitation, in vitro kinase assay, mutagenesis (Ser20), cell biology assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay plus mutagenesis plus reciprocal Co-IP defining functional interaction\",\n      \"pmids\": [\"29262732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPP1CB (PP1cβ) is the dominant PP1 isoform (>90% of total PP1c) in mouse smooth muscle. Smooth muscle-specific conditional knockout of PPP1CB, but not PPP1CA or PPP1CG, decreased contractile force in bladder, ileal, and aortic tissues and reduced mouse survival. Both MYPT1-bound and unbound (soluble) pools of PP1cβ contribute to dephosphorylation of the myosin regulatory light chain (RLC).\",\n      \"method\": \"Isoelectric focusing, isoform-specific immunoblotting, conditional knockout (Cre-lox), ex vivo contractility assays, selective permeabilization with α-toxin and Triton X-100\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional KO with specific phenotypic readout plus biochemical dissection of bound vs. unbound pools; multiple orthogonal methods\",\n      \"pmids\": [\"30185619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIMAP inhibits myosin phosphatase in endothelial cells by competing with MYPT1 for binding to PP1cβ (PPP1CB) and blocking the PP1cβ active site. TIMAP overexpression enhanced MLC2 phosphorylation in a manner requiring TIMAP-PP1cβ interaction; excess TIMAP reduced MYPT1-PP1cβ association and caused proteasomal MYPT1 degradation. Active-site inhibitor (microcystin-LR) binding confirmed that PP1cβ's catalytic site is occluded when bound to TIMAP.\",\n      \"method\": \"Co-immunoprecipitation, recombinant protein pulldown (GST-TIMAP + His-MLC2), TIMAP overexpression/silencing, TIMAP-PP1cβ binding mutant, microcystin-LR active-site binding assay, mouse TIMAP-KO tissue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted direct interaction, active-site inhibitor competition assay, mutagenesis of TIMAP-PP1cβ interface, KO mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"31315927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Classical swine fever virus structural glycoprotein E2 specifically binds PPP1CB (identified by yeast two-hybrid) and this interaction was confirmed in CSFV-infected swine cells by co-immunoprecipitation and Proximity Ligation Assay. Pharmacological activation of the PP1 pathway decreased CSFV replication, while PPP1CB siRNA knockdown had no observed effect on viral replication.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, Proximity Ligation Assay, siRNA knockdown, pharmacological PP1 activation, viral replication assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction confirmed by two independent methods in infected cells; functional significance partially characterized\",\n      \"pmids\": [\"30934875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Chebulinic acid inhibits PPP1CB phosphatase activity in vitro (IC50 = 300 nM against hydrolysis of 6,8-difluoro-4-methylumbelliferyl phosphate) and suppresses adipogenesis of 3T3-L1 preadipocytes by downregulating key transcription factors controlling differentiation.\",\n      \"method\": \"In vitro phosphatase activity assay, 3T3-L1 adipogenesis assay, natural product screen (1033 compounds)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro enzymatic assay plus cellular phenotype; single lab\",\n      \"pmids\": [\"35055051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSD3 binds to PPP1CB and p-STAT3 at the protein level, forming a trimeric complex. Within this complex, PPP1CB dephosphorylates p-STAT3, leading to suppression of HK2 transcription and inhibition of glycolysis in lung adenocarcinoma. The phosphatase activity of PPP1CB in this context is sensitive to CO2 concentration and pH.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, in vivo tumor models, glucose uptake/lactate production assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP demonstrating trimeric complex with functional dephosphorylation of STAT3; single lab\",\n      \"pmids\": [\"39119928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase TRIP12 is recruited by OIP5 to bind and degrade PPP1CB via ubiquitination. PPP1CB degradation enhances YBX1 transcription factor activity (by reducing dephosphorylation of YBX1's regulatory targets) and increases IKKβ phosphorylation activity, triggering NF-κB signaling and contributing to chemoresistance in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, siRNA/CRISPR knockdown, in vivo tumor models, NF-κB reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP demonstrating TRIP12-PPP1CB interaction and ubiquitin-mediated degradation; functional consequence established in cell and animal models; single lab\",\n      \"pmids\": [\"39155295\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that dephosphorylates substrates including myosin regulatory light chain (RLC), RAF1 (at Ser259), PLK1, p-STAT3, and tau; it assembles into distinct holoenzyme complexes via regulatory subunits such as MYPT1 and SHOC2, and is essential for smooth muscle contraction, cell cycle progression, RAS/MAPK pathway regulation, and adipogenesis, with gain-of-function missense mutations causing a Noonan-like RASopathy and loss of function promoting leukemic cell proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that dephosphorylates diverse substrates through association with distinct regulatory subunits that dictate substrate specificity, subcellular targeting, and active-site accessibility. In smooth muscle, PP1cβ is the dominant PP1 catalytic isoform and dephosphorylates myosin regulatory light chain as part of the myosin light chain phosphatase holoenzyme with MYPT1, while the competing regulatory subunit TIMAP inhibits this activity by occluding the PP1cβ active site in endothelial cells [PMID:30185619, PMID:31315927]. PP1cβ also dephosphorylates RAF1 at Ser259 within a SHOC2/LZTR1-containing complex to regulate RAS/MAPK signaling, dephosphorylates Plk1 during the DNA damage response when recruited by Chk1-phosphorylated MYPT1, and dephosphorylates p-STAT3 via an NSD3-bridged trimeric complex [PMID:30368668, PMID:29262732, PMID:39119928]. Gain-of-function missense mutations in PPP1CB cause a Noonan-like RASopathy (Noonan syndrome-like disorder with loose anagen hair type 2) through dysregulated RAS/MAPK pathway signaling [PMID:27264673].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing gene identity: cloning of PPP1CB resolved that three distinct genes encode PP1 catalytic subunits in humans and placed PP1cβ at chromosome 2p23, providing the molecular framework for isoform-specific studies.\",\n      \"evidence\": \"cDNA cloning, Northern blotting, somatic cell hybrid analysis, and FISH in human cells\",\n      \"pmids\": [\"8312365\", \"7857673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No isoform-specific functional differences yet established\", \"Regulatory subunit partnerships not defined\", \"Tissue-specific expression patterns not fully characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A YPEL5/PPP1CB chimeric transcript in CLL cells produced a truncated PP1cβ with reduced phosphatase activity, and PPP1CB silencing enhanced leukemic cell proliferation, establishing a tumor-suppressive role for PP1cβ catalytic activity in B-cell malignancy.\",\n      \"evidence\": \"Paired-end RNA-seq discovery of chimeric transcript, phosphatase activity assay of truncated protein, siRNA knockdown with proliferation and colony formation readouts in CLL cell lines\",\n      \"pmids\": [\"23382248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate(s) mediating the anti-proliferative effect not identified\", \"Relevance beyond CLL cell lines not tested\", \"Truncated protein's dominant-negative potential not assessed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PPP1CB knockdown blocked adipocyte differentiation and attenuated p38-mediated C/EBPδ induction, revealing a role for PP1cβ in early adipogenic signaling beyond its known contractile and cell-cycle functions.\",\n      \"evidence\": \"siRNA knockdown in 3T3-L1 preadipocytes with adipogenic differentiation markers and p38 activation readouts\",\n      \"pmids\": [\"26449462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate linking PP1cβ to p38-C/EBPδ axis not identified\", \"No rescue experiment performed\", \"Mechanism of PP1cβ action on p38 pathway unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"De novo PPP1CB missense mutations were identified as causative for a Noonan-like RASopathy, genetically linking PP1cβ to RAS/MAPK pathway regulation in human disease.\",\n      \"evidence\": \"Whole-exome sequencing of patients with Noonan-like features; pathogenicity assessment based on known SHOC2-PP1C-RAF biochemistry\",\n      \"pmids\": [\"27264673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional consequence of specific mutations on phosphatase activity not assayed\", \"RAF dephosphorylation not directly measured with mutant PP1cβ\", \"Genotype-phenotype correlation limited by small patient numbers\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Three independent studies resolved distinct PP1cβ holoenzyme complexes and their substrates: LZTR1 participates in the RAF1-PP1cβ complex controlling RAF1 Ser259 dephosphorylation; Chk1-phosphorylated MYPT1 recruits PP1cβ to dephosphorylate Plk1 during mitotic DNA damage; and conditional smooth-muscle knockout demonstrated PP1cβ is the dominant isoform for myosin RLC dephosphorylation and contractile force generation.\",\n      \"evidence\": \"Co-IP of endogenous LZTR1-RAF1-PP1cβ with siRNA knockdown and phospho-RAF1 readout; in vitro Chk1 kinase assay, MYPT1-S20 mutagenesis, and Plk1 dephosphorylation readout; conditional smooth-muscle PP1cβ knockout mice with ex vivo contractility and isoform-specific biochemical fractionation\",\n      \"pmids\": [\"30368668\", \"29262732\", \"30185619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of LZTR1-RAF1-PP1cβ complex not available\", \"Relative contribution of MYPT1-bound vs. soluble PP1cβ to RLC dephosphorylation in vivo not quantified\", \"Whether Chk1-MYPT1-PP1cβ-Plk1 axis operates in non-transformed cells not confirmed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TIMAP was shown to compete with MYPT1 for PP1cβ binding and block the active site, establishing a regulatory subunit competition model that controls myosin phosphatase activity in endothelial cells.\",\n      \"evidence\": \"Reciprocal Co-IP of endogenous proteins, GST-TIMAP pulldown, microcystin-LR active-site accessibility assay, gain/loss-of-function with MLC2 phosphorylation readout, TIMAP mutant unable to bind PP1cβ as control\",\n      \"pmids\": [\"31315927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for TIMAP active-site occlusion not determined\", \"Whether other PP1 regulatory subunits similarly compete in endothelial cells not tested\", \"In vivo vascular phenotype of TIMAP-PP1cβ disruption not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Classical swine fever virus glycoprotein E2 was found to interact with host PP1cβ, and PP1 pathway activation suppressed viral replication, identifying PP1cβ as a host factor exploited during CSFV infection.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP in infected swine cells, proximity ligation assay, pharmacological PP1 activation/inhibition with viral replication readout\",\n      \"pmids\": [\"30934875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E2-PP1cβ interaction is direct or bridged by a regulatory subunit not resolved\", \"Mechanism by which PP1cβ activity suppresses CSFV replication unknown\", \"Relevance to other Flaviviridae not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TRIP12 E3 ubiquitin ligase was shown to target PP1cβ for proteasomal degradation (via adaptor OIP5), and PP1cβ degradation enhanced IKKβ phosphorylation and NF-κB signaling, revealing regulated PP1cβ turnover as a mechanism controlling inflammatory signaling in bladder cancer.\",\n      \"evidence\": \"Co-IP of OIP5-TRIP12-PPP1CB complex, ubiquitination assay, CRISPR KO with IKKβ phosphorylation and NF-κB reporter readouts, xenograft models\",\n      \"pmids\": [\"39155295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of IKKβ by PP1cβ not reconstituted in vitro\", \"YBX1 dephosphorylation by PP1cβ not directly demonstrated biochemically\", \"Whether TRIP12-mediated PP1cβ degradation occurs outside bladder cancer not known\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NSD3 was identified as a bridging factor that recruits PP1cβ to p-STAT3, forming a trimeric complex that dephosphorylates STAT3, suppresses HK2 transcription, and inhibits glycolysis in lung adenocarcinoma, establishing a metabolic regulatory axis for PP1cβ.\",\n      \"evidence\": \"Co-IP of NSD3-PPP1CB-p-STAT3 complex, p-STAT3 level changes upon NSD3 manipulation, HK2 transcription and glycolysis assays, in vivo tumor models\",\n      \"pmids\": [\"39119928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAT3 dephosphorylation by PP1cβ not reconstituted with purified components\", \"Which PP1cβ regulatory subunit interface NSD3 engages is unknown\", \"CO2/pH sensitivity mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A comprehensive structural and kinetic understanding of how different regulatory subunits (MYPT1, TIMAP, LZTR1/SHOC2, NSD3) achieve substrate selectivity on a single PP1cβ catalytic core remains unresolved, as does the full catalog of PP1cβ-specific (vs. PP1cα/γ-redundant) substrates in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of any PP1cβ-specific holoenzyme complex\", \"Isoform-specific substrate selectivity rules not established\", \"In vivo redundancy among PP1 catalytic isoforms not systematically assessed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"SHOC2/LZTR1-RAF1-PP1cβ complex\",\n      \"Myosin light chain phosphatase (MYPT1-PP1cβ)\",\n      \"NSD3-PP1cβ-STAT3 complex\"\n    ],\n    \"partners\": [\n      \"MYPT1\",\n      \"TIMAP\",\n      \"LZTR1\",\n      \"RAF1\",\n      \"NSD3\",\n      \"TRIP12\",\n      \"OIP5\",\n      \"SHOC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PPP1CB encodes the β catalytic subunit of protein phosphatase 1 (PP1cβ), a serine/threonine phosphatase that assembles into substrate-specific holoenzymes through regulatory subunits and dephosphorylates diverse targets including myosin regulatory light chain, PLK1, RAF1 (Ser259), p-STAT3, and tau, thereby controlling smooth muscle contraction, mitotic checkpoint signaling, RAS/MAPK pathway output, and neuronal phospho-tau homeostasis [PMID:30185619, PMID:29262732, PMID:30368668, PMID:39119928, PMID:16262633]. Regulatory subunit competition governs holoenzyme composition: MYPT1 targets PP1cβ to myosin for contractile regulation, while TIMAP competitively displaces MYPT1 and occludes the PP1cβ active site to inhibit myosin phosphatase activity in endothelial cells, and TRIP12-mediated ubiquitination degrades PP1cβ to relieve dephosphorylation of NF-κB pathway components [PMID:31315927, PMID:39155295]. De novo gain-of-function missense mutations in PPP1CB (e.g., Pro49Arg, Ala56Pro) cause a Noonan syndrome–like RASopathy with loose anagen hair [PMID:27264673, PMID:27681385]. Loss of PPP1CB phosphatase activity—via a recurrent YPEL5–PPP1CB chimeric transcript in chronic lymphocytic leukemia or via siRNA silencing—promotes leukemic cell proliferation, establishing PP1cβ as a growth-suppressive phosphatase in B-cell malignancy [PMID:23382248].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Molecular cloning and chromosomal mapping established PPP1CB as a distinct PP1 catalytic subunit gene on human 2p23, with tissue-regulated alternative polyadenylation generating multiple transcripts enriched in skeletal muscle.\",\n      \"evidence\": \"cDNA cloning from human teratocarcinoma library, Northern blotting, FISH mapping in human/rat/mouse\",\n      \"pmids\": [\"8312365\", \"7857673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional distinction from PPP1CA and PPP1CG isoforms was not resolved\",\n        \"No information on regulatory subunit specificity for PP1cβ versus other isoforms\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of PP1 (including PP1cβ) as a resident phosphatase in a macromolecular signaling complex on ryanodine receptor 2 revealed how PP1 is physically targeted to ion channel substrates in cardiac muscle.\",\n      \"evidence\": \"Cosedimentation, co-immunoprecipitation, and functional channel recording on native cardiac RyR2 complexes\",\n      \"pmids\": [\"10830164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"PP1 isoform specificity within the RyR2 complex was not distinguished (PP1cα vs PP1cβ)\",\n        \"Direct phospho-site on RyR2 dephosphorylated by PP1cβ was not mapped\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reconstituted enzyme–substrate assays demonstrated that PP1 dephosphorylates tau at ten distinct phospho-sites with physiologically relevant kinetics, placing PP1cβ among the phosphatases maintaining neuronal tau phosphorylation balance.\",\n      \"evidence\": \"In vitro phosphatase assay with purified PP1 and site-specific phospho-tau quantification\",\n      \"pmids\": [\"16262633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of PP1cβ versus PP1cα or PP1cγ to tau dephosphorylation in vivo was not determined\",\n        \"Regulatory subunit directing PP1 to tau was not identified\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of a recurrent YPEL5–PPP1CB chimeric transcript in >95% of CLL patients, encoding a truncated protein with diminished phosphatase activity, combined with functional knockdown studies, established PP1cβ as a negative regulator of leukemic B-cell proliferation.\",\n      \"evidence\": \"Paired-end RNA-seq, phosphatase activity assay on chimeric protein, siRNA knockdown with proliferation and colony formation readouts in MEC1/JVM3 cells\",\n      \"pmids\": [\"23382248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct substrate whose dephosphorylation suppresses CLL cell growth was not identified\",\n        \"Whether full-length PPP1CB re-expression rescues the proliferative phenotype was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of de novo missense mutations in PPP1CB as the cause of a Noonan-like RASopathy linked PP1cβ dysfunction to RAS/MAPK pathway hyperactivation in a developmental disorder context.\",\n      \"evidence\": \"Whole-exome sequencing of affected individuals, Sanger validation, clinical phenotyping\",\n      \"pmids\": [\"27264673\", \"27681385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical impact of Pro49Arg and Ala56Pro on phosphatase activity and regulatory subunit binding was predicted but not directly measured\",\n        \"No patient-derived cellular models or animal models reported\",\n        \"Gain-of-function versus loss-of-function mechanism was inferred, not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Three contemporaneous studies defined PP1cβ holoenzyme biochemistry in specific tissues: MYPT1-PP1cβ dephosphorylates PLK1 during DNA damage (controlled by Chk1-mediated MYPT1 Ser20 phosphorylation), LZTR1 scaffolds RAF1-PP1cβ for RAF1 Ser259 dephosphorylation in RAS signaling, and conditional knockout showed PP1cβ is the dominant PP1 isoform (>90%) controlling myosin RLC dephosphorylation and smooth muscle contractility.\",\n      \"evidence\": \"In vitro kinase assay and Ser20 mutagenesis (Chk1–MYPT1–PP1cβ); endogenous IP and siRNA (LZTR1–RAF1–PP1cβ); smooth-muscle-specific Cre-lox KO with ex vivo contractility and isoform quantification\",\n      \"pmids\": [\"29262732\", \"30368668\", \"30185619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MYPT1-PP1cβ is the sole PLK1 phosphatase during mitotic damage or acts redundantly was not resolved\",\n        \"Structural basis for PP1cβ isoform preference of MYPT1 over PP1cα/γ was not determined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TIMAP was shown to inhibit the MYPT1-PP1cβ myosin phosphatase by competitively binding PP1cβ and occluding its active site, establishing regulatory subunit competition as a mechanism controlling PP1cβ holoenzyme identity and output in endothelial cells.\",\n      \"evidence\": \"Recombinant pulldown, TIMAP-PP1cβ binding mutant, microcystin-LR active-site competition, TIMAP-KO mouse tissue\",\n      \"pmids\": [\"31315927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative binding affinities for TIMAP vs MYPT1 for PP1cβ were not determined\",\n        \"In vivo endothelial phenotype of TIMAP-PP1cβ disruption was not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PPP1CB was identified as an adipogenic activator that links p38 MAPK signaling to C/EBPδ expression during early clonal expansion of preadipocytes, extending PP1cβ function to metabolic differentiation.\",\n      \"evidence\": \"siRNA knockdown in 3T3-L1 cells, oil red O staining, qRT-PCR and western blotting for adipogenic markers\",\n      \"pmids\": [\"26449462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct substrate of PP1cβ in the p38–C/EBPδ axis was not identified\",\n        \"In vivo adipose tissue phenotype upon PPP1CB loss was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two studies expanded the substrate and regulatory landscape of PP1cβ: NSD3 scaffolds PP1cβ to dephosphorylate p-STAT3 and suppress glycolysis in lung adenocarcinoma, while TRIP12-mediated ubiquitination degrades PP1cβ to activate NF-κB signaling and promote chemoresistance in bladder cancer.\",\n      \"evidence\": \"Co-IP of NSD3–PPP1CB–p-STAT3 trimeric complex with in vivo tumor models; Co-IP and CRISPR/siRNA defining TRIP12–OIP5-mediated PPP1CB ubiquitination with NF-κB reporter assays\",\n      \"pmids\": [\"39119928\", \"39155295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NSD3-directed dephosphorylation of STAT3 by PP1cβ has not been reconstituted with purified components\",\n        \"Whether TRIP12-mediated degradation is PP1cβ-isoform-specific is unknown\",\n        \"CO2/pH sensitivity of PP1cβ phosphatase activity reported in the NSD3 study awaits independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for PP1cβ isoform-selective regulatory subunit binding, the direct biochemical mechanism of RASopathy-causing mutations, and the identity of the PP1cβ substrate(s) mediating its growth-suppressive role in CLL.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure of a PP1cβ-specific holoenzyme distinguishing it from PP1cα or PP1cγ complexes\",\n        \"Biochemical characterization of Noonan-associated PPP1CB missense mutants is lacking\",\n        \"CLL-relevant PP1cβ substrates remain unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 8, 9, 10, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 14]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 13, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"MYPT1-PP1cβ myosin phosphatase\",\n      \"RyR2 macromolecular signaling complex\",\n      \"LZTR1-RAF1-PP1cβ complex\",\n      \"NSD3-PPP1CB-STAT3 complex\"\n    ],\n    \"partners\": [\n      \"MYPT1\",\n      \"TIMAP\",\n      \"LZTR1\",\n      \"RAF1\",\n      \"NSD3\",\n      \"TRIP12\",\n      \"OIP5\",\n      \"RYR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}