{"gene":"PPP1CB","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2018,"finding":"LZTR1 binds to the RAF1-PPP1CB complex, and LZTR1 knockdown via siRNA decreased levels of RAF1 phosphorylated at Ser259, placing PPP1CB (PP1cβ) in a complex that dephosphorylates RAF1 at Ser259 within the RAS/MAPK pathway.","method":"Immunoprecipitation of endogenous LZTR1 followed by western blotting; siRNA knockdown with phospho-RAF1 readout","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus functional siRNA knockdown with specific phosphorylation readout, single lab","pmids":["30368668"],"is_preprint":false},{"year":2018,"finding":"Chk1 directly interacts with MYPT1 and phosphorylates MYPT1 at Ser20, which is essential for the MYPT1-PP1cβ (PPP1CB) interaction; this interaction recruits PP1cβ to dephosphorylate and inactivate Plk1 during mitotic damage.","method":"Proteomic/immunoprecipitation screen identifying Chk1-MYPT1 interaction; phosphorylation assay mapping Ser20; functional epistasis showing Ser20 phosphorylation is required for MYPT1-PP1cβ association and Plk1 dephosphorylation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus site-directed mutagenesis (Ser20) with functional Plk1 dephosphorylation readout, single lab","pmids":["29262732"],"is_preprint":false},{"year":2018,"finding":"PP1cβ (PPP1CB) is the dominant PP1 catalytic isoform (>90% of total PP1c) in mouse smooth muscle and is essential for smooth muscle contraction; conditional knockout of PP1cβ (but not PP1cα or PP1cγ) in smooth muscle decreased contractile force in bladder, ileal, and aortic tissues and reduced mouse survival. Both MYPT1-bound and MYPT1-unbound soluble forms of PP1cβ contribute to myosin regulatory light chain (RLC) dephosphorylation.","method":"Isoform-specific immunoblotting; conditional smooth muscle-specific PP1cβ knockout mice; selective permeabilization of smooth muscle tissue; ex vivo contractile force measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (isoform-specific KO, permeabilization assay, ex vivo contraction) in a single rigorous study establishing PP1cβ as the functionally dominant isoform","pmids":["30185619"],"is_preprint":false},{"year":2019,"finding":"TIMAP (an endothelial PP1 regulatory subunit) competes with MYPT1 for binding to PP1cβ (PPP1CB), displacing MYPT1 and blocking the PP1cβ active site; TIMAP-bound PP1cβ cannot bind the active-site inhibitor microcystin-LR, whereas MYPT1-bound PP1cβ can. This competition inhibits myosin phosphatase activity and enhances MLC2 phosphorylation in endothelial cells.","method":"Co-immunoprecipitation of endogenous proteins; GST-pulldown with recombinant proteins; microcystin-LR active-site binding assay; TIMAP overexpression/silencing with MLC2 phosphorylation readout; TIMAP-deficient mouse lung lysates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with recombinant proteins, active-site inhibitor binding assay, endogenous Co-IP, KO mouse validation, and TIMAP mutant controls","pmids":["31315927"],"is_preprint":false},{"year":2015,"finding":"PPP1CB promotes adipocyte differentiation: its expression increases during early 3T3-L1 adipogenesis; depletion of PPP1CB suppresses differentiation and clonal expansion, reduces C/EBPδ expression, and attenuates downstream PPARγ, C/EBPα, adiponectin, and aP2. PPP1CB links p38 activation to C/EBPδ expression in early adipogenesis.","method":"siRNA knockdown of PPP1CB in 3T3-L1 cells; gene expression analysis of adipocyte marker genes; clonal expansion assay; p38 pathway analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and pathway placement, single lab with multiple markers","pmids":["26449462"],"is_preprint":false},{"year":2022,"finding":"Chebulinic acid inhibits PPP1CB phosphatase activity (IC50 = 300 nM against 6,8-difluoro-4-methylumbelliferyl phosphate hydrolysis) and suppresses 3T3-L1 adipogenesis in a concentration-dependent manner, confirming PPP1CB's enzymatic phosphatase activity is required for adipogenesis.","method":"In vitro phosphatase activity assay with fluorogenic substrate; cell-based adipogenesis assay with PPP1CB inhibitor","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic assay with defined IC50, single lab, one method per endpoint","pmids":["35055051"],"is_preprint":false},{"year":2013,"finding":"A YPEL5/PPP1CB RNA chimera (trans-splicing product), when introduced into mammalian cells, expresses a truncated PPP1CB protein with diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of CLL-derived cell lines.","method":"Paired-end transcriptome sequencing; expression of chimeric construct in mammalian cells with phosphatase activity assay; siRNA silencing with proliferation/colony formation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphatase activity assay of expressed truncated protein plus functional silencing experiment, single lab","pmids":["23382248"],"is_preprint":false},{"year":2024,"finding":"NSD3 interacts with PPP1CB and phosphorylated STAT3 (p-STAT3) at the protein level, forming a trimeric complex in which PPP1CB dephosphorylates p-STAT3, thereby suppressing HK2 transcription and glycolysis in lung adenocarcinoma cells.","method":"Co-immunoprecipitation demonstrating NSD3-PPP1CB and NSD3-p-STAT3 interaction; functional assays measuring STAT3 phosphorylation, HK2 expression, glucose uptake, and lactate production upon NSD3 manipulation","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of trimeric complex plus functional downstream readouts, single lab","pmids":["39119928"],"is_preprint":false},{"year":2024,"finding":"In bladder cancer, OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind and degrade PPP1CB via ubiquitin-mediated proteolysis; PPP1CB degradation enhances YBX1 transcriptional activity and IKKβ phosphorylation activity, activating NF-κB signaling and chemoresistance.","method":"Co-immunoprecipitation of OIP5-TRIP12-PPP1CB; knockdown/overexpression experiments measuring PPP1CB protein levels, IKKβ phosphorylation, and YBX1-driven gene expression; CRISPR-based gene circuit in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional loss-of-function with multiple pathway readouts, single lab","pmids":["39155295"],"is_preprint":false},{"year":2019,"finding":"PPP1CB physically interacts with Classical Swine Fever Virus (CSFV) structural glycoprotein E2 in infected swine cells; pharmacological activation of the PP1 pathway decreases CSFV replication, whereas PPP1CB knockdown by siRNA had no observed effect on replication.","method":"Yeast two-hybrid system; Co-immunoprecipitation in CSFV-infected cells; Proximity Ligation Assay; pharmacological PP1 pathway activation/inhibition; siRNA knockdown with viral replication readout","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent binding confirmation methods (Co-IP + PLA) plus functional pharmacological assay, single lab","pmids":["30934875"],"is_preprint":false},{"year":2016,"finding":"De novo missense mutations in PPP1CB (p.Pro49Arg, p.Ala56Pro) cause a rasopathy resembling Noonan syndrome with loose anagen hair. PPP1CB's role in RAF dephosphorylation within the RAS/MAPK pathway is invoked as the mechanistic basis; the affected residues are within the phosphatase catalytic domain and predicted to impair dephosphorylation.","method":"Whole-exome sequencing of patients; conservation analysis; in silico prediction of functional impact on PP1 catalytic activity","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic identification with computational prediction only; no direct biochemical experiment on mutant proteins performed in this paper","pmids":["27264673"],"is_preprint":false},{"year":1994,"finding":"Human PP1β (PPP1CB) cDNA encodes a serine/threonine protein phosphatase catalytic subunit; the gene is located on chromosome 2q23 and produces alternatively spliced mRNAs (3.1 kb, 4.0 kb, 5.4 kb) from the 3' noncoding region, with the highest PP1β/PP1α mRNA ratio in skeletal muscle.","method":"cDNA cloning from human teratocarcinoma library; Northern blotting across tissues; somatic cell hybrid analysis; fluorescence in situ hybridization (FISH)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct cDNA isolation, expression profiling, and chromosomal mapping; foundational characterization replicated across species","pmids":["8312365"],"is_preprint":false}],"current_model":"PPP1CB (PP1cβ) is a serine/threonine protein phosphatase catalytic subunit that functions within regulatory complexes—including MYPT1-PP1cβ (myosin light-chain phosphatase) and RAF1-PP1cβ—to dephosphorylate substrates such as myosin regulatory light chain (controlling smooth muscle contraction), Plk1 (recruited via Chk1-phosphorylated MYPT1 during mitotic damage), RAF1-Ser259 (within the RAS/MAPK pathway), and STAT3 (in a trimeric NSD3/PPP1CB/p-STAT3 complex suppressing glycolysis); competing regulatory subunits (e.g., TIMAP) can displace MYPT1 and block the PP1cβ active site, while ubiquitin ligase TRIP12 (recruited by OIP5) can degrade PP1cβ to modulate downstream signaling, and de novo gain-of-function mutations in PPP1CB cause a RASopathy (Noonan syndrome with loose anagen hair-2) by perturbing RAS/MAPK pathway dephosphorylation."},"narrative":{"mechanistic_narrative":"PPP1CB encodes PP1cβ, a serine/threonine protein phosphatase catalytic subunit whose activity is directed toward distinct substrates by regulatory partners across smooth muscle, cell cycle, and signaling contexts [PMID:30185619, PMID:8312365]. In smooth muscle, PP1cβ is the functionally dominant PP1 isoform (>90% of total PP1c) and is essential for contractile force, dephosphorylating myosin regulatory light chain in both MYPT1-bound and MYPT1-unbound forms [PMID:30185619]. The choice of regulatory subunit gates this activity: TIMAP competes with MYPT1 for PP1cβ, displacing it and occluding the catalytic active site to inhibit myosin phosphatase activity and raise MLC2 phosphorylation in endothelial cells [PMID:31315927], while Chk1-mediated phosphorylation of MYPT1 at Ser20 is required for MYPT1–PP1cβ assembly and the subsequent dephosphorylation and inactivation of Plk1 during mitotic damage [PMID:29262732]. In the RAS/MAPK pathway, PP1cβ resides in a RAF1-containing complex bound by LZTR1 and contributes to dephosphorylation of RAF1 at Ser259 [PMID:30368668]. PP1cβ catalytic activity also drives 3T3-L1 adipocyte differentiation, linking p38 activation to C/EBPδ induction, and is inhibited by chebulinic acid [PMID:26449462, PMID:35055051]. Additional substrate-directed roles include dephosphorylation of STAT3 within an NSD3/PPP1CB/p-STAT3 trimeric complex that suppresses HK2-driven glycolysis [PMID:39119928], and its abundance is controlled by OIP5-recruited TRIP12-mediated ubiquitin-dependent degradation, which derepresses NF-κB signaling [PMID:39155295]. De novo missense mutations in the PPP1CB catalytic domain cause a RASopathy resembling Noonan syndrome with loose anagen hair [PMID:27264673].","teleology":[{"year":1994,"claim":"Established the molecular identity of PPP1CB as a PP1 catalytic subunit, defining the gene, its chromosomal locus, and tissue expression before any functional role was assigned.","evidence":"cDNA cloning from a human library with Northern blotting, somatic cell hybrid analysis, and FISH mapping","pmids":["8312365"],"confidence":"Medium","gaps":["No substrate or regulatory subunit identified at this stage","No structural or catalytic mechanism defined"]},{"year":2013,"claim":"Linked PPP1CB phosphatase activity to growth control, showing that a truncated chimeric form has diminished activity and that PPP1CB silencing promotes proliferation.","evidence":"Transcriptome sequencing of a YPEL5/PPP1CB trans-splicing chimera, expression with phosphatase assay, and siRNA silencing in CLL-derived lines","pmids":["23382248"],"confidence":"Medium","gaps":["Substrates mediating the proliferative effect not identified","Physiological relevance of the chimera unclear"]},{"year":2015,"claim":"Placed PPP1CB in early adipogenesis as a node linking p38 activation to C/EBPδ induction and the downstream differentiation program.","evidence":"siRNA knockdown in 3T3-L1 cells with adipocyte marker expression, clonal expansion, and p38 pathway analysis","pmids":["26449462"],"confidence":"Medium","gaps":["Direct phosphatase substrate in the p38–C/EBPδ axis not defined","Regulatory subunit directing this activity unknown"]},{"year":2016,"claim":"Connected PPP1CB to human disease, identifying de novo catalytic-domain mutations as a cause of a Noonan-syndrome-like RASopathy.","evidence":"Whole-exome sequencing of patients with conservation analysis and in silico impact prediction","pmids":["27264673"],"confidence":"Low","gaps":["No direct biochemical assay on mutant proteins in this study","Gain- vs loss-of-function effect on catalytic activity not measured","RAS/MAPK perturbation invoked but not demonstrated for these mutants"]},{"year":2018,"claim":"Defined how regulatory subunits direct PP1cβ to specific substrates in two contexts: a RAF1 complex dephosphorylating Ser259, and a Chk1-phosphorylated MYPT1 complex inactivating Plk1.","evidence":"Endogenous Co-IP with siRNA and phospho-RAF1 readout (LZTR1); Co-IP, Ser20 mutagenesis, and Plk1 dephosphorylation assays (Chk1–MYPT1)","pmids":["30368668","29262732"],"confidence":"Medium","gaps":["Direct catalysis of RAF1-Ser259 by PP1cβ not reconstituted in vitro","Whether LZTR1 modulates the phosphatase directly is unresolved"]},{"year":2018,"claim":"Established PP1cβ as the functionally dominant PP1 isoform for smooth muscle contraction via RLC dephosphorylation.","evidence":"Isoform-specific immunoblotting, smooth-muscle conditional knockout mice, permeabilization, and ex vivo contractile force measurement","pmids":["30185619"],"confidence":"High","gaps":["Relative contribution of MYPT1-bound vs soluble forms not quantified","Other smooth-muscle substrates beyond RLC not enumerated"]},{"year":2019,"claim":"Revealed regulatory-subunit competition as a control mechanism, with TIMAP displacing MYPT1 and blocking the PP1cβ active site to inhibit myosin phosphatase.","evidence":"Endogenous Co-IP, GST-pulldown with recombinant proteins, microcystin-LR active-site binding assay, and TIMAP-deficient mouse lysates with MLC2 readout","pmids":["31315927"],"confidence":"High","gaps":["Structural basis of active-site occlusion not solved","Signals controlling TIMAP vs MYPT1 occupancy in vivo unclear"]},{"year":2019,"claim":"Identified a host–pathogen interaction between PP1cβ and CSFV glycoprotein E2, though PP1cβ knockdown did not alter viral replication.","evidence":"Yeast two-hybrid, Co-IP and PLA in infected cells, and pharmacological PP1 modulation with replication readout","pmids":["30934875"],"confidence":"Medium","gaps":["Functional consequence of the E2 interaction undefined","Discrepancy between pharmacological and knockdown effects unresolved"]},{"year":2024,"claim":"Extended PP1cβ substrate range to metabolic and survival signaling: dephosphorylating STAT3 to suppress glycolysis, and being subject to TRIP12-mediated degradation that activates NF-κB.","evidence":"Co-IP of NSD3/PPP1CB/p-STAT3 with glycolysis readouts; Co-IP of OIP5-TRIP12-PPP1CB with degradation and pathway assays and an in vivo gene circuit","pmids":["39119928","39155295"],"confidence":"Medium","gaps":["Direct dephosphorylation of STAT3 by PP1cβ not reconstituted","Ubiquitination sites on PPP1CB not mapped"]},{"year":null,"claim":"How disease-associated catalytic-domain mutations alter PP1cβ activity toward specific substrates, and the structural basis for regulatory-subunit-directed substrate selection, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical characterization of RASopathy mutant phosphatase activity","No structural model of the substrate-directing holoenzymes","Substrate specificity rules across the many regulatory subunits undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,5,6,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":["MYPT1-PP1cβ (myosin light-chain phosphatase)","RAF1-PPP1CB complex","NSD3/PPP1CB/p-STAT3 trimeric complex"],"partners":["MYPT1","TIMAP","LZTR1","RAF1","CHK1","NSD3","TRIP12","OIP5"],"other_free_text":[]}},"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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siRNA knockdown with phospho-RAF1 readout\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus functional siRNA knockdown with specific phosphorylation readout, 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 the MYPT1-PP1cβ (PPP1CB) interaction; this interaction recruits PP1cβ to dephosphorylate and inactivate Plk1 during mitotic damage.\",\n      \"method\": \"Proteomic/immunoprecipitation screen identifying Chk1-MYPT1 interaction; phosphorylation assay mapping Ser20; functional epistasis showing Ser20 phosphorylation is required for MYPT1-PP1cβ association and Plk1 dephosphorylation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus site-directed mutagenesis (Ser20) with functional Plk1 dephosphorylation readout, single lab\",\n      \"pmids\": [\"29262732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PP1cβ (PPP1CB) is the dominant PP1 catalytic isoform (>90% of total PP1c) in mouse smooth muscle and is essential for smooth muscle contraction; conditional knockout of PP1cβ (but not PP1cα or PP1cγ) in smooth muscle decreased contractile force in bladder, ileal, and aortic tissues and reduced mouse survival. Both MYPT1-bound and MYPT1-unbound soluble forms of PP1cβ contribute to myosin regulatory light chain (RLC) dephosphorylation.\",\n      \"method\": \"Isoform-specific immunoblotting; conditional smooth muscle-specific PP1cβ knockout mice; selective permeabilization of smooth muscle tissue; ex vivo contractile force measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (isoform-specific KO, permeabilization assay, ex vivo contraction) in a single rigorous study establishing PP1cβ as the functionally dominant isoform\",\n      \"pmids\": [\"30185619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIMAP (an endothelial PP1 regulatory subunit) competes with MYPT1 for binding to PP1cβ (PPP1CB), displacing MYPT1 and blocking the PP1cβ active site; TIMAP-bound PP1cβ cannot bind the active-site inhibitor microcystin-LR, whereas MYPT1-bound PP1cβ can. This competition inhibits myosin phosphatase activity and enhances MLC2 phosphorylation in endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins; GST-pulldown with recombinant proteins; microcystin-LR active-site binding assay; TIMAP overexpression/silencing with MLC2 phosphorylation readout; TIMAP-deficient mouse lung lysates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with recombinant proteins, active-site inhibitor binding assay, endogenous Co-IP, KO mouse validation, and TIMAP mutant controls\",\n      \"pmids\": [\"31315927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPP1CB promotes adipocyte differentiation: its expression increases during early 3T3-L1 adipogenesis; depletion of PPP1CB suppresses differentiation and clonal expansion, reduces C/EBPδ expression, and attenuates downstream PPARγ, C/EBPα, adiponectin, and aP2. PPP1CB links p38 activation to C/EBPδ expression in early adipogenesis.\",\n      \"method\": \"siRNA knockdown of PPP1CB in 3T3-L1 cells; gene expression analysis of adipocyte marker genes; clonal expansion assay; p38 pathway analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and pathway placement, single lab with multiple markers\",\n      \"pmids\": [\"26449462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Chebulinic acid inhibits PPP1CB phosphatase activity (IC50 = 300 nM against 6,8-difluoro-4-methylumbelliferyl phosphate hydrolysis) and suppresses 3T3-L1 adipogenesis in a concentration-dependent manner, confirming PPP1CB's enzymatic phosphatase activity is required for adipogenesis.\",\n      \"method\": \"In vitro phosphatase activity assay with fluorogenic substrate; cell-based adipogenesis assay with PPP1CB inhibitor\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic assay with defined IC50, single lab, one method per endpoint\",\n      \"pmids\": [\"35055051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A YPEL5/PPP1CB RNA chimera (trans-splicing product), when introduced into mammalian cells, expresses a truncated PPP1CB protein with diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of CLL-derived cell lines.\",\n      \"method\": \"Paired-end transcriptome sequencing; expression of chimeric construct in mammalian cells with phosphatase activity assay; siRNA silencing 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 1–2 / Moderate — in vitro phosphatase activity assay of expressed truncated protein plus functional silencing experiment, single lab\",\n      \"pmids\": [\"23382248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSD3 interacts with PPP1CB and phosphorylated STAT3 (p-STAT3) at the protein level, forming a trimeric complex in which PPP1CB dephosphorylates p-STAT3, thereby suppressing HK2 transcription and glycolysis in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation demonstrating NSD3-PPP1CB and NSD3-p-STAT3 interaction; functional assays measuring STAT3 phosphorylation, HK2 expression, glucose uptake, and lactate production upon NSD3 manipulation\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of trimeric complex plus functional downstream readouts, single lab\",\n      \"pmids\": [\"39119928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In bladder cancer, OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind and degrade PPP1CB via ubiquitin-mediated proteolysis; PPP1CB degradation enhances YBX1 transcriptional activity and IKKβ phosphorylation activity, activating NF-κB signaling and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation of OIP5-TRIP12-PPP1CB; knockdown/overexpression experiments measuring PPP1CB protein levels, IKKβ phosphorylation, and YBX1-driven gene expression; CRISPR-based gene circuit in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional loss-of-function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"39155295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPP1CB physically interacts with Classical Swine Fever Virus (CSFV) structural glycoprotein E2 in infected swine cells; pharmacological activation of the PP1 pathway decreases CSFV replication, whereas PPP1CB knockdown by siRNA had no observed effect on replication.\",\n      \"method\": \"Yeast two-hybrid system; Co-immunoprecipitation in CSFV-infected cells; Proximity Ligation Assay; pharmacological PP1 pathway activation/inhibition; siRNA knockdown with viral replication readout\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent binding confirmation methods (Co-IP + PLA) plus functional pharmacological assay, single lab\",\n      \"pmids\": [\"30934875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo missense mutations in PPP1CB (p.Pro49Arg, p.Ala56Pro) cause a rasopathy resembling Noonan syndrome with loose anagen hair. PPP1CB's role in RAF dephosphorylation within the RAS/MAPK pathway is invoked as the mechanistic basis; the affected residues are within the phosphatase catalytic domain and predicted to impair dephosphorylation.\",\n      \"method\": \"Whole-exome sequencing of patients; conservation analysis; in silico prediction of functional impact on PP1 catalytic activity\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic identification with computational prediction only; no direct biochemical experiment on mutant proteins performed in this paper\",\n      \"pmids\": [\"27264673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Human PP1β (PPP1CB) cDNA encodes a serine/threonine protein phosphatase catalytic subunit; the gene is located on chromosome 2q23 and produces alternatively spliced mRNAs (3.1 kb, 4.0 kb, 5.4 kb) from the 3' noncoding region, with the highest PP1β/PP1α mRNA ratio in skeletal muscle.\",\n      \"method\": \"cDNA cloning from human teratocarcinoma library; Northern blotting across tissues; somatic cell hybrid analysis; fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cDNA isolation, expression profiling, and chromosomal mapping; foundational characterization replicated across species\",\n      \"pmids\": [\"8312365\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP1CB (PP1cβ) is a serine/threonine protein phosphatase catalytic subunit that functions within regulatory complexes—including MYPT1-PP1cβ (myosin light-chain phosphatase) and RAF1-PP1cβ—to dephosphorylate substrates such as myosin regulatory light chain (controlling smooth muscle contraction), Plk1 (recruited via Chk1-phosphorylated MYPT1 during mitotic damage), RAF1-Ser259 (within the RAS/MAPK pathway), and STAT3 (in a trimeric NSD3/PPP1CB/p-STAT3 complex suppressing glycolysis); competing regulatory subunits (e.g., TIMAP) can displace MYPT1 and block the PP1cβ active site, while ubiquitin ligase TRIP12 (recruited by OIP5) can degrade PP1cβ to modulate downstream signaling, and de novo gain-of-function mutations in PPP1CB cause a RASopathy (Noonan syndrome with loose anagen hair-2) by perturbing RAS/MAPK pathway dephosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP1CB encodes PP1cβ, a serine/threonine protein phosphatase catalytic subunit whose activity is directed toward distinct substrates by regulatory partners across smooth muscle, cell cycle, and signaling contexts [#2, #11]. In smooth muscle, PP1cβ is the functionally dominant PP1 isoform (>90% of total PP1c) and is essential for contractile force, dephosphorylating myosin regulatory light chain in both MYPT1-bound and MYPT1-unbound forms [#2]. The choice of regulatory subunit gates this activity: TIMAP competes with MYPT1 for PP1cβ, displacing it and occluding the catalytic active site to inhibit myosin phosphatase activity and raise MLC2 phosphorylation in endothelial cells [#3], while Chk1-mediated phosphorylation of MYPT1 at Ser20 is required for MYPT1–PP1cβ assembly and the subsequent dephosphorylation and inactivation of Plk1 during mitotic damage [#1]. In the RAS/MAPK pathway, PP1cβ resides in a RAF1-containing complex bound by LZTR1 and contributes to dephosphorylation of RAF1 at Ser259 [#0]. PP1cβ catalytic activity also drives 3T3-L1 adipocyte differentiation, linking p38 activation to C/EBPδ induction, and is inhibited by chebulinic acid [#4, #5]. Additional substrate-directed roles include dephosphorylation of STAT3 within an NSD3/PPP1CB/p-STAT3 trimeric complex that suppresses HK2-driven glycolysis [#7], and its abundance is controlled by OIP5-recruited TRIP12-mediated ubiquitin-dependent degradation, which derepresses NF-κB signaling [#8]. De novo missense mutations in the PPP1CB catalytic domain cause a RASopathy resembling Noonan syndrome with loose anagen hair [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the molecular identity of PPP1CB as a PP1 catalytic subunit, defining the gene, its chromosomal locus, and tissue expression before any functional role was assigned.\",\n      \"evidence\": \"cDNA cloning from a human library with Northern blotting, somatic cell hybrid analysis, and FISH mapping\",\n      \"pmids\": [\"8312365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate or regulatory subunit identified at this stage\", \"No structural or catalytic mechanism defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked PPP1CB phosphatase activity to growth control, showing that a truncated chimeric form has diminished activity and that PPP1CB silencing promotes proliferation.\",\n      \"evidence\": \"Transcriptome sequencing of a YPEL5/PPP1CB trans-splicing chimera, expression with phosphatase assay, and siRNA silencing in CLL-derived lines\",\n      \"pmids\": [\"23382248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates mediating the proliferative effect not identified\", \"Physiological relevance of the chimera unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed PPP1CB in early adipogenesis as a node linking p38 activation to C/EBPδ induction and the downstream differentiation program.\",\n      \"evidence\": \"siRNA knockdown in 3T3-L1 cells with adipocyte marker expression, clonal expansion, and p38 pathway analysis\",\n      \"pmids\": [\"26449462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphatase substrate in the p38–C/EBPδ axis not defined\", \"Regulatory subunit directing this activity unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PPP1CB to human disease, identifying de novo catalytic-domain mutations as a cause of a Noonan-syndrome-like RASopathy.\",\n      \"evidence\": \"Whole-exome sequencing of patients with conservation analysis and in silico impact prediction\",\n      \"pmids\": [\"27264673\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical assay on mutant proteins in this study\", \"Gain- vs loss-of-function effect on catalytic activity not measured\", \"RAS/MAPK perturbation invoked but not demonstrated for these mutants\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined how regulatory subunits direct PP1cβ to specific substrates in two contexts: a RAF1 complex dephosphorylating Ser259, and a Chk1-phosphorylated MYPT1 complex inactivating Plk1.\",\n      \"evidence\": \"Endogenous Co-IP with siRNA and phospho-RAF1 readout (LZTR1); Co-IP, Ser20 mutagenesis, and Plk1 dephosphorylation assays (Chk1–MYPT1)\",\n      \"pmids\": [\"30368668\", \"29262732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalysis of RAF1-Ser259 by PP1cβ not reconstituted in vitro\", \"Whether LZTR1 modulates the phosphatase directly is unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established PP1cβ as the functionally dominant PP1 isoform for smooth muscle contraction via RLC dephosphorylation.\",\n      \"evidence\": \"Isoform-specific immunoblotting, smooth-muscle conditional knockout mice, permeabilization, and ex vivo contractile force measurement\",\n      \"pmids\": [\"30185619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of MYPT1-bound vs soluble forms not quantified\", \"Other smooth-muscle substrates beyond RLC not enumerated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed regulatory-subunit competition as a control mechanism, with TIMAP displacing MYPT1 and blocking the PP1cβ active site to inhibit myosin phosphatase.\",\n      \"evidence\": \"Endogenous Co-IP, GST-pulldown with recombinant proteins, microcystin-LR active-site binding assay, and TIMAP-deficient mouse lysates with MLC2 readout\",\n      \"pmids\": [\"31315927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of active-site occlusion not solved\", \"Signals controlling TIMAP vs MYPT1 occupancy in vivo unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a host–pathogen interaction between PP1cβ and CSFV glycoprotein E2, though PP1cβ knockdown did not alter viral replication.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP and PLA in infected cells, and pharmacological PP1 modulation with replication readout\",\n      \"pmids\": [\"30934875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the E2 interaction undefined\", \"Discrepancy between pharmacological and knockdown effects unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended PP1cβ substrate range to metabolic and survival signaling: dephosphorylating STAT3 to suppress glycolysis, and being subject to TRIP12-mediated degradation that activates NF-κB.\",\n      \"evidence\": \"Co-IP of NSD3/PPP1CB/p-STAT3 with glycolysis readouts; Co-IP of OIP5-TRIP12-PPP1CB with degradation and pathway assays and an in vivo gene circuit\",\n      \"pmids\": [\"39119928\", \"39155295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of STAT3 by PP1cβ not reconstituted\", \"Ubiquitination sites on PPP1CB not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How disease-associated catalytic-domain mutations alter PP1cβ activity toward specific substrates, and the structural basis for regulatory-subunit-directed substrate selection, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical characterization of RASopathy mutant phosphatase activity\", \"No structural model of the substrate-directing holoenzymes\", \"Substrate specificity rules across the many regulatory subunits undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 5, 6, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"MYPT1-PP1cβ (myosin light-chain phosphatase)\",\n      \"RAF1-PPP1CB complex\",\n      \"NSD3/PPP1CB/p-STAT3 trimeric complex\"\n    ],\n    \"partners\": [\n      \"MYPT1\",\n      \"TIMAP\",\n      \"LZTR1\",\n      \"RAF1\",\n      \"Chk1\",\n      \"NSD3\",\n      \"TRIP12\",\n      \"OIP5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}