{"gene":"PPP2R3A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"Two functional Ca2+-binding EF-hand motifs (EF1 and EF2) were identified in human PR72/B''. Ca2+ binding induces a conformational change dependent on motif integrity. EF2 integrity is required for structural A/PR65 subunit interaction and proper nuclear targeting of PR72, whereas EF1 mediates Ca2+-dependent effects on PP2A(T72) catalytic activity in vitro and is partially required for PR72's ability to alter cell cycle progression upon forced expression.","method":"Site-directed mutagenesis of EF-hand motifs, in vitro Ca2+-binding assays, subcellular fractionation/localization, co-immunoprecipitation with A/PR65 subunit, in vitro phosphatase activity assays, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis of active-site residues, multiple orthogonal functional readouts in a single rigorous study","pmids":["12524438"],"is_preprint":false},{"year":2007,"finding":"The PR72 regulatory subunit directs PP2A to mediate Ca2+-dependent dephosphorylation of DARPP-32 at Thr-75 in striatal neurons. EF-hand 1 of PR72 is necessary for Ca2+-dependent regulation of PP2A activity both in vitro and in vivo. The PR72-containing PP2A heterotrimer is also required for glutamate acting at AMPA and NMDA receptors to regulate Thr-75 dephosphorylation.","method":"Overexpression and RNAi-mediated knockdown of PR72 in neurons, in vitro phosphatase assay, EF-hand mutagenesis, measurement of DARPP-32 phosphorylation by immunoblot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro assay plus mutagenesis plus in vivo RNAi with specific phosphorylation readout, replicated across conditions","pmids":["17535922"],"is_preprint":false},{"year":2005,"finding":"PR72 physically and functionally interacts with Naked cuticle (Nkd) and acts as a negative regulator of the canonical Wnt signaling cascade. The inhibitory effect of Naked cuticle on Wnt signaling requires PR72, both in mammalian cell culture and in Xenopus embryos. PR72 is also required for regulation of cell morphogenetic movements during body axis formation.","method":"Co-immunoprecipitation, reporter assays for Wnt pathway activity, Xenopus embryo injection/loss-of-function experiments, mammalian cell culture overexpression/knockdown","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal physical interaction plus epistasis in two independent systems (mammalian cells and Xenopus embryos)","pmids":["15687260"],"is_preprint":false},{"year":2006,"finding":"PR130, which shares the C-terminus with PR72 but has a distinct N-terminus, also physically interacts with Naked cuticle but acts as an activator of the canonical Wnt signaling pathway (opposite to PR72). PR130 restricts Naked cuticle's ability to function as a Wnt inhibitor, modulating Wnt signal transduction through differential expression of the two PPP2R3A transcripts.","method":"Co-immunoprecipitation, Wnt reporter assays in mammalian cells, Xenopus embryo injection/rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction plus functional epistasis in two independent model systems, published by same lab building on prior replicated work","pmids":["16567647"],"is_preprint":false},{"year":2009,"finding":"PR72/B''alpha2 and PR130/B''alpha1 are specifically cleaved by the Ca2+-dependent protease m-calpain into a 45–48 kDa proteolysis-resistant fragment ('PR45'). This limited proteolysis depends on EF-hand integrity, weakens PR72-core enzyme interaction, activates basal PP2A(T72) phosphatase activity, and dramatically increases sensitivity to polycation activation. PR45 generation was also observed in staurosporine-induced apoptotic MCF7 cells in a calpain-dependent manner.","method":"In vitro calpain cleavage assay, mass spectrometry peptide mapping, EF-hand mutant analysis, PP2A phosphatase activity assay, apoptosis model with calpain inhibitors","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of proteolysis with mutagenesis validation, corroborated in a cell model, single lab","pmids":["19555667"],"is_preprint":false},{"year":2009,"finding":"PR130/B''alpha1 forms a constitutive complex with SHIP2 and a transient EGF-stimulated complex with EGFR in mammalian cell lines. PR130 and SHIP2 co-localize and both translocate to the cell membrane upon EGF stimulation. RNAi-mediated knockdown of PR130 increases EGF-induced proteasome-dependent EGFR degradation and increases EGFR interaction with E3 ligase c-Cbl, leading to faster inactivation of downstream AKT and ERK/MAPK signaling; these effects are rescued by RNAi-resistant PR130.","method":"Co-immunoprecipitation, co-localization by fluorescence microscopy, siRNA knockdown, rescue with RNAi-resistant construct, immunoblot for EGFR degradation and phosphorylation of downstream targets","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA with functional readout, and rescue experiment in a single study","pmids":["19825976"],"is_preprint":false},{"year":2016,"finding":"PR130/B''alpha1 binds the LIM domains of lipoma-preferred partner (LPP) through a conserved Zn2+-finger-like motif in the differentially spliced N-terminus of PR130. Isolated LPP-associated PP2A complexes are catalytically active. PR130 co-localizes with LPP at focal contacts but is excluded from mature focal adhesions. An LPP-PR130 fusion that cannot release from LPP (by deletion of the PP2A/C-binding domain of PR130) only localizes to focal adhesions, suggesting the interaction is dynamic. siRNA knockdown of PR130 increases cell adhesion to collagen I and decreases migration; these phenotypes cannot be rescued by a PR130 mutant unable to bind LPP.","method":"Co-immunoprecipitation/pulldown, co-localization by confocal microscopy, in vitro phosphatase activity assay, siRNA knockdown, rescue with domain-deletion mutants, scratch wound and Transwell migration assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis rescue, multiple orthogonal cellular phenotypic assays in a single study","pmids":["26945059"],"is_preprint":false},{"year":2016,"finding":"Deletion of pr130 in zebrafish (CRISPR/Cas9) causes cardiac looping defects, decreased fractional area and fractional shortening, reduced cardiomyocyte number, disrupted sarcomere ultrastructure (blurred Z- and M-lines, narrowed I- and A-bands), and increased cardiomyocyte apoptosis, establishing that pr130 is required for normal myocardium formation and efficient cardiac contractile function.","method":"CRISPR/Cas9 knockout in zebrafish, echocardiography/functional imaging, H&E histology, transmission electron microscopy, TUNEL apoptosis assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo genetic knockout with multiple phenotypic readouts, single lab, no mechanistic pathway placement beyond PP2A function","pmids":["27845735"],"is_preprint":false},{"year":2018,"finding":"HDAC1 and HDAC2 suppress expression of PPP2R3A/PR130; elevated PR130 in turn promotes dephosphorylation of ATM by PP2A. Genetic elimination of PR130 slows G1/S phase transition, increases phospho-CHK1, RPA foci, and DNA damage upon replicative stress, and renders cells susceptible to HDAC inhibitor-induced mitotic catastrophe and apoptosis, with reduced RAD51-dependent homologous recombination.","method":"siRNA/genetic knockdown of PR130, HDAC inhibitor treatment, immunoblot for ATM/CHK1/WEE1/CDK1/p53 phosphorylation, immunofluorescence for RPA foci and RAD51, cell cycle analysis, apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal biochemical and cellular readouts, mechanistic pathway placement (HDAC→PR130→PP2A→ATM), single lab","pmids":["29472538"],"is_preprint":false},{"year":2018,"finding":"Deletion of pr72 in zebrafish (TALEN) causes enlarged ventricular chambers, reduced cardiomyocyte number, decreased cardiac function, defective sarcomere ultrastructure (abnormal mitochondria, I bands, Z lines, and intercalated disks), abnormal heart looping rescued by wild-type pr72 mRNA injection, and elevated Wnt effectors—indicating pr72 regulates cardiac development via the Wnt pathway.","method":"TALEN-mediated knockout in zebrafish, cardiac imaging/functional measurements, transmission electron microscopy, mRNA rescue injection, Wnt pathway effector immunoblot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mRNA rescue and molecular pathway readout (Wnt effectors), single lab","pmids":["30481179"],"is_preprint":false},{"year":2021,"finding":"PPP2R3A silencing in primary neonatal rat cardiomyocytes and H9c2 cells inhibits cell proliferation, arrests the cell cycle in S phase, and promotes apoptosis. Yeast two-hybrid screening identified 19 candidate PPP2R3A-interacting proteins in a human cardiomyocyte cDNA library, with COL1A2 being the most frequent interactor.","method":"shRNA lentiviral knockdown, CCK-8 viability assay, flow cytometry for cell cycle and apoptosis, yeast two-hybrid screen","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, yeast two-hybrid interaction without biochemical validation, phenotypic but no pathway placement","pmids":["34982454"],"is_preprint":false},{"year":2023,"finding":"In an osteoprogenitor Sfrp1-deletion mouse model, PP2A-PR72/130 regulates phosphorylation of the transcriptional co-activator p300; pharmacological activation of PP2A-PR72/130 with IQ-1 reduces the β-catenin/phospho-p300 nuclear association and restores hematopoietic stem cell repopulating activity, placing PP2A-PR72/130 upstream of the β-catenin/p300 axis in HSC maintenance.","method":"In vivo IQ-1 pharmacological treatment of Sfrp1 conditional KO mice, co-immunoprecipitation for β-catenin/p300 interaction, nuclear fractionation, HSC transplantation/repopulation assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological intervention with molecular readout and functional rescue, single lab","pmids":["35950533"],"is_preprint":false},{"year":2023,"finding":"Heart-specific overexpression of PP2A-PR72 (2.5-fold) in transgenic mice causes moderate cardiac hypertrophy, increased maximal ventricular pressure, faster sarcomere shortening and relaxation, increased Ca2+ transient amplitude, shortened Ca2+ decay, increased phospholamban phosphorylation at Thr-17, and reduced Na+/Ca2+ exchanger expression, establishing PR72 as a regulator of cardiac contractility and Ca2+ cycling.","method":"Transgenic mouse model, cardiac catheterization, sarcomere length/shortening measurements in isolated cardiomyocytes, Ca2+ spark/transient imaging, immunoblot for phospholamban pThr17 and NCX","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean transgenic gain-of-function with multiple orthogonal biochemical and physiological readouts, single lab","pmids":["37868783"],"is_preprint":false},{"year":2024,"finding":"Genetic elimination of PR130 sensitizes murine and human pancreatic ductal adenocarcinoma (PDAC) cells to PP2A inhibitor phendione-induced apoptosis and cytotoxic protein aggregate formation independently of p53. PP2A-PR130 complex activity prevents protein aggregation in tumor cells; phendione promotes proteasomal degradation of PR130, and HSP70 upregulation partially compensates for PP2A-PR130 loss.","method":"Genetic knockout/siRNA of PR130, flow cytometry for apoptosis, confocal microscopy for protein aggregates, proteomics, immunoblot for PR130/HSP70, HSP70 inhibitor combination treatment","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal assays and proteomics in a single study, single lab","pmids":["38570831"],"is_preprint":false},{"year":2026,"finding":"PR130 (PPP2R3A) restricts replication of HSV-1 in epithelial and neuronal cells; HSV-1 infection in turn decreases PR130 levels. PR130 controls expression and phosphorylation of the CDK inhibitor p21 (CDKN1A) at Ser-130 (catalyzed by CDK2). PR130 depletion enhances ATM signaling upon HSV-1 infection and creates a dependency of HSV-1 replication on ATM activity. Inhibition of USP7 stabilizes the p53-p21 axis and reduces HSV-1 viral titers.","method":"PR130 knockdown/overexpression in epithelial and neuronal cells, global proteome and phosphoproteome profiling, viral titer assays, ATM inhibitor epistasis, USP7 inhibitor treatment, immunoblot for p21/CDK2/ATM phosphorylation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with proteomics and functional epistasis in multiple cell types, single lab, not yet independently replicated","pmids":["42138961"],"is_preprint":false}],"current_model":"PPP2R3A encodes the PR72 and PR130 regulatory B''-type subunits of PP2A that direct substrate specificity and subcellular targeting of the PP2A heterotrimer: PR72 contains two Ca2+-binding EF-hand motifs (EF1 required for Ca2+-dependent activation, EF2 required for A-subunit interaction and nuclear targeting), mediates Ca2+-dependent dephosphorylation of DARPP-32 Thr-75 in neurons, negatively regulates canonical Wnt signaling through physical interaction with Naked cuticle, and controls cardiac contractility and Ca2+ cycling; PR130 uses a distinct N-terminal Zn2+-finger-like motif to bind partners including LPP, SHIP2/EGFR, and Naked cuticle (acting as a Wnt activator in opposition to PR72), promotes ATM dephosphorylation to modulate DNA-damage checkpoint decisions, protects proteins from aggregation in tumor cells, restricts HSV-1 replication via the CDK2-p21 axis, and regulates cardiac and hematopoietic development; both isoforms are substrates of calpain-mediated limited proteolysis that alters their PP2A regulatory activity."},"narrative":{"mechanistic_narrative":"PPP2R3A encodes two B''-type regulatory subunits of protein phosphatase 2A, PR72 and PR130, generated from distinct transcripts that share a common C-terminus but differ in their N-termini, and that direct PP2A substrate specificity, localization, and signaling output [PMID:12524438, PMID:16567647]. PR72 carries two functional Ca2+-binding EF-hand motifs: EF1 mediates Ca2+-dependent regulation of PP2A(T72) catalytic activity, while EF2 is required for interaction with the structural A/PR65 subunit and for nuclear targeting [PMID:12524438]. Through this Ca2+-responsive activity PR72-containing PP2A dephosphorylates DARPP-32 at Thr-75 in striatal neurons downstream of glutamatergic (AMPA/NMDA) signaling [PMID:17535922], and as a contractility regulator it controls cardiac Ca2+ cycling, raising phospholamban Thr-17 phosphorylation and Ca2+ transient amplitude [PMID:37868783]. The two isoforms exert opposing control over canonical Wnt signaling through physical interaction with Naked cuticle, PR72 acting as a Wnt inhibitor and PR130 as a Wnt activator, and PR72 is required for cardiac development via the Wnt pathway [PMID:15687260, PMID:16567647, PMID:30481179]. PR130 instead engages a distinct set of partners through its N-terminal Zn2+-finger-like motif and adaptor interactions—LPP at focal contacts to control adhesion and migration [PMID:26945059], and SHIP2/EGFR to restrain EGFR degradation and sustain AKT and ERK signaling [PMID:19825976]. PR130 also promotes PP2A-mediated dephosphorylation of ATM to modulate replicative-stress and DNA-damage checkpoint responses (downstream of HDAC1/2 control), guards tumor cells against cytotoxic protein aggregation, and restricts HSV-1 replication via the CDK2–p21 axis [PMID:29472538, PMID:38570831, PMID:42138961]. Both subunits are substrates of m-calpain limited proteolysis that generates a PR45 fragment and activates basal PP2A(T72) activity [PMID:19555667].","teleology":[{"year":2003,"claim":"Established that PR72 is a Ca2+-sensing PP2A subunit by defining how its two EF-hand motifs partition between catalytic regulation and holoenzyme assembly/localization.","evidence":"EF-hand site-directed mutagenesis with in vitro Ca2+-binding and phosphatase assays, A/PR65 co-IP, and subcellular localization","pmids":["12524438"],"confidence":"High","gaps":["Physiological substrates dephosphorylated by Ca2+-activated PR72-PP2A not identified here","No structure of the Ca2+-bound holoenzyme"]},{"year":2005,"claim":"Placed PR72 in canonical Wnt signaling as the obligatory mediator of Naked cuticle's inhibitory effect, defining a specific pathway context for the subunit.","evidence":"Co-IP, Wnt reporter assays, and loss-of-function in mammalian cells and Xenopus embryos","pmids":["15687260"],"confidence":"High","gaps":["Direct PP2A substrate within the Wnt cascade not defined","Mechanism of how PR72-PP2A enables Nkd inhibition unresolved"]},{"year":2006,"claim":"Showed the two PPP2R3A transcripts have opposite signaling outputs, with PR130 acting as a Wnt activator that antagonizes PR72/Nkd, framing isoform-specific control of Wnt.","evidence":"Co-IP, Wnt reporter assays, and Xenopus rescue experiments","pmids":["16567647"],"confidence":"High","gaps":["Molecular basis for the opposite outputs of the two isoforms not fully resolved","Relative in vivo abundance/regulation of the two transcripts unaddressed"]},{"year":2007,"claim":"Demonstrated a concrete neuronal substrate, showing PR72-PP2A drives Ca2+- and glutamate-dependent DARPP-32 Thr-75 dephosphorylation, linking the EF1 motif to signaling in vivo.","evidence":"PR72 overexpression/RNAi in neurons, EF-hand mutagenesis, in vitro phosphatase assay, DARPP-32 phospho-immunoblot","pmids":["17535922"],"confidence":"High","gaps":["Whether direct dephosphorylation versus indirect effect not fully separated","Broader neuronal substrate repertoire unknown"]},{"year":2009,"claim":"Revealed a regulatory mechanism whereby m-calpain limited proteolysis converts PR72/PR130 into a PR45 fragment that activates basal PP2A(T72) activity, linking Ca2+-proteases to PP2A control.","evidence":"In vitro calpain cleavage, MS peptide mapping, EF-hand mutants, phosphatase assays, and an apoptotic cell model","pmids":["19555667"],"confidence":"High","gaps":["Physiological triggers and substrates of PR45-activated PP2A in vivo not established","Fate/function of PR45 fragment beyond activity change unclear"]},{"year":2009,"claim":"Defined a PR130 receptor-tyrosine-kinase role, showing PR130 complexes with SHIP2 and EGFR to restrain EGFR degradation and sustain AKT/ERK signaling.","evidence":"Reciprocal co-IP, co-localization, siRNA with RNAi-resistant rescue, EGFR degradation and downstream phospho-immunoblots","pmids":["19825976"],"confidence":"High","gaps":["Direct PP2A substrate controlling EGFR/c-Cbl interaction not identified","Connection to the Wnt/Nkd functions of PR130 unaddressed"]},{"year":2016,"claim":"Identified the LPP LIM domains as a PR130 partner via its N-terminal Zn2+-finger-like motif, defining a focal-contact pool of PR130 that controls adhesion and migration.","evidence":"Co-IP/pulldown, confocal co-localization, in vitro phosphatase assay, siRNA with domain-deletion rescue, and migration/adhesion assays","pmids":["26945059"],"confidence":"High","gaps":["Adhesion-site substrate dephosphorylated by LPP-PR130-PP2A not defined","Dynamics of release from LPP not fully resolved"]},{"year":2016,"claim":"Established PR130 (pr130) as required for myocardium formation and contractile function in vivo using zebrafish loss-of-function.","evidence":"CRISPR/Cas9 zebrafish knockout with echocardiography, histology, EM, and TUNEL","pmids":["27845735"],"confidence":"Medium","gaps":["No molecular pathway placement beyond PP2A function","Relationship to PR72's cardiac roles not addressed"]},{"year":2018,"claim":"Placed PR130 in the DNA-damage checkpoint via an HDAC1/2→PR130→PP2A→ATM axis controlling replicative-stress responses and homologous recombination.","evidence":"PR130 knockdown, HDAC inhibitor treatment, ATM/CHK1 phospho-immunoblots, RPA/RAD51 immunofluorescence, cell cycle and apoptosis assays","pmids":["29472538"],"confidence":"High","gaps":["Direct demonstration that PP2A-PR130 dephosphorylates ATM at specific sites not shown","Therapeutic context limited to HDAC inhibitor sensitization"]},{"year":2018,"claim":"Showed pr72 is required for cardiac development through the Wnt pathway, connecting the Wnt-regulatory function to organ morphogenesis in vivo.","evidence":"TALEN zebrafish knockout with cardiac imaging, EM, mRNA rescue, and Wnt effector immunoblot","pmids":["30481179"],"confidence":"Medium","gaps":["Direct PP2A substrate within cardiac Wnt signaling not identified","Single-lab in vivo model"]},{"year":2021,"claim":"Reported that PPP2R3A loss impairs cardiomyocyte proliferation and survival and screened for binding partners, nominating COL1A2.","evidence":"shRNA knockdown, viability/cell-cycle/apoptosis assays, and a yeast two-hybrid screen","pmids":["34982454"],"confidence":"Low","gaps":["Yeast two-hybrid interactors lack biochemical validation","No pathway placement for the proliferation/apoptosis phenotype"]},{"year":2023,"claim":"Placed PP2A-PR72/130 upstream of the β-catenin/p300 axis in hematopoietic stem cell maintenance, with pharmacological PP2A activation restoring HSC function.","evidence":"In vivo IQ-1 treatment of Sfrp1 conditional KO mice, β-catenin/p300 co-IP, nuclear fractionation, and HSC transplantation assays","pmids":["35950533"],"confidence":"Medium","gaps":["IQ-1 is not PR72/130-specific, so direct subunit causality is indirect","Which isoform mediates the p300 effect not resolved"]},{"year":2023,"claim":"Established PR72 as a positive regulator of cardiac contractility and Ca2+ cycling in vivo via gain-of-function.","evidence":"Heart-specific PR72 transgenic mice with catheterization, sarcomere shortening, Ca2+ imaging, and phospholamban pThr17/NCX immunoblots","pmids":["37868783"],"confidence":"Medium","gaps":["Direct PP2A substrate driving Ca2+-cycling changes not pinpointed","Single-lab transgenic model"]},{"year":2024,"claim":"Revealed a proteostasis function whereby PP2A-PR130 prevents cytotoxic protein aggregation in pancreatic cancer cells independently of p53.","evidence":"Genetic knockout/siRNA of PR130 in PDAC cells, apoptosis flow cytometry, aggregate imaging, proteomics, and HSP70 inhibitor combination","pmids":["38570831"],"confidence":"Medium","gaps":["Substrates whose dephosphorylation prevents aggregation not defined","Generality beyond PDAC unknown"]},{"year":2026,"claim":"Identified PR130 as an antiviral restriction factor against HSV-1 acting through the CDK2-controlled p21 axis and modulation of ATM signaling.","evidence":"PR130 knockdown/overexpression in epithelial and neuronal cells, proteome/phosphoproteome profiling, viral titers, ATM and USP7 inhibitor epistasis","pmids":["42138961"],"confidence":"Medium","gaps":["Direct PP2A substrate among p21/CDK2/ATM not biochemically confirmed","Not yet independently replicated"]},{"year":null,"claim":"How distinct PR72 versus PR130 N-termini select among the many reported partners and substrates to produce isoform-specific, context-dependent PP2A outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking N-terminal motifs to substrate choice","Most reported phenotypes lack a directly validated dephosphorylation substrate","Crosstalk between Ca2+/calpain regulation and the diverse signaling roles not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14]}],"complexes":["PP2A heterotrimer (PR72/PR130 B''-subunit)"],"partners":["PPP2R1A","NAKED CUTICLE (NKD)","LPP","SHIP2 (INPPL1)","EGFR","ATM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q06190","full_name":"Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha","aliases":["PP2A subunit B isoform PR72/PR130","PP2A subunit B isoform R3 isoform","PP2A subunit B isoforms B''-PR72/PR130","PP2A subunit B isoforms B72/B130","Serine/threonine-protein phosphatase 2A 72/130 kDa regulatory subunit B"],"length_aa":1150,"mass_kda":130.3,"function":"The B regulatory subunit might modulate substrate selectivity and catalytic activity, and might also direct the localization of the catalytic enzyme to a particular subcellular compartment","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q06190/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP2R3A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPP2CA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP2R3A","total_profiled":1310},"omim":[{"mim_id":"604944","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B-DOUBLE PRIME, ALPHA; PPP2R3A","url":"https://www.omim.org/entry/604944"},{"mim_id":"300339","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B-DOUBLE PRIME, BETA; PPP2R3B","url":"https://www.omim.org/entry/300339"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":47.9},{"tissue":"skeletal muscle","ntpm":168.9},{"tissue":"tongue","ntpm":110.0}],"url":"https://www.proteinatlas.org/search/PPP2R3A"},"hgnc":{"alias_symbol":["PR130","PR72"],"prev_symbol":["PPP2R3"]},"alphafold":{"accession":"Q06190","domains":[{"cath_id":"1.10.238.230","chopping":"723-794","consensus_level":"medium","plddt":93.3751,"start":723,"end":794},{"cath_id":"1.10.238.220","chopping":"809-896","consensus_level":"medium","plddt":95.9242,"start":809,"end":896},{"cath_id":"1.10.238.10","chopping":"912-1073_1085-1109","consensus_level":"medium","plddt":92.6803,"start":912,"end":1109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06190","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06190-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06190-F1-predicted_aligned_error_v6.png","plddt_mean":58.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP2R3A","jax_strain_url":"https://www.jax.org/strain/search?query=PPP2R3A"},"sequence":{"accession":"Q06190","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06190.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06190/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06190"}},"corpus_meta":[{"pmid":"17535922","id":"PMC_17535922","title":"The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17535922","citation_count":84,"is_preprint":false},{"pmid":"12524438","id":"PMC_12524438","title":"Identification and functional analysis of two Ca2+-binding EF-hand motifs in the B\"/PR72 subunit of protein phosphatase 2A.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12524438","citation_count":72,"is_preprint":false},{"pmid":"29472538","id":"PMC_29472538","title":"HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29472538","citation_count":65,"is_preprint":false},{"pmid":"15687260","id":"PMC_15687260","title":"PR72, a novel regulator of Wnt signaling required for Naked cuticle function.","date":"2005","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15687260","citation_count":60,"is_preprint":false},{"pmid":"19825976","id":"PMC_19825976","title":"Protein phosphatase 2A PR130/B''alpha1 subunit binds to the SH2 domain-containing inositol polyphosphate 5-phosphatase 2 and prevents epidermal growth factor (EGF)-induced EGF receptor degradation sustaining EGF-mediated signaling.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19825976","citation_count":42,"is_preprint":false},{"pmid":"16567647","id":"PMC_16567647","title":"PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16567647","citation_count":36,"is_preprint":false},{"pmid":"18715506","id":"PMC_18715506","title":"Diversity in genomic organisation, developmental regulation and distribution of the murine PR72/B\" subunits of protein phosphatase 2A.","date":"2008","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18715506","citation_count":27,"is_preprint":false},{"pmid":"35933397","id":"PMC_35933397","title":"GREM1/PPP2R3A expression in heterogeneous fibroblasts initiates pulmonary fibrosis.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/35933397","citation_count":26,"is_preprint":false},{"pmid":"33068647","id":"PMC_33068647","title":"The PP2A subunit PR130 is a key regulator of cell development and oncogenic transformation.","date":"2020","source":"Biochimica et biophysica acta. Reviews on cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33068647","citation_count":21,"is_preprint":false},{"pmid":"26945059","id":"PMC_26945059","title":"PP2A binds to the LIM domains of lipoma-preferred partner through its PR130/B″ subunit to regulate cell adhesion and migration.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26945059","citation_count":21,"is_preprint":false},{"pmid":"27845735","id":"PMC_27845735","title":"Deletion of Pr130 Interrupts Cardiac Development in Zebrafish.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27845735","citation_count":14,"is_preprint":false},{"pmid":"19555667","id":"PMC_19555667","title":"Specific regulation of protein phosphatase 2A PR72/B'' subunits by calpain.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19555667","citation_count":11,"is_preprint":false},{"pmid":"30481179","id":"PMC_30481179","title":"Deletion of Pr72 causes cardiac developmental defects in Zebrafish.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30481179","citation_count":9,"is_preprint":false},{"pmid":"11551645","id":"PMC_11551645","title":"Cellular distribution of bovine leukemia virus proteins gp51SU, Pr72(env), and Pr66(gag-pro) in persistently infected cells.","date":"2001","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/11551645","citation_count":8,"is_preprint":false},{"pmid":"37226801","id":"PMC_37226801","title":"Exosomal miR-192-5p secreted by bone marrow mesenchymal stem cells inhibits hepatic stellate cell activation and targets PPP2R3A.","date":"2023","source":"Journal of histotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37226801","citation_count":7,"is_preprint":false},{"pmid":"35950533","id":"PMC_35950533","title":"Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.","date":"2023","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/35950533","citation_count":5,"is_preprint":false},{"pmid":"38570831","id":"PMC_38570831","title":"The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38570831","citation_count":4,"is_preprint":false},{"pmid":"34982454","id":"PMC_34982454","title":"The potential mechanism of PPP2R3A in myocardial cells and its interacting proteins.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34982454","citation_count":4,"is_preprint":false},{"pmid":"32392189","id":"PMC_32392189","title":"[Functional Hypermethylation of ALDH1L1, PLCL2, and PPP2R3A in Colon Cancer].","date":"2020","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/32392189","citation_count":3,"is_preprint":false},{"pmid":"37868783","id":"PMC_37868783","title":"Hypercontractile cardiac phenotype in mice overexpressing the regulatory subunit PR72 of protein phosphatase 2A.","date":"2023","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37868783","citation_count":3,"is_preprint":false},{"pmid":"41086913","id":"PMC_41086913","title":"Catecholaminergic stress results in signs of heart failure in PP2A-PR72 overexpressor mice.","date":"2025","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/41086913","citation_count":1,"is_preprint":false},{"pmid":"42138961","id":"PMC_42138961","title":"The Host Cell Factor Phosphatase-2A Subunit PR130 Restricts Replication of Herpes Simplex Virus Type-1.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42138961","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13028,"output_tokens":4601,"usd":0.05405,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12794,"output_tokens":4985,"usd":0.094298,"stage2_stop_reason":"end_turn"},"total_usd":0.148348,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Two functional Ca2+-binding EF-hand motifs (EF1 and EF2) were identified in human PR72/B''. Ca2+ binding induces a conformational change dependent on motif integrity. EF2 integrity is required for structural A/PR65 subunit interaction and proper nuclear targeting of PR72, whereas EF1 mediates Ca2+-dependent effects on PP2A(T72) catalytic activity in vitro and is partially required for PR72's ability to alter cell cycle progression upon forced expression.\",\n      \"method\": \"Site-directed mutagenesis of EF-hand motifs, in vitro Ca2+-binding assays, subcellular fractionation/localization, co-immunoprecipitation with A/PR65 subunit, in vitro phosphatase activity assays, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis of active-site residues, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"12524438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The PR72 regulatory subunit directs PP2A to mediate Ca2+-dependent dephosphorylation of DARPP-32 at Thr-75 in striatal neurons. EF-hand 1 of PR72 is necessary for Ca2+-dependent regulation of PP2A activity both in vitro and in vivo. The PR72-containing PP2A heterotrimer is also required for glutamate acting at AMPA and NMDA receptors to regulate Thr-75 dephosphorylation.\",\n      \"method\": \"Overexpression and RNAi-mediated knockdown of PR72 in neurons, in vitro phosphatase assay, EF-hand mutagenesis, measurement of DARPP-32 phosphorylation by immunoblot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro assay plus mutagenesis plus in vivo RNAi with specific phosphorylation readout, replicated across conditions\",\n      \"pmids\": [\"17535922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PR72 physically and functionally interacts with Naked cuticle (Nkd) and acts as a negative regulator of the canonical Wnt signaling cascade. The inhibitory effect of Naked cuticle on Wnt signaling requires PR72, both in mammalian cell culture and in Xenopus embryos. PR72 is also required for regulation of cell morphogenetic movements during body axis formation.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays for Wnt pathway activity, Xenopus embryo injection/loss-of-function experiments, mammalian cell culture overexpression/knockdown\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal physical interaction plus epistasis in two independent systems (mammalian cells and Xenopus embryos)\",\n      \"pmids\": [\"15687260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PR130, which shares the C-terminus with PR72 but has a distinct N-terminus, also physically interacts with Naked cuticle but acts as an activator of the canonical Wnt signaling pathway (opposite to PR72). PR130 restricts Naked cuticle's ability to function as a Wnt inhibitor, modulating Wnt signal transduction through differential expression of the two PPP2R3A transcripts.\",\n      \"method\": \"Co-immunoprecipitation, Wnt reporter assays in mammalian cells, Xenopus embryo injection/rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical interaction plus functional epistasis in two independent model systems, published by same lab building on prior replicated work\",\n      \"pmids\": [\"16567647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PR72/B''alpha2 and PR130/B''alpha1 are specifically cleaved by the Ca2+-dependent protease m-calpain into a 45–48 kDa proteolysis-resistant fragment ('PR45'). This limited proteolysis depends on EF-hand integrity, weakens PR72-core enzyme interaction, activates basal PP2A(T72) phosphatase activity, and dramatically increases sensitivity to polycation activation. PR45 generation was also observed in staurosporine-induced apoptotic MCF7 cells in a calpain-dependent manner.\",\n      \"method\": \"In vitro calpain cleavage assay, mass spectrometry peptide mapping, EF-hand mutant analysis, PP2A phosphatase activity assay, apoptosis model with calpain inhibitors\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of proteolysis with mutagenesis validation, corroborated in a cell model, single lab\",\n      \"pmids\": [\"19555667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PR130/B''alpha1 forms a constitutive complex with SHIP2 and a transient EGF-stimulated complex with EGFR in mammalian cell lines. PR130 and SHIP2 co-localize and both translocate to the cell membrane upon EGF stimulation. RNAi-mediated knockdown of PR130 increases EGF-induced proteasome-dependent EGFR degradation and increases EGFR interaction with E3 ligase c-Cbl, leading to faster inactivation of downstream AKT and ERK/MAPK signaling; these effects are rescued by RNAi-resistant PR130.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by fluorescence microscopy, siRNA knockdown, rescue with RNAi-resistant construct, immunoblot for EGFR degradation and phosphorylation of downstream targets\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA with functional readout, and rescue experiment in a single study\",\n      \"pmids\": [\"19825976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PR130/B''alpha1 binds the LIM domains of lipoma-preferred partner (LPP) through a conserved Zn2+-finger-like motif in the differentially spliced N-terminus of PR130. Isolated LPP-associated PP2A complexes are catalytically active. PR130 co-localizes with LPP at focal contacts but is excluded from mature focal adhesions. An LPP-PR130 fusion that cannot release from LPP (by deletion of the PP2A/C-binding domain of PR130) only localizes to focal adhesions, suggesting the interaction is dynamic. siRNA knockdown of PR130 increases cell adhesion to collagen I and decreases migration; these phenotypes cannot be rescued by a PR130 mutant unable to bind LPP.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, co-localization by confocal microscopy, in vitro phosphatase activity assay, siRNA knockdown, rescue with domain-deletion mutants, scratch wound and Transwell migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis rescue, multiple orthogonal cellular phenotypic assays in a single study\",\n      \"pmids\": [\"26945059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Deletion of pr130 in zebrafish (CRISPR/Cas9) causes cardiac looping defects, decreased fractional area and fractional shortening, reduced cardiomyocyte number, disrupted sarcomere ultrastructure (blurred Z- and M-lines, narrowed I- and A-bands), and increased cardiomyocyte apoptosis, establishing that pr130 is required for normal myocardium formation and efficient cardiac contractile function.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, echocardiography/functional imaging, H&E histology, transmission electron microscopy, TUNEL apoptosis assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo genetic knockout with multiple phenotypic readouts, single lab, no mechanistic pathway placement beyond PP2A function\",\n      \"pmids\": [\"27845735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC1 and HDAC2 suppress expression of PPP2R3A/PR130; elevated PR130 in turn promotes dephosphorylation of ATM by PP2A. Genetic elimination of PR130 slows G1/S phase transition, increases phospho-CHK1, RPA foci, and DNA damage upon replicative stress, and renders cells susceptible to HDAC inhibitor-induced mitotic catastrophe and apoptosis, with reduced RAD51-dependent homologous recombination.\",\n      \"method\": \"siRNA/genetic knockdown of PR130, HDAC inhibitor treatment, immunoblot for ATM/CHK1/WEE1/CDK1/p53 phosphorylation, immunofluorescence for RPA foci and RAD51, cell cycle analysis, apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal biochemical and cellular readouts, mechanistic pathway placement (HDAC→PR130→PP2A→ATM), single lab\",\n      \"pmids\": [\"29472538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of pr72 in zebrafish (TALEN) causes enlarged ventricular chambers, reduced cardiomyocyte number, decreased cardiac function, defective sarcomere ultrastructure (abnormal mitochondria, I bands, Z lines, and intercalated disks), abnormal heart looping rescued by wild-type pr72 mRNA injection, and elevated Wnt effectors—indicating pr72 regulates cardiac development via the Wnt pathway.\",\n      \"method\": \"TALEN-mediated knockout in zebrafish, cardiac imaging/functional measurements, transmission electron microscopy, mRNA rescue injection, Wnt pathway effector immunoblot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mRNA rescue and molecular pathway readout (Wnt effectors), single lab\",\n      \"pmids\": [\"30481179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPP2R3A silencing in primary neonatal rat cardiomyocytes and H9c2 cells inhibits cell proliferation, arrests the cell cycle in S phase, and promotes apoptosis. Yeast two-hybrid screening identified 19 candidate PPP2R3A-interacting proteins in a human cardiomyocyte cDNA library, with COL1A2 being the most frequent interactor.\",\n      \"method\": \"shRNA lentiviral knockdown, CCK-8 viability assay, flow cytometry for cell cycle and apoptosis, yeast two-hybrid screen\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, yeast two-hybrid interaction without biochemical validation, phenotypic but no pathway placement\",\n      \"pmids\": [\"34982454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In an osteoprogenitor Sfrp1-deletion mouse model, PP2A-PR72/130 regulates phosphorylation of the transcriptional co-activator p300; pharmacological activation of PP2A-PR72/130 with IQ-1 reduces the β-catenin/phospho-p300 nuclear association and restores hematopoietic stem cell repopulating activity, placing PP2A-PR72/130 upstream of the β-catenin/p300 axis in HSC maintenance.\",\n      \"method\": \"In vivo IQ-1 pharmacological treatment of Sfrp1 conditional KO mice, co-immunoprecipitation for β-catenin/p300 interaction, nuclear fractionation, HSC transplantation/repopulation assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological intervention with molecular readout and functional rescue, single lab\",\n      \"pmids\": [\"35950533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heart-specific overexpression of PP2A-PR72 (2.5-fold) in transgenic mice causes moderate cardiac hypertrophy, increased maximal ventricular pressure, faster sarcomere shortening and relaxation, increased Ca2+ transient amplitude, shortened Ca2+ decay, increased phospholamban phosphorylation at Thr-17, and reduced Na+/Ca2+ exchanger expression, establishing PR72 as a regulator of cardiac contractility and Ca2+ cycling.\",\n      \"method\": \"Transgenic mouse model, cardiac catheterization, sarcomere length/shortening measurements in isolated cardiomyocytes, Ca2+ spark/transient imaging, immunoblot for phospholamban pThr17 and NCX\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean transgenic gain-of-function with multiple orthogonal biochemical and physiological readouts, single lab\",\n      \"pmids\": [\"37868783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic elimination of PR130 sensitizes murine and human pancreatic ductal adenocarcinoma (PDAC) cells to PP2A inhibitor phendione-induced apoptosis and cytotoxic protein aggregate formation independently of p53. PP2A-PR130 complex activity prevents protein aggregation in tumor cells; phendione promotes proteasomal degradation of PR130, and HSP70 upregulation partially compensates for PP2A-PR130 loss.\",\n      \"method\": \"Genetic knockout/siRNA of PR130, flow cytometry for apoptosis, confocal microscopy for protein aggregates, proteomics, immunoblot for PR130/HSP70, HSP70 inhibitor combination treatment\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple orthogonal assays and proteomics in a single study, single lab\",\n      \"pmids\": [\"38570831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PR130 (PPP2R3A) restricts replication of HSV-1 in epithelial and neuronal cells; HSV-1 infection in turn decreases PR130 levels. PR130 controls expression and phosphorylation of the CDK inhibitor p21 (CDKN1A) at Ser-130 (catalyzed by CDK2). PR130 depletion enhances ATM signaling upon HSV-1 infection and creates a dependency of HSV-1 replication on ATM activity. Inhibition of USP7 stabilizes the p53-p21 axis and reduces HSV-1 viral titers.\",\n      \"method\": \"PR130 knockdown/overexpression in epithelial and neuronal cells, global proteome and phosphoproteome profiling, viral titer assays, ATM inhibitor epistasis, USP7 inhibitor treatment, immunoblot for p21/CDK2/ATM phosphorylation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with proteomics and functional epistasis in multiple cell types, single lab, not yet independently replicated\",\n      \"pmids\": [\"42138961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2R3A encodes the PR72 and PR130 regulatory B''-type subunits of PP2A that direct substrate specificity and subcellular targeting of the PP2A heterotrimer: PR72 contains two Ca2+-binding EF-hand motifs (EF1 required for Ca2+-dependent activation, EF2 required for A-subunit interaction and nuclear targeting), mediates Ca2+-dependent dephosphorylation of DARPP-32 Thr-75 in neurons, negatively regulates canonical Wnt signaling through physical interaction with Naked cuticle, and controls cardiac contractility and Ca2+ cycling; PR130 uses a distinct N-terminal Zn2+-finger-like motif to bind partners including LPP, SHIP2/EGFR, and Naked cuticle (acting as a Wnt activator in opposition to PR72), promotes ATM dephosphorylation to modulate DNA-damage checkpoint decisions, protects proteins from aggregation in tumor cells, restricts HSV-1 replication via the CDK2-p21 axis, and regulates cardiac and hematopoietic development; both isoforms are substrates of calpain-mediated limited proteolysis that alters their PP2A regulatory activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2R3A encodes two B''-type regulatory subunits of protein phosphatase 2A, PR72 and PR130, generated from distinct transcripts that share a common C-terminus but differ in their N-termini, and that direct PP2A substrate specificity, localization, and signaling output [#0, #3]. PR72 carries two functional Ca2+-binding EF-hand motifs: EF1 mediates Ca2+-dependent regulation of PP2A(T72) catalytic activity, while EF2 is required for interaction with the structural A/PR65 subunit and for nuclear targeting [#0]. Through this Ca2+-responsive activity PR72-containing PP2A dephosphorylates DARPP-32 at Thr-75 in striatal neurons downstream of glutamatergic (AMPA/NMDA) signaling [#1], and as a contractility regulator it controls cardiac Ca2+ cycling, raising phospholamban Thr-17 phosphorylation and Ca2+ transient amplitude [#12]. The two isoforms exert opposing control over canonical Wnt signaling through physical interaction with Naked cuticle, PR72 acting as a Wnt inhibitor and PR130 as a Wnt activator, and PR72 is required for cardiac development via the Wnt pathway [#2, #3, #9]. PR130 instead engages a distinct set of partners through its N-terminal Zn2+-finger-like motif and adaptor interactions—LPP at focal contacts to control adhesion and migration [#6], and SHIP2/EGFR to restrain EGFR degradation and sustain AKT and ERK signaling [#5]. PR130 also promotes PP2A-mediated dephosphorylation of ATM to modulate replicative-stress and DNA-damage checkpoint responses (downstream of HDAC1/2 control), guards tumor cells against cytotoxic protein aggregation, and restricts HSV-1 replication via the CDK2–p21 axis [#8, #13, #14]. Both subunits are substrates of m-calpain limited proteolysis that generates a PR45 fragment and activates basal PP2A(T72) activity [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that PR72 is a Ca2+-sensing PP2A subunit by defining how its two EF-hand motifs partition between catalytic regulation and holoenzyme assembly/localization.\",\n      \"evidence\": \"EF-hand site-directed mutagenesis with in vitro Ca2+-binding and phosphatase assays, A/PR65 co-IP, and subcellular localization\",\n      \"pmids\": [\"12524438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates dephosphorylated by Ca2+-activated PR72-PP2A not identified here\", \"No structure of the Ca2+-bound holoenzyme\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed PR72 in canonical Wnt signaling as the obligatory mediator of Naked cuticle's inhibitory effect, defining a specific pathway context for the subunit.\",\n      \"evidence\": \"Co-IP, Wnt reporter assays, and loss-of-function in mammalian cells and Xenopus embryos\",\n      \"pmids\": [\"15687260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PP2A substrate within the Wnt cascade not defined\", \"Mechanism of how PR72-PP2A enables Nkd inhibition unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the two PPP2R3A transcripts have opposite signaling outputs, with PR130 acting as a Wnt activator that antagonizes PR72/Nkd, framing isoform-specific control of Wnt.\",\n      \"evidence\": \"Co-IP, Wnt reporter assays, and Xenopus rescue experiments\",\n      \"pmids\": [\"16567647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for the opposite outputs of the two isoforms not fully resolved\", \"Relative in vivo abundance/regulation of the two transcripts unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a concrete neuronal substrate, showing PR72-PP2A drives Ca2+- and glutamate-dependent DARPP-32 Thr-75 dephosphorylation, linking the EF1 motif to signaling in vivo.\",\n      \"evidence\": \"PR72 overexpression/RNAi in neurons, EF-hand mutagenesis, in vitro phosphatase assay, DARPP-32 phospho-immunoblot\",\n      \"pmids\": [\"17535922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether direct dephosphorylation versus indirect effect not fully separated\", \"Broader neuronal substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a regulatory mechanism whereby m-calpain limited proteolysis converts PR72/PR130 into a PR45 fragment that activates basal PP2A(T72) activity, linking Ca2+-proteases to PP2A control.\",\n      \"evidence\": \"In vitro calpain cleavage, MS peptide mapping, EF-hand mutants, phosphatase assays, and an apoptotic cell model\",\n      \"pmids\": [\"19555667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers and substrates of PR45-activated PP2A in vivo not established\", \"Fate/function of PR45 fragment beyond activity change unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a PR130 receptor-tyrosine-kinase role, showing PR130 complexes with SHIP2 and EGFR to restrain EGFR degradation and sustain AKT/ERK signaling.\",\n      \"evidence\": \"Reciprocal co-IP, co-localization, siRNA with RNAi-resistant rescue, EGFR degradation and downstream phospho-immunoblots\",\n      \"pmids\": [\"19825976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PP2A substrate controlling EGFR/c-Cbl interaction not identified\", \"Connection to the Wnt/Nkd functions of PR130 unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the LPP LIM domains as a PR130 partner via its N-terminal Zn2+-finger-like motif, defining a focal-contact pool of PR130 that controls adhesion and migration.\",\n      \"evidence\": \"Co-IP/pulldown, confocal co-localization, in vitro phosphatase assay, siRNA with domain-deletion rescue, and migration/adhesion assays\",\n      \"pmids\": [\"26945059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion-site substrate dephosphorylated by LPP-PR130-PP2A not defined\", \"Dynamics of release from LPP not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established PR130 (pr130) as required for myocardium formation and contractile function in vivo using zebrafish loss-of-function.\",\n      \"evidence\": \"CRISPR/Cas9 zebrafish knockout with echocardiography, histology, EM, and TUNEL\",\n      \"pmids\": [\"27845735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway placement beyond PP2A function\", \"Relationship to PR72's cardiac roles not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PR130 in the DNA-damage checkpoint via an HDAC1/2→PR130→PP2A→ATM axis controlling replicative-stress responses and homologous recombination.\",\n      \"evidence\": \"PR130 knockdown, HDAC inhibitor treatment, ATM/CHK1 phospho-immunoblots, RPA/RAD51 immunofluorescence, cell cycle and apoptosis assays\",\n      \"pmids\": [\"29472538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that PP2A-PR130 dephosphorylates ATM at specific sites not shown\", \"Therapeutic context limited to HDAC inhibitor sensitization\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed pr72 is required for cardiac development through the Wnt pathway, connecting the Wnt-regulatory function to organ morphogenesis in vivo.\",\n      \"evidence\": \"TALEN zebrafish knockout with cardiac imaging, EM, mRNA rescue, and Wnt effector immunoblot\",\n      \"pmids\": [\"30481179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PP2A substrate within cardiac Wnt signaling not identified\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reported that PPP2R3A loss impairs cardiomyocyte proliferation and survival and screened for binding partners, nominating COL1A2.\",\n      \"evidence\": \"shRNA knockdown, viability/cell-cycle/apoptosis assays, and a yeast two-hybrid screen\",\n      \"pmids\": [\"34982454\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Yeast two-hybrid interactors lack biochemical validation\", \"No pathway placement for the proliferation/apoptosis phenotype\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed PP2A-PR72/130 upstream of the β-catenin/p300 axis in hematopoietic stem cell maintenance, with pharmacological PP2A activation restoring HSC function.\",\n      \"evidence\": \"In vivo IQ-1 treatment of Sfrp1 conditional KO mice, β-catenin/p300 co-IP, nuclear fractionation, and HSC transplantation assays\",\n      \"pmids\": [\"35950533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IQ-1 is not PR72/130-specific, so direct subunit causality is indirect\", \"Which isoform mediates the p300 effect not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PR72 as a positive regulator of cardiac contractility and Ca2+ cycling in vivo via gain-of-function.\",\n      \"evidence\": \"Heart-specific PR72 transgenic mice with catheterization, sarcomere shortening, Ca2+ imaging, and phospholamban pThr17/NCX immunoblots\",\n      \"pmids\": [\"37868783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PP2A substrate driving Ca2+-cycling changes not pinpointed\", \"Single-lab transgenic model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a proteostasis function whereby PP2A-PR130 prevents cytotoxic protein aggregation in pancreatic cancer cells independently of p53.\",\n      \"evidence\": \"Genetic knockout/siRNA of PR130 in PDAC cells, apoptosis flow cytometry, aggregate imaging, proteomics, and HSP70 inhibitor combination\",\n      \"pmids\": [\"38570831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates whose dephosphorylation prevents aggregation not defined\", \"Generality beyond PDAC unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified PR130 as an antiviral restriction factor against HSV-1 acting through the CDK2-controlled p21 axis and modulation of ATM signaling.\",\n      \"evidence\": \"PR130 knockdown/overexpression in epithelial and neuronal cells, proteome/phosphoproteome profiling, viral titers, ATM and USP7 inhibitor epistasis\",\n      \"pmids\": [\"42138961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PP2A substrate among p21/CDK2/ATM not biochemically confirmed\", \"Not yet independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct PR72 versus PR130 N-termini select among the many reported partners and substrates to produce isoform-specific, context-dependent PP2A outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking N-terminal motifs to substrate choice\", \"Most reported phenotypes lack a directly validated dephosphorylation substrate\", \"Crosstalk between Ca2+/calpain regulation and the diverse signaling roles not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [\"PP2A heterotrimer (PR72/PR130 B''-subunit)\"],\n    \"partners\": [\"PPP2R1A\", \"Naked cuticle (NKD)\", \"LPP\", \"SHIP2 (INPPL1)\", \"EGFR\", \"ATM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}