{"gene":"PPP2R1B","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1998,"finding":"A truncated PP2A-Abeta (PPP2R1B) protein generated by a deletion mutation was unable to bind to the catalytic (C) subunit of the PP2A holoenzyme, establishing that the C-terminal region of PPP2R1B is required for catalytic subunit interaction.","method":"Sequencing of tumor-derived deletion mutant; functional binding assay showing loss of catalytic subunit interaction","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional binding assay on tumor-derived mutant protein, single lab but mechanistically clear result","pmids":["9765152"],"is_preprint":false},{"year":2004,"finding":"Missense mutations and deletions within amino acids 412–601 of PPP2R1B (the PP2A-C binding region, encompassing HEAT repeats 11–15) inhibit co-immunoprecipitation of PP2A-Abeta and PP2A-C proteins, demonstrating that this domain mediates catalytic subunit binding.","method":"Co-immunoprecipitation of PP2A-Abeta and PP2A-C from colorectal cancer tissues harboring PPP2R1B mutations","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with endogenous proteins, replicated across multiple tumor samples with distinct mutations, single lab","pmids":["14767517"],"is_preprint":false},{"year":2006,"finding":"Wild-type PP2A-Abeta (PPP2R1B) binds B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 regulatory subunits but not B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) in an in vitro binding assay. The cancer-associated G90D mutation inhibits interaction with B56gamma but does not affect binding to PR72, identifying an isoform-selective regulatory subunit interface.","method":"In vitro binding assay with recombinant regulatory subunits; site-directed mutagenesis (G90D)","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution binding assay with mutagenesis, single lab","pmids":["16276521"],"is_preprint":false},{"year":2007,"finding":"PP2A-Abeta (PPP2R1B) forms a complex with the small GTPase RalA and dephosphorylates RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. Cancer-associated Abeta mutants fail to form this complex, and suppression of PP2A Abeta permits immortalized human cells to achieve tumorigenic transformation.","method":"Co-immunoprecipitation (PP2A-Abeta/RalA complex), phosphorylation assay, cell transformation assays with wild-type and mutant Abeta re-expression, shRNA knockdown","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation assay, functional transformation rescue with mutants), rigorous mechanistic dissection in a single high-quality study","pmids":["17540176"],"is_preprint":false},{"year":2015,"finding":"PPP2R1B negatively regulates AKT activation; knockdown of PPP2R1B increases AKT phosphorylation, leading to elevated XIAP expression and enhanced 5-FU resistance, while rescue of PPP2R1B expression decreases AKT phosphorylation and XIAP levels and re-sensitizes colon cancer cells to 5-FU-induced apoptosis.","method":"siRNA knockdown and rescue overexpression of PPP2R1B; western blotting for pAKT and XIAP; cell viability and apoptosis assays; xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and rescue experiment, in vitro and in vivo, single lab","pmids":["26247730"],"is_preprint":false},{"year":2007,"finding":"Alternative splicing of PPP2R1B (skipping of exons 2/3 or 3) in B-CLL was associated with reduced PP2A phosphatase activity, indicating that the exon 2/3-encoded region is required for full enzymatic function of the PP2A holoenzyme.","method":"RT-PCR detection of aberrant splicing; PP2A activity assay","journal":"European journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — association between splice variant and enzyme activity, single method, single lab, limited mechanistic detail in abstract","pmids":["17449237"],"is_preprint":false},{"year":2012,"finding":"The proximal promoter of the PP2A-Abeta (PPP2R1B) gene contains functional binding sites for Ets-1 (negative regulator), SP1/SP3 (positive regulators), and RXRalpha/beta (positive regulators), as demonstrated by gel mobility shift assays, in vitro mutagenesis, luciferase reporter assays, and chromatin immunoprecipitation.","method":"Gel mobility shift assay, in vitro mutagenesis, luciferase reporter gene assay, ChIP","journal":"Current molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (EMSA, mutagenesis, reporter assay, ChIP) in single lab establishing transcriptional regulation","pmids":["22827437"],"is_preprint":false},{"year":2021,"finding":"Homozygous deletion of Ppp2r1b in mice impairs meiotic recombination and causes meiotic arrest in spermatocytes, resulting in male infertility. PPP2R1B protein stability is regulated by ubiquitination: E3 ligase CRL4A-DCAF6 promotes polyubiquitination and degradation of PPP2R1B, while ubiquitin-specific protease 5 (USP5) counteracts this by deubiquitination.","method":"Homozygous mouse knockout (phenotype: meiotic arrest, infertility); identification of CRL4A-DCAF6 as E3 ligase and USP5 as deubiquitinase via functional assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype plus identification of upstream ubiquitin writer/eraser, single lab","pmids":["33913576"],"is_preprint":false},{"year":2022,"finding":"Hepatic IRF3 directly transcriptionally induces Ppp2r1b expression; IRF3-mediated induction of Ppp2r1b amplifies PP2A activity, leading to dephosphorylation of AMPKalpha and AKT, thereby suppressing hepatic glucose production and contributing to dysglycemia in obesity.","method":"Hepatocyte-specific IRF3 knockout mice; integration of IRF3-dependent transcriptome and cistrome (ChIP-seq); PP2A activity assay; phosphorylation assays for AMPKalpha and AKT; antisense oligonucleotide suppression of hepatic Irf3 in obese mice","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (conditional KO, cistrome, activity assay, phosphorylation readout, in vivo ASO), mechanistic pathway established with direct causality","pmids":["35320000"],"is_preprint":false},{"year":2024,"finding":"PPP2R1B co-immunoprecipitates with phospho-ERK (p-ERK) in colorectal cancer cells, and PPP2R1B expression negatively correlates with p-ERK levels; PPP2R1B induces dephosphorylation of ERK, inhibiting the MAPK/ERK signaling pathway and suppressing EMT-mediated liver metastasis.","method":"Co-immunoprecipitation (PPP2R1B with p-ERK); LC-MS/MS substrate identification; western blotting for p-ERK and EMT markers; wound healing/invasion assays; in vivo liver metastasis model (spleen injection)","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional KD/OE with defined molecular phenotype and in vivo confirmation, single lab","pmids":["38429738"],"is_preprint":false},{"year":2025,"finding":"Germline missense variant R233C in PPP2R1B disrupts binding of PP2A catalytic subunit to the scaffold, resulting in loss of phosphatase activity. Additionally, germline loss-of-function truncating variants produce rapidly degraded protein, establishing that PPP2R1B protein stability and catalytic subunit binding are both required for PP2A phosphatase function.","method":"Functional characterization of mutant Abeta overexpression (protein turnover assay); catalytic subunit binding assay; phosphatase activity assay","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding and phosphatase activity assays with mutagenesis, single lab, mechanistically clear","pmids":["40178903"],"is_preprint":false},{"year":2021,"finding":"eIF3a controls ERK activity by regulating PPP2R1B expression via a translational mechanism; downregulation of eIF3a reduces PPP2R1B protein levels, thereby increasing p-ERK and conferring resistance to vemurafenib (BRAF inhibitor) in melanoma cells.","method":"Overexpression of eIF3a in resistant cells; western blotting for PPP2R1B and p-ERK; cell sensitivity assays","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (OE + WB), no direct reconstitution of translational regulation","pmids":["34512348"],"is_preprint":false}],"current_model":"PPP2R1B (PP2A-Abeta) encodes the beta isoform of the PP2A scaffold A subunit, which forms the structural platform of the PP2A heterotrimer; its HEAT repeat region (particularly repeats 11–15 and the exon 2/3-encoded N-terminal domain) mediates binding of the catalytic C subunit and select regulatory B subunits (B56gamma, PR72, PR48 but not B55alpha, B56alpha, or B56beta); the assembled PP2A-Abeta complex dephosphorylates substrates including RalA (at Ser183/Ser194), AKT, AMPKalpha, and ERK, thereby suppressing oncogenic signaling and cell transformation; PPP2R1B expression is transcriptionally activated by SP1/SP3 and RXRalpha/beta and repressed by Ets-1, and is transcriptionally induced by IRF3 in hepatocytes to suppress glucose production; PPP2R1B protein stability is controlled by ubiquitination via CRL4A-DCAF6 (E3 ligase) and USP5 (deubiquitinase); cancer-associated mutations impair catalytic or regulatory subunit binding and abolish tumor-suppressive function, while complete loss causes meiotic arrest and male infertility in mice."},"narrative":{"mechanistic_narrative":"PPP2R1B (PP2A-Abeta) encodes the beta isoform of the PP2A scaffold A subunit, which assembles the PP2A heterotrimer and functions as a tumor suppressor that restrains oncogenic signaling [PMID:17540176]. Its C-terminal HEAT-repeat region (amino acids 412–601, repeats 11–15) is required to bind the catalytic C subunit, and tumor-derived deletions and missense variants in this region abolish that interaction [PMID:9765152, PMID:14767517, PMID:40178903]; an independent N-terminal interface selectively recruits regulatory subunits B56gamma, PR72, and PR48 but not B55alpha, B56alpha, or B56beta, and the cancer-associated G90D mutation disrupts B56gamma binding [PMID:16276521]. The assembled Abeta holoenzyme dephosphorylates multiple signaling substrates: RalA at Ser183/Ser194 to inactivate its transforming function [PMID:17540176], AKT to limit XIAP-driven 5-FU resistance [PMID:26247730], AMPKalpha and AKT in hepatocytes [PMID:35320000], and ERK to suppress MAPK-driven EMT and liver metastasis [PMID:38429738]; cancer-associated mutants that fail to form these complexes lose tumor-suppressive activity [PMID:17540176, PMID:40178903]. PPP2R1B abundance is set transcriptionally by SP1/SP3 and RXRalpha/beta activators and Ets-1 repression at its promoter [PMID:22827437] and by hepatic IRF3 induction that amplifies PP2A activity to suppress glucose production [PMID:35320000], and its protein stability is controlled by CRL4A-DCAF6–mediated ubiquitination opposed by USP5 deubiquitination [PMID:33913576]. Loss of Ppp2r1b in mice impairs meiotic recombination and causes spermatocyte meiotic arrest and male infertility [PMID:33913576].","teleology":[{"year":1998,"claim":"Established which region of the scaffold subunit is needed to engage the catalytic core, defining the structural basis of holoenzyme assembly.","evidence":"Sequencing and functional binding assay on a tumor-derived deletion mutant","pmids":["9765152"],"confidence":"Medium","gaps":["Did not map the interface at residue resolution","No functional consequence for downstream signaling tested"]},{"year":2004,"claim":"Localized the catalytic-subunit binding determinant to HEAT repeats 11–15 (aa 412–601), showing tumor mutations there break the A–C interaction.","evidence":"Reciprocal Co-IP of endogenous PP2A-Abeta and PP2A-C from mutation-bearing colorectal tumors","pmids":["14767517"],"confidence":"Medium","gaps":["Did not assess effect on regulatory subunit recruitment","Phosphatase activity of mutant holoenzymes not measured"]},{"year":2006,"claim":"Defined an isoform-selective regulatory-subunit interface, distinguishing Abeta from Aalpha by its subset of B-subunit partners.","evidence":"In vitro binding assay with recombinant B subunits plus G90D mutagenesis","pmids":["16276521"],"confidence":"Medium","gaps":["Selectivity not confirmed in cells","Functional output of B56gamma- vs PR72-containing holoenzymes unresolved"]},{"year":2007,"claim":"Identified RalA as a direct substrate and demonstrated that loss of Abeta enables transformation, establishing its tumor-suppressor mechanism.","evidence":"Co-IP, phosphorylation assay, and transformation rescue with WT/mutant Abeta plus shRNA knockdown","pmids":["17540176"],"confidence":"High","gaps":["Did not establish Abeta-specific regulatory subunit for RalA dephosphorylation in vivo","Other transformation-relevant substrates not surveyed"]},{"year":2007,"claim":"Linked the exon 2/3-encoded N-terminal region to full enzymatic function via splice variants seen in B-CLL.","evidence":"RT-PCR detection of aberrant splicing with PP2A activity assay","pmids":["17449237"],"confidence":"Low","gaps":["Association only; causal effect of splicing on activity not reconstituted","Single method, limited mechanistic detail"]},{"year":2012,"claim":"Mapped the transcriptional control of PPP2R1B, identifying activating and repressing factors at its proximal promoter.","evidence":"EMSA, promoter mutagenesis, luciferase reporters, and ChIP","pmids":["22827437"],"confidence":"Medium","gaps":["Physiological contexts driving each factor not defined","No link to downstream phosphatase output"]},{"year":2015,"claim":"Connected PPP2R1B loss to AKT-driven chemoresistance, extending its substrate repertoire beyond RalA.","evidence":"siRNA knockdown/rescue, pAKT and XIAP western blots, apoptosis assays, and xenografts","pmids":["26247730"],"confidence":"Medium","gaps":["Direct dephosphorylation of AKT by Abeta holoenzyme not biochemically shown","Regulatory subunit involved not identified"]},{"year":2021,"claim":"Revealed post-translational control of PPP2R1B abundance and a required in vivo role in male meiosis.","evidence":"Ppp2r1b knockout mice with meiotic phenotype plus identification of CRL4A-DCAF6 and USP5 as ubiquitin writer/eraser","pmids":["33913576"],"confidence":"Medium","gaps":["Substrates relevant to meiotic recombination not identified","How ubiquitination is signaled is unknown"]},{"year":2021,"claim":"Proposed translational control of PPP2R1B by eIF3a as a determinant of ERK activity and BRAF-inhibitor resistance.","evidence":"eIF3a overexpression with PPP2R1B/p-ERK western blots and drug sensitivity assays","pmids":["34512348"],"confidence":"Low","gaps":["Translational mechanism not directly reconstituted","Single method, single lab"]},{"year":2022,"claim":"Placed PPP2R1B in a hepatic metabolic axis, showing IRF3-driven induction amplifies PP2A to dephosphorylate AMPKalpha/AKT and suppress glucose production.","evidence":"Hepatocyte IRF3 knockout, cistrome integration, PP2A activity and phosphorylation assays, in vivo ASO suppression in obese mice","pmids":["35320000"],"confidence":"High","gaps":["Direct biochemical demonstration of Abeta holoenzyme acting on AMPKalpha not isolated from total PP2A","Regulatory subunit mediating metabolic substrates unidentified"]},{"year":2024,"claim":"Identified ERK as a direct substrate, linking PPP2R1B to suppression of MAPK-driven metastasis.","evidence":"Co-IP with p-ERK, LC-MS/MS substrate ID, EMT marker blots, invasion assays, and in vivo liver metastasis model","pmids":["38429738"],"confidence":"Medium","gaps":["Dephosphorylation site on ERK not mapped","Holoenzyme composition for ERK targeting not defined"]},{"year":2025,"claim":"Showed germline variants impair PP2A function through two distinct routes—loss of catalytic binding and accelerated protein degradation.","evidence":"Protein turnover, catalytic subunit binding, and phosphatase activity assays on R233C and truncating variants","pmids":["40178903"],"confidence":"Medium","gaps":["Associated human phenotype not mechanistically connected to a specific substrate","In vivo consequences of these germline variants not modeled"]},{"year":null,"claim":"Which regulatory B subunit pairs with Abeta to direct each substrate (RalA, AKT, AMPKalpha, ERK) in a given tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted holoenzyme assigned to specific substrates","Tissue-specific subunit usage undefined","Structural basis of substrate selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,8,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[7]}],"complexes":["PP2A holoenzyme"],"partners":["PPP2R5C","PPP2R3A","RALA","AKT1","MAPK1","DCAF6","USP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30154","full_name":"Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform","aliases":["PP2A subunit A isoform PR65-beta","PP2A subunit A isoform R1-beta"],"length_aa":601,"mass_kda":66.2,"function":"The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P30154/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP2R1B","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":10.0},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"PPP2CB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP2R1B","total_profiled":1310},"omim":[{"mim_id":"610643","title":"CELL PROLIFERATION-REGULATING INHIBITOR OF PROTEIN PHOSPHATASE 2A; CIP2A","url":"https://www.omim.org/entry/610643"},{"mim_id":"607870","title":"UNC5 NETRIN RECEPTOR B; UNC5B","url":"https://www.omim.org/entry/607870"},{"mim_id":"605983","title":"PROTEIN PHOSPHATASE 2, STRUCTURAL/REGULATORY SUBUNIT A, ALPHA; PPP2R1A","url":"https://www.omim.org/entry/605983"},{"mim_id":"605590","title":"SPLICING FACTOR 3B, SUBUNIT 1; SF3B1","url":"https://www.omim.org/entry/605590"},{"mim_id":"604908","title":"PROTEIN PHOSPHATASE 4, REGULATORY SUBUNIT 1; PPP4R1","url":"https://www.omim.org/entry/604908"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":152.7}],"url":"https://www.proteinatlas.org/search/PPP2R1B"},"hgnc":{"alias_symbol":["PR65B","PP2A-Abeta"],"prev_symbol":[]},"alphafold":{"accession":"P30154","domains":[{"cath_id":"1.25.10.10","chopping":"361-486","consensus_level":"medium","plddt":93.1192,"start":361,"end":486},{"cath_id":"1.25.10.10","chopping":"503-601","consensus_level":"medium","plddt":96.1092,"start":503,"end":601}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30154","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30154-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30154-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP2R1B","jax_strain_url":"https://www.jax.org/strain/search?query=PPP2R1B"},"sequence":{"accession":"P30154","fasta_url":"https://rest.uniprot.org/uniprotkb/P30154.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30154/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30154"}},"corpus_meta":[{"pmid":"9765152","id":"PMC_9765152","title":"Alterations 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/23588898","citation_count":6,"is_preprint":false},{"pmid":"34512348","id":"PMC_34512348","title":"The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34512348","citation_count":5,"is_preprint":false},{"pmid":"40178903","id":"PMC_40178903","title":"Germline mutations in PPP2R1B in patients with a personal and family history of cancer.","date":"2025","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/40178903","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14582,"output_tokens":3250,"usd":0.046248,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10714,"output_tokens":3629,"usd":0.072148,"stage2_stop_reason":"end_turn"},"total_usd":0.118396,"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\": 1998,\n      \"finding\": \"A truncated PP2A-Abeta (PPP2R1B) protein generated by a deletion mutation was unable to bind to the catalytic (C) subunit of the PP2A holoenzyme, establishing that the C-terminal region of PPP2R1B is required for catalytic subunit interaction.\",\n      \"method\": \"Sequencing of tumor-derived deletion mutant; functional binding assay showing loss of catalytic subunit interaction\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional binding assay on tumor-derived mutant protein, single lab but mechanistically clear result\",\n      \"pmids\": [\"9765152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations and deletions within amino acids 412–601 of PPP2R1B (the PP2A-C binding region, encompassing HEAT repeats 11–15) inhibit co-immunoprecipitation of PP2A-Abeta and PP2A-C proteins, demonstrating that this domain mediates catalytic subunit binding.\",\n      \"method\": \"Co-immunoprecipitation of PP2A-Abeta and PP2A-C from colorectal cancer tissues harboring PPP2R1B mutations\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with endogenous proteins, replicated across multiple tumor samples with distinct mutations, single lab\",\n      \"pmids\": [\"14767517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wild-type PP2A-Abeta (PPP2R1B) binds B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 regulatory subunits but not B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) in an in vitro binding assay. The cancer-associated G90D mutation inhibits interaction with B56gamma but does not affect binding to PR72, identifying an isoform-selective regulatory subunit interface.\",\n      \"method\": \"In vitro binding assay with recombinant regulatory subunits; site-directed mutagenesis (G90D)\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution binding assay with mutagenesis, single lab\",\n      \"pmids\": [\"16276521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PP2A-Abeta (PPP2R1B) forms a complex with the small GTPase RalA and dephosphorylates RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. Cancer-associated Abeta mutants fail to form this complex, and suppression of PP2A Abeta permits immortalized human cells to achieve tumorigenic transformation.\",\n      \"method\": \"Co-immunoprecipitation (PP2A-Abeta/RalA complex), phosphorylation assay, cell transformation assays with wild-type and mutant Abeta re-expression, shRNA knockdown\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation assay, functional transformation rescue with mutants), rigorous mechanistic dissection in a single high-quality study\",\n      \"pmids\": [\"17540176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPP2R1B negatively regulates AKT activation; knockdown of PPP2R1B increases AKT phosphorylation, leading to elevated XIAP expression and enhanced 5-FU resistance, while rescue of PPP2R1B expression decreases AKT phosphorylation and XIAP levels and re-sensitizes colon cancer cells to 5-FU-induced apoptosis.\",\n      \"method\": \"siRNA knockdown and rescue overexpression of PPP2R1B; western blotting for pAKT and XIAP; cell viability and apoptosis assays; xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and rescue experiment, in vitro and in vivo, single lab\",\n      \"pmids\": [\"26247730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Alternative splicing of PPP2R1B (skipping of exons 2/3 or 3) in B-CLL was associated with reduced PP2A phosphatase activity, indicating that the exon 2/3-encoded region is required for full enzymatic function of the PP2A holoenzyme.\",\n      \"method\": \"RT-PCR detection of aberrant splicing; PP2A activity assay\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — association between splice variant and enzyme activity, single method, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"17449237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The proximal promoter of the PP2A-Abeta (PPP2R1B) gene contains functional binding sites for Ets-1 (negative regulator), SP1/SP3 (positive regulators), and RXRalpha/beta (positive regulators), as demonstrated by gel mobility shift assays, in vitro mutagenesis, luciferase reporter assays, and chromatin immunoprecipitation.\",\n      \"method\": \"Gel mobility shift assay, in vitro mutagenesis, luciferase reporter gene assay, ChIP\",\n      \"journal\": \"Current molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (EMSA, mutagenesis, reporter assay, ChIP) in single lab establishing transcriptional regulation\",\n      \"pmids\": [\"22827437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous deletion of Ppp2r1b in mice impairs meiotic recombination and causes meiotic arrest in spermatocytes, resulting in male infertility. PPP2R1B protein stability is regulated by ubiquitination: E3 ligase CRL4A-DCAF6 promotes polyubiquitination and degradation of PPP2R1B, while ubiquitin-specific protease 5 (USP5) counteracts this by deubiquitination.\",\n      \"method\": \"Homozygous mouse knockout (phenotype: meiotic arrest, infertility); identification of CRL4A-DCAF6 as E3 ligase and USP5 as deubiquitinase via functional assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype plus identification of upstream ubiquitin writer/eraser, single lab\",\n      \"pmids\": [\"33913576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatic IRF3 directly transcriptionally induces Ppp2r1b expression; IRF3-mediated induction of Ppp2r1b amplifies PP2A activity, leading to dephosphorylation of AMPKalpha and AKT, thereby suppressing hepatic glucose production and contributing to dysglycemia in obesity.\",\n      \"method\": \"Hepatocyte-specific IRF3 knockout mice; integration of IRF3-dependent transcriptome and cistrome (ChIP-seq); PP2A activity assay; phosphorylation assays for AMPKalpha and AKT; antisense oligonucleotide suppression of hepatic Irf3 in obese mice\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (conditional KO, cistrome, activity assay, phosphorylation readout, in vivo ASO), mechanistic pathway established with direct causality\",\n      \"pmids\": [\"35320000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPP2R1B co-immunoprecipitates with phospho-ERK (p-ERK) in colorectal cancer cells, and PPP2R1B expression negatively correlates with p-ERK levels; PPP2R1B induces dephosphorylation of ERK, inhibiting the MAPK/ERK signaling pathway and suppressing EMT-mediated liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation (PPP2R1B with p-ERK); LC-MS/MS substrate identification; western blotting for p-ERK and EMT markers; wound healing/invasion assays; in vivo liver metastasis model (spleen injection)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional KD/OE with defined molecular phenotype and in vivo confirmation, single lab\",\n      \"pmids\": [\"38429738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Germline missense variant R233C in PPP2R1B disrupts binding of PP2A catalytic subunit to the scaffold, resulting in loss of phosphatase activity. Additionally, germline loss-of-function truncating variants produce rapidly degraded protein, establishing that PPP2R1B protein stability and catalytic subunit binding are both required for PP2A phosphatase function.\",\n      \"method\": \"Functional characterization of mutant Abeta overexpression (protein turnover assay); catalytic subunit binding assay; phosphatase activity assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding and phosphatase activity assays with mutagenesis, single lab, mechanistically clear\",\n      \"pmids\": [\"40178903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eIF3a controls ERK activity by regulating PPP2R1B expression via a translational mechanism; downregulation of eIF3a reduces PPP2R1B protein levels, thereby increasing p-ERK and conferring resistance to vemurafenib (BRAF inhibitor) in melanoma cells.\",\n      \"method\": \"Overexpression of eIF3a in resistant cells; western blotting for PPP2R1B and p-ERK; cell sensitivity assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (OE + WB), no direct reconstitution of translational regulation\",\n      \"pmids\": [\"34512348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2R1B (PP2A-Abeta) encodes the beta isoform of the PP2A scaffold A subunit, which forms the structural platform of the PP2A heterotrimer; its HEAT repeat region (particularly repeats 11–15 and the exon 2/3-encoded N-terminal domain) mediates binding of the catalytic C subunit and select regulatory B subunits (B56gamma, PR72, PR48 but not B55alpha, B56alpha, or B56beta); the assembled PP2A-Abeta complex dephosphorylates substrates including RalA (at Ser183/Ser194), AKT, AMPKalpha, and ERK, thereby suppressing oncogenic signaling and cell transformation; PPP2R1B expression is transcriptionally activated by SP1/SP3 and RXRalpha/beta and repressed by Ets-1, and is transcriptionally induced by IRF3 in hepatocytes to suppress glucose production; PPP2R1B protein stability is controlled by ubiquitination via CRL4A-DCAF6 (E3 ligase) and USP5 (deubiquitinase); cancer-associated mutations impair catalytic or regulatory subunit binding and abolish tumor-suppressive function, while complete loss causes meiotic arrest and male infertility in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2R1B (PP2A-Abeta) encodes the beta isoform of the PP2A scaffold A subunit, which assembles the PP2A heterotrimer and functions as a tumor suppressor that restrains oncogenic signaling [#3]. Its C-terminal HEAT-repeat region (amino acids 412\\u2013601, repeats 11\\u201315) is required to bind the catalytic C subunit, and tumor-derived deletions and missense variants in this region abolish that interaction [#0, #1, #10]; an independent N-terminal interface selectively recruits regulatory subunits B56gamma, PR72, and PR48 but not B55alpha, B56alpha, or B56beta, and the cancer-associated G90D mutation disrupts B56gamma binding [#2]. The assembled Abeta holoenzyme dephosphorylates multiple signaling substrates: RalA at Ser183/Ser194 to inactivate its transforming function [#3], AKT to limit XIAP-driven 5-FU resistance [#4], AMPKalpha and AKT in hepatocytes [#8], and ERK to suppress MAPK-driven EMT and liver metastasis [#9]; cancer-associated mutants that fail to form these complexes lose tumor-suppressive activity [#3, #10]. PPP2R1B abundance is set transcriptionally by SP1/SP3 and RXRalpha/beta activators and Ets-1 repression at its promoter [#6] and by hepatic IRF3 induction that amplifies PP2A activity to suppress glucose production [#8], and its protein stability is controlled by CRL4A-DCAF6\\u2013mediated ubiquitination opposed by USP5 deubiquitination [#7]. Loss of Ppp2r1b in mice impairs meiotic recombination and causes spermatocyte meiotic arrest and male infertility [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established which region of the scaffold subunit is needed to engage the catalytic core, defining the structural basis of holoenzyme assembly.\",\n      \"evidence\": \"Sequencing and functional binding assay on a tumor-derived deletion mutant\",\n      \"pmids\": [\"9765152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the interface at residue resolution\", \"No functional consequence for downstream signaling tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized the catalytic-subunit binding determinant to HEAT repeats 11\\u201315 (aa 412\\u2013601), showing tumor mutations there break the A\\u2013C interaction.\",\n      \"evidence\": \"Reciprocal Co-IP of endogenous PP2A-Abeta and PP2A-C from mutation-bearing colorectal tumors\",\n      \"pmids\": [\"14767517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not assess effect on regulatory subunit recruitment\", \"Phosphatase activity of mutant holoenzymes not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined an isoform-selective regulatory-subunit interface, distinguishing Abeta from Aalpha by its subset of B-subunit partners.\",\n      \"evidence\": \"In vitro binding assay with recombinant B subunits plus G90D mutagenesis\",\n      \"pmids\": [\"16276521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity not confirmed in cells\", \"Functional output of B56gamma- vs PR72-containing holoenzymes unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified RalA as a direct substrate and demonstrated that loss of Abeta enables transformation, establishing its tumor-suppressor mechanism.\",\n      \"evidence\": \"Co-IP, phosphorylation assay, and transformation rescue with WT/mutant Abeta plus shRNA knockdown\",\n      \"pmids\": [\"17540176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish Abeta-specific regulatory subunit for RalA dephosphorylation in vivo\", \"Other transformation-relevant substrates not surveyed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked the exon 2/3-encoded N-terminal region to full enzymatic function via splice variants seen in B-CLL.\",\n      \"evidence\": \"RT-PCR detection of aberrant splicing with PP2A activity assay\",\n      \"pmids\": [\"17449237\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association only; causal effect of splicing on activity not reconstituted\", \"Single method, limited mechanistic detail\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the transcriptional control of PPP2R1B, identifying activating and repressing factors at its proximal promoter.\",\n      \"evidence\": \"EMSA, promoter mutagenesis, luciferase reporters, and ChIP\",\n      \"pmids\": [\"22827437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts driving each factor not defined\", \"No link to downstream phosphatase output\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected PPP2R1B loss to AKT-driven chemoresistance, extending its substrate repertoire beyond RalA.\",\n      \"evidence\": \"siRNA knockdown/rescue, pAKT and XIAP western blots, apoptosis assays, and xenografts\",\n      \"pmids\": [\"26247730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of AKT by Abeta holoenzyme not biochemically shown\", \"Regulatory subunit involved not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed post-translational control of PPP2R1B abundance and a required in vivo role in male meiosis.\",\n      \"evidence\": \"Ppp2r1b knockout mice with meiotic phenotype plus identification of CRL4A-DCAF6 and USP5 as ubiquitin writer/eraser\",\n      \"pmids\": [\"33913576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates relevant to meiotic recombination not identified\", \"How ubiquitination is signaled is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proposed translational control of PPP2R1B by eIF3a as a determinant of ERK activity and BRAF-inhibitor resistance.\",\n      \"evidence\": \"eIF3a overexpression with PPP2R1B/p-ERK western blots and drug sensitivity assays\",\n      \"pmids\": [\"34512348\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Translational mechanism not directly reconstituted\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PPP2R1B in a hepatic metabolic axis, showing IRF3-driven induction amplifies PP2A to dephosphorylate AMPKalpha/AKT and suppress glucose production.\",\n      \"evidence\": \"Hepatocyte IRF3 knockout, cistrome integration, PP2A activity and phosphorylation assays, in vivo ASO suppression in obese mice\",\n      \"pmids\": [\"35320000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical demonstration of Abeta holoenzyme acting on AMPKalpha not isolated from total PP2A\", \"Regulatory subunit mediating metabolic substrates unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ERK as a direct substrate, linking PPP2R1B to suppression of MAPK-driven metastasis.\",\n      \"evidence\": \"Co-IP with p-ERK, LC-MS/MS substrate ID, EMT marker blots, invasion assays, and in vivo liver metastasis model\",\n      \"pmids\": [\"38429738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dephosphorylation site on ERK not mapped\", \"Holoenzyme composition for ERK targeting not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed germline variants impair PP2A function through two distinct routes\\u2014loss of catalytic binding and accelerated protein degradation.\",\n      \"evidence\": \"Protein turnover, catalytic subunit binding, and phosphatase activity assays on R233C and truncating variants\",\n      \"pmids\": [\"40178903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Associated human phenotype not mechanistically connected to a specific substrate\", \"In vivo consequences of these germline variants not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Which regulatory B subunit pairs with Abeta to direct each substrate (RalA, AKT, AMPKalpha, ERK) in a given tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted holoenzyme assigned to specific substrates\", \"Tissue-specific subunit usage undefined\", \"Structural basis of substrate selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 8, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"PP2A holoenzyme\"],\n    \"partners\": [\"PPP2R5C\", \"PPP2R3A\", \"RALA\", \"AKT1\", \"MAPK1\", \"DCAF6\", \"USP5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}