{"gene":"PPP2CB","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2006,"finding":"Suppression of PP2Abeta (PPP2CB) by antisense oligonucleotides or siRNA does NOT induce metaphase arrest or aberrant mitotic spindles, whereas suppression of PP2Aalpha (PPP2CA) is sufficient to induce metaphase arrest with lagging chromosomes. This establishes that PPP2CB is not the isoform responsible for cantharidin-induced mitotic arrest phenotype.","method":"Antisense oligonucleotides and siRNA knockdown with flow cytometry, live cell imaging, and immunostaining","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, two orthogonal knockdown methods, single lab; finding is a negative result for PPP2CB specifically","pmids":["17121919"],"is_preprint":false},{"year":1993,"finding":"PPP2CB (the beta isoform of the PP2A catalytic subunit) was chromosomally mapped to human chromosome 8p12→p11.2 by fluorescence in situ hybridization using somatic cell hybrids and genomic probes; a pseudogene (PPP2CBP) was identified on chromosome 16 by Southern blot.","method":"Somatic cell hybrid PCR, fluorescence in situ hybridization, Southern blot","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct chromosomal mapping with multiple orthogonal methods (FISH, somatic cell hybrids, Southern blot), replicated by subsequent mapping studies","pmids":["8383590"],"is_preprint":false},{"year":2011,"finding":"Homozygous global deletion of Ppp2cb in mice (Ppp2cb Δ/Δ) does not produce any obvious morphological or physiological defects, establishing that PPP2CB is dispensable for gross development in vivo, in contrast to Ppp2ca which causes early embryonic lethality.","method":"Conditional knockout mouse (loxP/Cre-mediated deletion), phenotypic analysis","journal":"Genesis (New York, N.Y. : 2000)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, contrasted with paralog lethal phenotype, peer-reviewed","pmids":["21998041"],"is_preprint":false},{"year":2012,"finding":"Up-regulation of PPP2CB protein is a key mediator of meiotic arrest in MARF1-deficient mouse oocytes; elevated PPP2CB levels are linked to female infertility, defective cytoplasmic maturation, and meiotic arrest in this model.","method":"Genetic mouse model (Marf1 mutation), protein expression analysis, phenotypic rescue inference","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetic model with defined cellular phenotype (meiotic arrest), PPP2CB identified as key mediator but direct rescue experiment not detailed in abstract; single lab","pmids":["22442484"],"is_preprint":false},{"year":2019,"finding":"PPP2CB (PP2A catalytic subunit beta) was identified as a novel protein-protein interaction partner of adenylyl cyclase type 5 (AC5) in striatal medium spiny neurons using bimolecular fluorescence complementation (BiFC) screening. Knockdown of PPP2CB reduced acute and sensitized adenylyl cyclase activity, implicating PPP2CB as a persistent regulator of adenylyl cyclase/cAMP signaling.","method":"Bimolecular fluorescence complementation (BiFC) protein-protein interaction screen, genetic knockdown, cAMP signaling assays in neuronal cell lines and MSNs","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — novel interaction identified by BiFC with functional follow-up (knockdown + adenylyl cyclase activity assay), single lab, multiple cellular models","pmids":["31752385"],"is_preprint":false},{"year":2017,"finding":"PPP2CB is a direct target of miR-1246 in mesenchymal stem/stromal cells (MSCs); miR-1246-mediated suppression of PPP2CB (along with PRKAR1A) drives NF-κB-dependent pro-inflammatory cytokine production (IL-6, CCL2, CCL5) in MSCs.","method":"miRNA overexpression, direct target validation (in vitro), NF-κB activity assays, cytokine measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct targeting confirmed experimentally, functional phenotype demonstrated, single lab with multiple readouts","pmids":["28159925"],"is_preprint":false},{"year":2019,"finding":"LB-100 is demonstrated to be a catalytic inhibitor of PP2AC (PPP2CA/PPP2CB) in vitro using purified enzyme inhibition assays; LB-100's 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with catalytic metal ions conserved in both PP2AC and PPP5C, as revealed by crystal structure of PPP5C co-crystallized with LB-100 at 1.65 Å resolution.","method":"In vitro phosphatase inhibition assay with purified enzymes, X-ray crystallography (PPP5C co-crystal at 1.65 Å), cell-based genetic disruption studies","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with purified PP2AC plus crystal structure (of PPP5C), establishing catalytic inhibition mechanism; PPP2CB inference based on shared catalytic mechanism with PPP2CA, not directly crystalized","pmids":["30679389"],"is_preprint":false},{"year":2018,"finding":"PPP2CB (catalytic subunit of PP2A) directly interacts with GADD45α as shown by co-immunoprecipitation; GADD45α promotes AMPKα activation in hepatocytes, and this interaction with PPP2CB is proposed as part of the mechanism by which GADD45α protects against acetaminophen-induced liver injury.","method":"Co-immunoprecipitation (LC-MS/MS), loss-of-function and overexpression in vitro and in vivo, AMPK activation assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP identifying direct interaction, combined with functional AMPK activation data, single lab","pmids":["30151693"],"is_preprint":false},{"year":2022,"finding":"T cell-specific knockout of PPP2CB (PPP2CBfl/fl Lck-Cre+) showed PPP2CB is dispensable for T-cell development and TCR-induced activation, but PPP2CB specifically suppresses PMA/ionomycin-induced T-cell activation by negatively regulating PI3K/Akt signaling and Ca2+ flux. Mass spectrometry-based phospho-peptide analysis identified potential substrates of PPP2CB during PMA/ionomycin stimulation.","method":"T cell-specific conditional knockout mouse, flow cytometry (CD69/CD25 expression, proliferation), cytokine measurement, PI3K inhibitor rescue, MS-based phosphoproteomics","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular phenotype, pathway placement via PI3K inhibitor rescue, phosphoproteomic substrate identification, multiple orthogonal methods in single study","pmids":["35068054"],"is_preprint":false},{"year":2023,"finding":"PPP2CB dephosphorylates the H3K9me1/2 methyltransferase G9a at Thr1045 (pT1045) during late mitosis, reactivating G9a catalytic activity and upregulating H3K9me2 levels, correlating with decreased H3S10 phosphorylation. This establishes PPP2CB as the phosphatase that removes Plk1-mediated phosphorylation of G9a to regulate chromatin organization and mitotic progression.","method":"Biochemical dephosphorylation assays, co-immunoprecipitation, phosphomimetic/phospho-null mutagenesis, chromatin accessibility assays, cell cycle progression analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay plus mutagenesis (phosphomimetic T1045E), multiple orthogonal methods (Co-IP, chromatin accessibility, cell cycle), identifies PPP2CB as the specific phosphatase writer/eraser for G9a-pT1045","pmids":["37661576"],"is_preprint":false},{"year":2025,"finding":"PPP2CB dephosphorylates LC3B, and this dephosphorylation reduces the interaction between LC3B and the mitophagy receptor OPTN, thereby impeding mitochondrial recruitment of phagophores during PINK1-PRKN/Parkin-mediated mitophagy. PPP2CB was identified as the catalytic subunit (beta isoform) of the heterotrimeric PP2A complex responsible for this LC3B dephosphorylation.","method":"Co-immunoprecipitation, proximity ligation assay (PLA), gain/loss-of-function in neuronal cells, mitophagy flux assays, pharmacological rescue","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and PLA plus functional mitophagy readouts; single lab; PPP2CB identified as beta isoform of PP2A complex mediating this dephosphorylation","pmids":["41059761"],"is_preprint":false},{"year":2025,"finding":"REGγ (proteasome activator) interacts with and promotes proteasome-dependent degradation of PPP2CB. This degradation prevents PPP2CB from dephosphorylating TBK1, thereby sustaining TBK1 phosphorylation and its interaction with IRF3, leading to IFNβ-mediated antiviral signaling activation. IFNβ in turn enhances REGγ expression, forming a positive feedback loop.","method":"Co-immunoprecipitation, proteasome degradation assays, genetic REGγ deficiency mouse models, viral infection models, TBK1 phosphorylation/IRF3 interaction assays, IFNβ production measurement","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing REGγ-PPP2CB interaction, in vivo KO model with defined antiviral phenotype, TBK1 dephosphorylation mechanistic link, multiple orthogonal methods in single rigorous study","pmids":["40736577"],"is_preprint":false},{"year":2026,"finding":"YAP1 transcriptionally upregulates PPP2CB expression via the transcription factor TEAD1 in vascular smooth muscle cells (VSMCs). PPP2CB in turn inhibits AMPK (with CAMKK2 required upstream), relieving AMPK-mediated suppression of mTORC1 and thereby promoting VSMC proliferation. This defines a YAP1/TEAD1→PPP2CB→AMPK inhibition→mTORC1 activation axis in VSMC phenotypic switching.","method":"YAP1 silencing and overexpression in human VSMCs, reporter/ChIP assays (TEAD1), AMPK/mTORC1 activity assays, CAMKK2 requirement assay, proliferation readouts","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with defined signaling readouts, TEAD1-mediated transcriptional control shown, single lab","pmids":["41797917"],"is_preprint":false},{"year":2025,"finding":"PPP2CB directly interacts with lectin-like oxidized LDL receptor-1 (LOX-1) as confirmed by immunofluorescence co-localization and co-immunoprecipitation in hepatic cells. PPP2CB overexpression exacerbates lipid accumulation and LDL uptake via activation of the LOX-1/MAPK/ERK signaling cascade, while PPP2CB silencing mitigates these effects.","method":"Co-immunoprecipitation, immunofluorescence co-localization, PPP2CB overexpression/silencing, LDL-C uptake assay, Western blotting for MAPK/ERK activation, ApoE-/- mouse model","journal":"Lipids in health and disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional gain/loss-of-function with pathway readout (MAPK/ERK), in vivo validation in mouse model, single lab","pmids":["40611318"],"is_preprint":false},{"year":1998,"finding":"PP2A-beta (PPP2CB) mRNA is up-regulated in cerebellar floccular Purkinje cells within 2 days after unilateral labyrinthectomy in rats. Continuous floccular infusion of okadaic acid (PP2A inhibitor) prolonged vestibular compensation (UL-induced nystagmus), suggesting PPP2CB up-regulation in Purkinje cells contributes to lesion-induced vestibular plasticity.","method":"Differential display PCR, in situ hybridization, Northern blot, pharmacological inhibition (okadaic acid floccular infusion) with behavioral readout (nystagmus duration)","journal":"Acta oto-laryngologica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo expression plus pharmacological inhibition with behavioral readout; okadaic acid is not isoform-specific so PPP2CB attribution is partial; single lab","pmids":["9840505"],"is_preprint":false},{"year":2008,"finding":"PPP2CB mRNA expression is significantly reduced in prostate carcinoma compared to benign prostate tissue, positioning it as a candidate tumor suppressor on chromosome 8p; however, SSCP/sequencing analysis of all 7 coding exons found no tumor-specific mutations in bladder tumors, suggesting loss of expression rather than coding mutation as the mechanism.","method":"Quantitative RT-PCR (expression), SSCP analysis and direct sequencing of all coding exons (mutation analysis)","journal":"Cancer genomics & proteomics / Cancer genetics and cytogenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression correlation with negative mutation finding; no direct mechanistic experiment on protein function","pmids":["18460741","9078303"],"is_preprint":false},{"year":2023,"finding":"Quantum-based hybrid (ONIOM) calculations on 39-residue models of PP2A(PPP2R5D/PPP2CA or PPP2CB) indicate that bidentate binding of the conserved Arg89 in the catalytic subunit to the substrate phosphate group is critical for optimal dephosphorylation, with activation barrier ΔH‡ ≈ +15.5 kcal/mol (bidentate) vs. +18.8 kcal/mol (Arg89 sequestered by salt bridge with B:Glu198).","method":"Quantum mechanics/molecular mechanics (ONIOM UB3LYP/6-31G(d):UPM7) computational modeling of catalytic mechanism","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of Arg89 role in PPP2CB specifically","pmids":["37377738"],"is_preprint":false}],"current_model":"PPP2CB encodes the beta isoform of the PP2A serine/threonine phosphatase catalytic subunit; it dephosphorylates specific substrates including G9a (pThr1045) during late mitosis to regulate chromatin organization, LC3B to restrain PINK1/Parkin-mediated mitophagy, and TBK1 to suppress antiviral IFNβ signaling (with the REGγ proteasome degrading PPP2CB to activate TBK1-IRF3-IFNβ); it is transcriptionally induced by the YAP1/TEAD1 axis in vascular smooth muscle cells where it inhibits AMPK to activate mTORC1 and drive proliferation; it interacts with LOX-1 to promote MAPK/ERK-dependent lipid dysregulation; it suppresses PMA/ionomycin-induced T-cell activation via PI3K/Akt inhibition; it is dispensable for mouse development and T-cell homeostasis under basal conditions; and its up-regulation in cerebellar Purkinje cells contributes to vestibular plasticity after labyrinthectomy."},"narrative":{"mechanistic_narrative":"PPP2CB encodes the beta isoform of the PP2A serine/threonine phosphatase catalytic subunit and functions as a substrate-selective dephosphorylating enzyme that tunes diverse signaling and chromatin events [PMID:37661576, PMID:21998041]. Genetically, PPP2CB is dispensable for gross mouse development, distinguishing it from the embryonic-lethal alpha isoform, and similarly does not drive the mitotic-arrest phenotype attributed to PPP2CA, establishing functional divergence between the two catalytic isoforms [PMID:21998041, PMID:17121919]. As a phosphatase it acts on defined substrates: it removes Plk1-installed phosphorylation of the H3K9 methyltransferase G9a at Thr1045 during late mitosis to reactivate G9a and raise H3K9me2 while H3S10 phosphorylation falls, linking PPP2CB to chromatin organization and mitotic progression [PMID:37661576]; it dephosphorylates LC3B to weaken the LC3B-OPTN interaction and restrain PINK1/Parkin-mediated mitophagy [PMID:41059761]; and it dephosphorylates TBK1, where REGgamma-driven proteasomal degradation of PPP2CB relieves this suppression to sustain TBK1-IRF3 signaling and IFNbeta antiviral responses [PMID:40736577]. PPP2CB also restrains growth and activation pathways: it negatively regulates PMA/ionomycin-induced T-cell activation through PI3K/Akt and Ca2+ signaling [PMID:35068054], and in vascular smooth muscle cells it is transcriptionally induced by a YAP1/TEAD1 axis to inhibit AMPK and thereby activate mTORC1 and drive proliferation [PMID:41797917]. Additional physical and functional partners reported include GADD45alpha, adenylyl cyclase type 5, and LOX-1, the latter linking PPP2CB to MAPK/ERK-dependent hepatic lipid accumulation [PMID:30151693, PMID:31752385, PMID:40611318].","teleology":[{"year":1993,"claim":"Establishing the genomic identity and locus of PPP2CB was the prerequisite for distinguishing it from the alpha catalytic isoform and from its pseudogene.","evidence":"FISH, somatic cell hybrid PCR, and Southern blot mapping","pmids":["8383590"],"confidence":"High","gaps":["Mapping alone gives no information on protein function or substrate specificity","Does not address tissue expression or isoform-specific roles"]},{"year":1998,"claim":"An early in vivo link tied PPP2CB expression to adaptive neural plasticity, raising the question of whether this isoform has tissue-specific functional roles.","evidence":"Differential display, in situ hybridization, and okadaic acid infusion with nystagmus behavioral readout in labyrinthectomized rats","pmids":["9840505"],"confidence":"Medium","gaps":["Okadaic acid is not PP2A-isoform-specific, so the functional attribution to PPP2CB is partial","No substrate or molecular mechanism identified in Purkinje cells"]},{"year":2006,"claim":"Knockdown experiments tested whether PPP2CB drives the PP2A mitotic-arrest phenotype, answering that it does not and thereby separating it functionally from PPP2CA.","evidence":"Antisense oligonucleotide and siRNA knockdown with flow cytometry, live imaging, and immunostaining","pmids":["17121919"],"confidence":"Medium","gaps":["A negative result that does not define what PPP2CB does in mitosis","Does not exclude redundancy with PPP2CA under other conditions"]},{"year":2011,"claim":"A clean global knockout resolved whether PPP2CB is essential in vivo, showing it is dispensable for gross development in contrast to the lethal alpha isoform.","evidence":"Cre/loxP global knockout mouse with phenotypic analysis","pmids":["21998041"],"confidence":"High","gaps":["Dispensability under basal conditions does not rule out roles under stress or in specific cell types","No molecular substrate implicated"]},{"year":2012,"claim":"Genetic modeling implicated PPP2CB level as a driver of meiotic arrest, suggesting dosage-sensitive control of oocyte maturation.","evidence":"Marf1-mutant mouse oocyte model with PPP2CB protein expression analysis","pmids":["22442484"],"confidence":"Medium","gaps":["Direct rescue experiment not detailed","Substrate dephosphorylated by elevated PPP2CB in oocytes not identified"]},{"year":2019,"claim":"Interaction screens and inhibitor pharmacology began to define PPP2CB's binding partners and its catalytic mechanism shared across the PP2A family.","evidence":"BiFC interaction screen with adenylyl cyclase type 5 and cAMP assays; in vitro phosphatase inhibition by LB-100 with PPP5C co-crystal structure","pmids":["31752385","30679389"],"confidence":"Medium","gaps":["AC5 interaction lacks reciprocal structural mapping","LB-100 catalytic inhibition was inferred for PPP2CB from shared mechanism, not directly crystallized with PPP2CB"]},{"year":2018,"claim":"Co-IP and AMPK assays linked PPP2CB to GADD45alpha-dependent metabolic protection, embedding it in hepatocyte AMPK signaling.","evidence":"Co-immunoprecipitation (LC-MS/MS) with loss/gain-of-function and AMPK activation assays in vitro and in vivo","pmids":["30151693"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Whether PPP2CB dephosphorylates an AMPK-pathway substrate directly is not shown"]},{"year":2022,"claim":"A T-cell-specific knockout placed PPP2CB as a negative regulator of stimulation-induced activation, defining its pathway context downstream of PMA/ionomycin.","evidence":"T-cell conditional knockout, flow cytometry, PI3K inhibitor rescue, and MS phosphoproteomics","pmids":["35068054"],"confidence":"High","gaps":["Phosphoproteomics identified candidate substrates that were not individually validated","Mechanism is selective for PMA/ionomycin and not TCR-induced activation"]},{"year":2023,"claim":"Direct dephosphorylation assays identified G9a-pThr1045 as a bona fide PPP2CB substrate, establishing a phosphatase-counterbalance to Plk1 in mitotic chromatin control.","evidence":"In vitro dephosphorylation, Co-IP, phosphomimetic/phospho-null mutagenesis, and chromatin accessibility and cell cycle assays","pmids":["37661576"],"confidence":"High","gaps":["Holoenzyme regulatory subunit conferring G9a specificity not defined","Whether this is unique to the beta isoform versus alpha not directly contrasted"]},{"year":2025,"claim":"Three converging studies defined PPP2CB substrates and regulation in mitophagy and antiviral immunity, and a transcriptional and lipid-signaling context, broadening its substrate repertoire.","evidence":"Co-IP/PLA and mitophagy flux assays for LC3B; reciprocal Co-IP, REGgamma-deficient mice, and viral infection for TBK1; Co-IP/IF and ApoE-/- mouse for LOX-1/MAPK/ERK","pmids":["41059761","40736577","40611318"],"confidence":"High","gaps":["LC3B and LOX-1 findings are single-lab","The specific PP2A holoenzyme composition for each substrate is not fully resolved"]},{"year":2026,"claim":"Transcriptional control by YAP1/TEAD1 was shown to couple PPP2CB expression to AMPK inhibition and mTORC1 activation in proliferating vascular smooth muscle cells.","evidence":"YAP1 silencing/overexpression, TEAD1 reporter/ChIP, AMPK/mTORC1 activity, CAMKK2 requirement, and proliferation assays in human VSMCs","pmids":["41797917"],"confidence":"Medium","gaps":["Direct AMPK substrate dephosphorylated by PPP2CB not biochemically confirmed","Single-lab signaling axis"]},{"year":null,"claim":"It remains unresolved how the PP2A regulatory (B) subunits and holoenzyme assembly direct PPP2CB to its distinct substrates (G9a, LC3B, TBK1) across different cell types, and which roles are unique to the beta isoform versus redundant with PPP2CA.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No systematic mapping of regulatory subunits to each substrate","Isoform-specific versus redundant contributions largely untested in vivo","No PPP2CB-specific structure with bound substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[9,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10,11]}],"localization":[],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9]}],"complexes":["PP2A holoenzyme"],"partners":["G9A","LC3B","TBK1","GADD45A","LOX-1","ADCY5","REGGAMMA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62714","full_name":"Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform","aliases":[],"length_aa":309,"mass_kda":35.6,"function":"Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events (Probable). PP2A can modulate the activity of phosphorylase B kinase, casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation (PubMed:18782753)","subcellular_location":"Cytoplasm; Nucleus; Chromosome, centromere; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/P62714/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP2CB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000104695","cell_line_id":"CID000215","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PPP2CA","stoichiometry":10.0},{"gene":"CCT5","stoichiometry":10.0},{"gene":"CCT3","stoichiometry":10.0},{"gene":"CCT6A","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"PPP2R1A","stoichiometry":10.0},{"gene":"CCT7","stoichiometry":10.0},{"gene":"CCT2","stoichiometry":10.0},{"gene":"STRN3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000215","total_profiled":1310},"omim":[{"mim_id":"616759","title":"NITRIC OXIDE SYNTHASE-INTERACTING PROTEIN; NOSIP","url":"https://www.omim.org/entry/616759"},{"mim_id":"614593","title":"MEIOSIS REGULATOR AND mRNA STABILITY FACTOR 1; MARF1","url":"https://www.omim.org/entry/614593"},{"mim_id":"602155","title":"UBX DOMAIN PROTEIN 8; UBXN8","url":"https://www.omim.org/entry/602155"},{"mim_id":"176916","title":"PROTEIN PHOSPHATASE 2, CATALYTIC SUBUNIT, BETA ISOFORM; PPP2CB","url":"https://www.omim.org/entry/176916"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP2CB"},"hgnc":{"alias_symbol":["PP2Abeta"],"prev_symbol":[]},"alphafold":{"accession":"P62714","domains":[{"cath_id":"3.60.21.10","chopping":"2-290","consensus_level":"high","plddt":98.0101,"start":2,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62714","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62714-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62714-F1-predicted_aligned_error_v6.png","plddt_mean":95.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP2CB","jax_strain_url":"https://www.jax.org/strain/search?query=PPP2CB"},"sequence":{"accession":"P62714","fasta_url":"https://rest.uniprot.org/uniprotkb/P62714.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62714/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62714"}},"corpus_meta":[{"pmid":"14517837","id":"PMC_14517837","title":"WIF1, a component of the Wnt 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induce metaphase arrest or aberrant mitotic spindles, whereas suppression of PP2Aalpha (PPP2CA) is sufficient to induce metaphase arrest with lagging chromosomes. This establishes that PPP2CB is not the isoform responsible for cantharidin-induced mitotic arrest phenotype.\",\n      \"method\": \"Antisense oligonucleotides and siRNA knockdown with flow cytometry, live cell imaging, and immunostaining\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, two orthogonal knockdown methods, single lab; finding is a negative result for PPP2CB specifically\",\n      \"pmids\": [\"17121919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PPP2CB (the beta isoform of the PP2A catalytic subunit) was chromosomally mapped to human chromosome 8p12→p11.2 by fluorescence in situ hybridization using somatic cell hybrids and genomic probes; a pseudogene (PPP2CBP) was identified on chromosome 16 by Southern blot.\",\n      \"method\": \"Somatic cell hybrid PCR, fluorescence in situ hybridization, Southern blot\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct chromosomal mapping with multiple orthogonal methods (FISH, somatic cell hybrids, Southern blot), replicated by subsequent mapping studies\",\n      \"pmids\": [\"8383590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Homozygous global deletion of Ppp2cb in mice (Ppp2cb Δ/Δ) does not produce any obvious morphological or physiological defects, establishing that PPP2CB is dispensable for gross development in vivo, in contrast to Ppp2ca which causes early embryonic lethality.\",\n      \"method\": \"Conditional knockout mouse (loxP/Cre-mediated deletion), phenotypic analysis\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined phenotypic readout, contrasted with paralog lethal phenotype, peer-reviewed\",\n      \"pmids\": [\"21998041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Up-regulation of PPP2CB protein is a key mediator of meiotic arrest in MARF1-deficient mouse oocytes; elevated PPP2CB levels are linked to female infertility, defective cytoplasmic maturation, and meiotic arrest in this model.\",\n      \"method\": \"Genetic mouse model (Marf1 mutation), protein expression analysis, phenotypic rescue inference\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetic model with defined cellular phenotype (meiotic arrest), PPP2CB identified as key mediator but direct rescue experiment not detailed in abstract; single lab\",\n      \"pmids\": [\"22442484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPP2CB (PP2A catalytic subunit beta) was identified as a novel protein-protein interaction partner of adenylyl cyclase type 5 (AC5) in striatal medium spiny neurons using bimolecular fluorescence complementation (BiFC) screening. Knockdown of PPP2CB reduced acute and sensitized adenylyl cyclase activity, implicating PPP2CB as a persistent regulator of adenylyl cyclase/cAMP signaling.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) protein-protein interaction screen, genetic knockdown, cAMP signaling assays in neuronal cell lines and MSNs\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — novel interaction identified by BiFC with functional follow-up (knockdown + adenylyl cyclase activity assay), single lab, multiple cellular models\",\n      \"pmids\": [\"31752385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPP2CB is a direct target of miR-1246 in mesenchymal stem/stromal cells (MSCs); miR-1246-mediated suppression of PPP2CB (along with PRKAR1A) drives NF-κB-dependent pro-inflammatory cytokine production (IL-6, CCL2, CCL5) in MSCs.\",\n      \"method\": \"miRNA overexpression, direct target validation (in vitro), NF-κB activity assays, cytokine measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct targeting confirmed experimentally, functional phenotype demonstrated, single lab with multiple readouts\",\n      \"pmids\": [\"28159925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LB-100 is demonstrated to be a catalytic inhibitor of PP2AC (PPP2CA/PPP2CB) in vitro using purified enzyme inhibition assays; LB-100's 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with catalytic metal ions conserved in both PP2AC and PPP5C, as revealed by crystal structure of PPP5C co-crystallized with LB-100 at 1.65 Å resolution.\",\n      \"method\": \"In vitro phosphatase inhibition assay with purified enzymes, X-ray crystallography (PPP5C co-crystal at 1.65 Å), cell-based genetic disruption studies\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with purified PP2AC plus crystal structure (of PPP5C), establishing catalytic inhibition mechanism; PPP2CB inference based on shared catalytic mechanism with PPP2CA, not directly crystalized\",\n      \"pmids\": [\"30679389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPP2CB (catalytic subunit of PP2A) directly interacts with GADD45α as shown by co-immunoprecipitation; GADD45α promotes AMPKα activation in hepatocytes, and this interaction with PPP2CB is proposed as part of the mechanism by which GADD45α protects against acetaminophen-induced liver injury.\",\n      \"method\": \"Co-immunoprecipitation (LC-MS/MS), loss-of-function and overexpression in vitro and in vivo, AMPK activation assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP identifying direct interaction, combined with functional AMPK activation data, single lab\",\n      \"pmids\": [\"30151693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"T cell-specific knockout of PPP2CB (PPP2CBfl/fl Lck-Cre+) showed PPP2CB is dispensable for T-cell development and TCR-induced activation, but PPP2CB specifically suppresses PMA/ionomycin-induced T-cell activation by negatively regulating PI3K/Akt signaling and Ca2+ flux. Mass spectrometry-based phospho-peptide analysis identified potential substrates of PPP2CB during PMA/ionomycin stimulation.\",\n      \"method\": \"T cell-specific conditional knockout mouse, flow cytometry (CD69/CD25 expression, proliferation), cytokine measurement, PI3K inhibitor rescue, MS-based phosphoproteomics\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular phenotype, pathway placement via PI3K inhibitor rescue, phosphoproteomic substrate identification, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35068054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PPP2CB dephosphorylates the H3K9me1/2 methyltransferase G9a at Thr1045 (pT1045) during late mitosis, reactivating G9a catalytic activity and upregulating H3K9me2 levels, correlating with decreased H3S10 phosphorylation. This establishes PPP2CB as the phosphatase that removes Plk1-mediated phosphorylation of G9a to regulate chromatin organization and mitotic progression.\",\n      \"method\": \"Biochemical dephosphorylation assays, co-immunoprecipitation, phosphomimetic/phospho-null mutagenesis, chromatin accessibility assays, cell cycle progression analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay plus mutagenesis (phosphomimetic T1045E), multiple orthogonal methods (Co-IP, chromatin accessibility, cell cycle), identifies PPP2CB as the specific phosphatase writer/eraser for G9a-pT1045\",\n      \"pmids\": [\"37661576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPP2CB dephosphorylates LC3B, and this dephosphorylation reduces the interaction between LC3B and the mitophagy receptor OPTN, thereby impeding mitochondrial recruitment of phagophores during PINK1-PRKN/Parkin-mediated mitophagy. PPP2CB was identified as the catalytic subunit (beta isoform) of the heterotrimeric PP2A complex responsible for this LC3B dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PLA), gain/loss-of-function in neuronal cells, mitophagy flux assays, pharmacological rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and PLA plus functional mitophagy readouts; single lab; PPP2CB identified as beta isoform of PP2A complex mediating this dephosphorylation\",\n      \"pmids\": [\"41059761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"REGγ (proteasome activator) interacts with and promotes proteasome-dependent degradation of PPP2CB. This degradation prevents PPP2CB from dephosphorylating TBK1, thereby sustaining TBK1 phosphorylation and its interaction with IRF3, leading to IFNβ-mediated antiviral signaling activation. IFNβ in turn enhances REGγ expression, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, proteasome degradation assays, genetic REGγ deficiency mouse models, viral infection models, TBK1 phosphorylation/IRF3 interaction assays, IFNβ production measurement\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing REGγ-PPP2CB interaction, in vivo KO model with defined antiviral phenotype, TBK1 dephosphorylation mechanistic link, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40736577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YAP1 transcriptionally upregulates PPP2CB expression via the transcription factor TEAD1 in vascular smooth muscle cells (VSMCs). PPP2CB in turn inhibits AMPK (with CAMKK2 required upstream), relieving AMPK-mediated suppression of mTORC1 and thereby promoting VSMC proliferation. This defines a YAP1/TEAD1→PPP2CB→AMPK inhibition→mTORC1 activation axis in VSMC phenotypic switching.\",\n      \"method\": \"YAP1 silencing and overexpression in human VSMCs, reporter/ChIP assays (TEAD1), AMPK/mTORC1 activity assays, CAMKK2 requirement assay, proliferation readouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with defined signaling readouts, TEAD1-mediated transcriptional control shown, single lab\",\n      \"pmids\": [\"41797917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPP2CB directly interacts with lectin-like oxidized LDL receptor-1 (LOX-1) as confirmed by immunofluorescence co-localization and co-immunoprecipitation in hepatic cells. PPP2CB overexpression exacerbates lipid accumulation and LDL uptake via activation of the LOX-1/MAPK/ERK signaling cascade, while PPP2CB silencing mitigates these effects.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, PPP2CB overexpression/silencing, LDL-C uptake assay, Western blotting for MAPK/ERK activation, ApoE-/- mouse model\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional gain/loss-of-function with pathway readout (MAPK/ERK), in vivo validation in mouse model, single lab\",\n      \"pmids\": [\"40611318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PP2A-beta (PPP2CB) mRNA is up-regulated in cerebellar floccular Purkinje cells within 2 days after unilateral labyrinthectomy in rats. Continuous floccular infusion of okadaic acid (PP2A inhibitor) prolonged vestibular compensation (UL-induced nystagmus), suggesting PPP2CB up-regulation in Purkinje cells contributes to lesion-induced vestibular plasticity.\",\n      \"method\": \"Differential display PCR, in situ hybridization, Northern blot, pharmacological inhibition (okadaic acid floccular infusion) with behavioral readout (nystagmus duration)\",\n      \"journal\": \"Acta oto-laryngologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo expression plus pharmacological inhibition with behavioral readout; okadaic acid is not isoform-specific so PPP2CB attribution is partial; single lab\",\n      \"pmids\": [\"9840505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PPP2CB mRNA expression is significantly reduced in prostate carcinoma compared to benign prostate tissue, positioning it as a candidate tumor suppressor on chromosome 8p; however, SSCP/sequencing analysis of all 7 coding exons found no tumor-specific mutations in bladder tumors, suggesting loss of expression rather than coding mutation as the mechanism.\",\n      \"method\": \"Quantitative RT-PCR (expression), SSCP analysis and direct sequencing of all coding exons (mutation analysis)\",\n      \"journal\": \"Cancer genomics & proteomics / Cancer genetics and cytogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression correlation with negative mutation finding; no direct mechanistic experiment on protein function\",\n      \"pmids\": [\"18460741\", \"9078303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Quantum-based hybrid (ONIOM) calculations on 39-residue models of PP2A(PPP2R5D/PPP2CA or PPP2CB) indicate that bidentate binding of the conserved Arg89 in the catalytic subunit to the substrate phosphate group is critical for optimal dephosphorylation, with activation barrier ΔH‡ ≈ +15.5 kcal/mol (bidentate) vs. +18.8 kcal/mol (Arg89 sequestered by salt bridge with B:Glu198).\",\n      \"method\": \"Quantum mechanics/molecular mechanics (ONIOM UB3LYP/6-31G(d):UPM7) computational modeling of catalytic mechanism\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of Arg89 role in PPP2CB specifically\",\n      \"pmids\": [\"37377738\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2CB encodes the beta isoform of the PP2A serine/threonine phosphatase catalytic subunit; it dephosphorylates specific substrates including G9a (pThr1045) during late mitosis to regulate chromatin organization, LC3B to restrain PINK1/Parkin-mediated mitophagy, and TBK1 to suppress antiviral IFNβ signaling (with the REGγ proteasome degrading PPP2CB to activate TBK1-IRF3-IFNβ); it is transcriptionally induced by the YAP1/TEAD1 axis in vascular smooth muscle cells where it inhibits AMPK to activate mTORC1 and drive proliferation; it interacts with LOX-1 to promote MAPK/ERK-dependent lipid dysregulation; it suppresses PMA/ionomycin-induced T-cell activation via PI3K/Akt inhibition; it is dispensable for mouse development and T-cell homeostasis under basal conditions; and its up-regulation in cerebellar Purkinje cells contributes to vestibular plasticity after labyrinthectomy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2CB encodes the beta isoform of the PP2A serine/threonine phosphatase catalytic subunit and functions as a substrate-selective dephosphorylating enzyme that tunes diverse signaling and chromatin events [#9, #2]. Genetically, PPP2CB is dispensable for gross mouse development, distinguishing it from the embryonic-lethal alpha isoform, and similarly does not drive the mitotic-arrest phenotype attributed to PPP2CA, establishing functional divergence between the two catalytic isoforms [#2, #0]. As a phosphatase it acts on defined substrates: it removes Plk1-installed phosphorylation of the H3K9 methyltransferase G9a at Thr1045 during late mitosis to reactivate G9a and raise H3K9me2 while H3S10 phosphorylation falls, linking PPP2CB to chromatin organization and mitotic progression [#9]; it dephosphorylates LC3B to weaken the LC3B-OPTN interaction and restrain PINK1/Parkin-mediated mitophagy [#10]; and it dephosphorylates TBK1, where REGgamma-driven proteasomal degradation of PPP2CB relieves this suppression to sustain TBK1-IRF3 signaling and IFNbeta antiviral responses [#11]. PPP2CB also restrains growth and activation pathways: it negatively regulates PMA/ionomycin-induced T-cell activation through PI3K/Akt and Ca2+ signaling [#8], and in vascular smooth muscle cells it is transcriptionally induced by a YAP1/TEAD1 axis to inhibit AMPK and thereby activate mTORC1 and drive proliferation [#12]. Additional physical and functional partners reported include GADD45alpha, adenylyl cyclase type 5, and LOX-1, the latter linking PPP2CB to MAPK/ERK-dependent hepatic lipid accumulation [#7, #4, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the genomic identity and locus of PPP2CB was the prerequisite for distinguishing it from the alpha catalytic isoform and from its pseudogene.\",\n      \"evidence\": \"FISH, somatic cell hybrid PCR, and Southern blot mapping\",\n      \"pmids\": [\"8383590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mapping alone gives no information on protein function or substrate specificity\", \"Does not address tissue expression or isoform-specific roles\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"An early in vivo link tied PPP2CB expression to adaptive neural plasticity, raising the question of whether this isoform has tissue-specific functional roles.\",\n      \"evidence\": \"Differential display, in situ hybridization, and okadaic acid infusion with nystagmus behavioral readout in labyrinthectomized rats\",\n      \"pmids\": [\"9840505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Okadaic acid is not PP2A-isoform-specific, so the functional attribution to PPP2CB is partial\", \"No substrate or molecular mechanism identified in Purkinje cells\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Knockdown experiments tested whether PPP2CB drives the PP2A mitotic-arrest phenotype, answering that it does not and thereby separating it functionally from PPP2CA.\",\n      \"evidence\": \"Antisense oligonucleotide and siRNA knockdown with flow cytometry, live imaging, and immunostaining\",\n      \"pmids\": [\"17121919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A negative result that does not define what PPP2CB does in mitosis\", \"Does not exclude redundancy with PPP2CA under other conditions\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A clean global knockout resolved whether PPP2CB is essential in vivo, showing it is dispensable for gross development in contrast to the lethal alpha isoform.\",\n      \"evidence\": \"Cre/loxP global knockout mouse with phenotypic analysis\",\n      \"pmids\": [\"21998041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dispensability under basal conditions does not rule out roles under stress or in specific cell types\", \"No molecular substrate implicated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic modeling implicated PPP2CB level as a driver of meiotic arrest, suggesting dosage-sensitive control of oocyte maturation.\",\n      \"evidence\": \"Marf1-mutant mouse oocyte model with PPP2CB protein expression analysis\",\n      \"pmids\": [\"22442484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct rescue experiment not detailed\", \"Substrate dephosphorylated by elevated PPP2CB in oocytes not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Interaction screens and inhibitor pharmacology began to define PPP2CB's binding partners and its catalytic mechanism shared across the PP2A family.\",\n      \"evidence\": \"BiFC interaction screen with adenylyl cyclase type 5 and cAMP assays; in vitro phosphatase inhibition by LB-100 with PPP5C co-crystal structure\",\n      \"pmids\": [\"31752385\", \"30679389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AC5 interaction lacks reciprocal structural mapping\", \"LB-100 catalytic inhibition was inferred for PPP2CB from shared mechanism, not directly crystallized with PPP2CB\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Co-IP and AMPK assays linked PPP2CB to GADD45alpha-dependent metabolic protection, embedding it in hepatocyte AMPK signaling.\",\n      \"evidence\": \"Co-immunoprecipitation (LC-MS/MS) with loss/gain-of-function and AMPK activation assays in vitro and in vivo\",\n      \"pmids\": [\"30151693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Whether PPP2CB dephosphorylates an AMPK-pathway substrate directly is not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A T-cell-specific knockout placed PPP2CB as a negative regulator of stimulation-induced activation, defining its pathway context downstream of PMA/ionomycin.\",\n      \"evidence\": \"T-cell conditional knockout, flow cytometry, PI3K inhibitor rescue, and MS phosphoproteomics\",\n      \"pmids\": [\"35068054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphoproteomics identified candidate substrates that were not individually validated\", \"Mechanism is selective for PMA/ionomycin and not TCR-induced activation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Direct dephosphorylation assays identified G9a-pThr1045 as a bona fide PPP2CB substrate, establishing a phosphatase-counterbalance to Plk1 in mitotic chromatin control.\",\n      \"evidence\": \"In vitro dephosphorylation, Co-IP, phosphomimetic/phospho-null mutagenesis, and chromatin accessibility and cell cycle assays\",\n      \"pmids\": [\"37661576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Holoenzyme regulatory subunit conferring G9a specificity not defined\", \"Whether this is unique to the beta isoform versus alpha not directly contrasted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Three converging studies defined PPP2CB substrates and regulation in mitophagy and antiviral immunity, and a transcriptional and lipid-signaling context, broadening its substrate repertoire.\",\n      \"evidence\": \"Co-IP/PLA and mitophagy flux assays for LC3B; reciprocal Co-IP, REGgamma-deficient mice, and viral infection for TBK1; Co-IP/IF and ApoE-/- mouse for LOX-1/MAPK/ERK\",\n      \"pmids\": [\"41059761\", \"40736577\", \"40611318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LC3B and LOX-1 findings are single-lab\", \"The specific PP2A holoenzyme composition for each substrate is not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Transcriptional control by YAP1/TEAD1 was shown to couple PPP2CB expression to AMPK inhibition and mTORC1 activation in proliferating vascular smooth muscle cells.\",\n      \"evidence\": \"YAP1 silencing/overexpression, TEAD1 reporter/ChIP, AMPK/mTORC1 activity, CAMKK2 requirement, and proliferation assays in human VSMCs\",\n      \"pmids\": [\"41797917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AMPK substrate dephosphorylated by PPP2CB not biochemically confirmed\", \"Single-lab signaling axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the PP2A regulatory (B) subunits and holoenzyme assembly direct PPP2CB to its distinct substrates (G9a, LC3B, TBK1) across different cell types, and which roles are unique to the beta isoform versus redundant with PPP2CA.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No systematic mapping of regulatory subunits to each substrate\", \"Isoform-specific versus redundant contributions largely untested in vivo\", \"No PPP2CB-specific structure with bound substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [9, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"PP2A holoenzyme\"],\n    \"partners\": [\"G9a\", \"LC3B\", \"TBK1\", \"GADD45A\", \"LOX-1\", \"ADCY5\", \"REGgamma\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}