{"gene":"PPP2R5C","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"B56γ1 and B56γ3 isoforms of PP2A mediate dephosphorylation of p53 at Thr55 in response to DNA damage. Ablation of B56γ by RNAi abolishes Thr55 dephosphorylation, reduces p53 stabilization, Bax expression, and cell apoptosis. Endogenous B56γ protein level and association with p53 increase after DNA damage.","method":"RNAi knockdown, co-immunoprecipitation, Western blot, cell proliferation and transformation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi with specific phenotypic readout, replicated in multiple subsequent studies","pmids":["17245430"],"is_preprint":false},{"year":2007,"finding":"ATM-dependent phosphorylation of p53 at Ser15 is required for the enhanced interaction between B56γ and p53 after DNA damage. This Ser15-phosphorylation-mediated p53-B56γ interaction is required for B56γ3-induced G1 cell cycle arrest and inhibition of anchorage-independent growth.","method":"Co-immunoprecipitation, mutant p53 constructs, cell cycle analysis, anchorage-independent growth assays, ATM inhibition","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal functional assays, mutagenesis of key phospho-site, single lab","pmids":["17967874"],"is_preprint":false},{"year":2011,"finding":"ATM directly phosphorylates B56γ3 at Ser510 after DNA damage, leading to increased B56γ3-PP2A complex formation and directed PP2A phosphatase activity toward p53, activating tumor-suppressive functions. Under normal growth conditions, B56γ3 is targeted for ubiquitination and degradation by MDM2, and ATM-mediated phosphorylation at Ser510 blocks MDM2-mediated B56γ3 ubiquitination, upregulating B56γ3 protein levels.","method":"In vitro kinase assay, Co-IP, ubiquitination assay, mutagenesis (Ser510 substitution), cell proliferation and transformation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, Co-IP, ubiquitination assay, functional transformation assay, single lab but multiple orthogonal methods","pmids":["21460856"],"is_preprint":false},{"year":2010,"finding":"A B56γ mutation F395C identified in lung cancer disrupts the B56γ-p53 interaction, abolishes p53 Thr55 dephosphorylation, prevents transcriptional activation of p21, and eliminates the p53-dependent tumor-suppressive function of B56γ-PP2A. A domain of B56γ required for p53 interaction was identified, distinguishing p53-dependent from p53-independent tumor suppressive functions.","method":"Co-immunoprecipitation, site-directed mutagenesis, dephosphorylation assays, luciferase reporter (p21 transcription), cell transformation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of cancer-associated variant, Co-IP, functional assays for substrate dephosphorylation and transcriptional output, single lab with multiple orthogonal methods","pmids":["20473327"],"is_preprint":false},{"year":2012,"finding":"HEAT repeat 1 of B56γ is required for interaction with the PP2A AC core (scaffolding A and catalytic C subunits) and for B56γ-PP2A tumor-suppressive function. A tumor-associated mutation C39R within HEAT repeat 1 disrupts the AC core interaction, abolishing both p53-dependent and p53-independent tumor suppression.","method":"Co-immunoprecipitation, site-directed mutagenesis, dephosphorylation assays, cell proliferation and transformation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis with structural basis (HEAT repeat), Co-IP, multiple functional assays, single lab with orthogonal methods","pmids":["22315229"],"is_preprint":false},{"year":2013,"finding":"B56γ tumor-associated mutations from human cancer samples lose tumor-suppressive activity by two distinct mechanisms: disruption of interaction with the PP2A AC core (abolishing all substrate dephosphorylation), or disruption of specific substrate interactions (p53 and unknown proteins), causing partial loss of either p53-dependent or p53-independent tumor suppression.","method":"Co-immunoprecipitation, mutagenesis of cancer-derived variants, p53 dephosphorylation assay, cell proliferation and transformation assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional assays on multiple cancer-derived mutants, single lab, no in vitro reconstitution","pmids":["23723076"],"is_preprint":false},{"year":2004,"finding":"Knockdown of PP2A B56γ subunit can substitute for SV40 small tumor antigen (ST) expression to fully transform human cells (expressing LT, hTERT, and Ras-V12), establishing B56γ-PP2A as the relevant target of ST's transforming activity. ST promotes cell transformation through integrin signaling, src phosphorylation, and NF-κB activation.","method":"shRNA knockdown, transformation assay, gene expression profiling, pharmacological inhibition","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis by B56γ knockdown substituting for ST, full transformation assay, replicated across multiple studies confirming PP2A-B56γ as ST target","pmids":["15466190"],"is_preprint":false},{"year":2014,"finding":"B56γ is a negative regulator of NF-κB in TCR signaling in T cells. B56γ silencing induced increased IKK and IκBα phosphorylation upon TCR stimulation, enhanced NF-κB activity and target gene expression (including IL-2), and increased T cell proliferation. B56γ was identified by siRNA screen in Jurkat cells using an NF-κB-responsive reporter.","method":"siRNA screen, NF-κB luciferase reporter, Western blot (IKK and IκBα phosphorylation), cytokine quantification, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen with reporter, confirmed by phosphorylation assays and functional readouts, single lab, no direct substrate dephosphorylation reconstituted","pmids":["24719332"],"is_preprint":false},{"year":2010,"finding":"PP2A with B56γ targeting subunit antagonizes ATM- and CK1/2-dependent phosphorylation of CREB and ATF1 in cells. B56γ-PP2A opposes phosphorylation at the conserved ATM/CK cluster on both transcription factors.","method":"Co-immunoprecipitation, phosphorylation assays, B56γ overexpression/knockdown, CK1/2 inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation assays in cellulo with B56γ manipulation, single lab, no in vitro reconstitution of direct dephosphorylation","pmids":["20730097"],"is_preprint":false},{"year":2002,"finding":"Transgenic overexpression of B56γ in the lung (using SP-C promoter) disrupts distal lung differentiation and causes neonatal death, associated with loss of beta-catenin, suggesting B56γ modulates PP2A action on the Wnt/beta-catenin signaling pathway during lung airway morphogenesis.","method":"Transgenic mouse model, in situ hybridization, immunohistochemistry, beta-catenin Western blot","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic loss-of-function with specific developmental phenotype and molecular readout (beta-catenin loss), single lab","pmids":["12003782"],"is_preprint":false},{"year":2014,"finding":"PP2A-B56γ knockout mice develop incomplete ventricular septal defects and decreased ventricular cardiomyocytes, with cardiomyocyte apoptosis during mid-to-late gestation. B56γ is expressed in the nucleus of alpha-actinin-positive cardiomyocytes containing Z-bands during cardiac development. Mice also show decreased neuromuscular coordination and gripping strength, indicating a role in neuromuscular function.","method":"Transgenic knockout mouse, histology, immunohistochemistry, TUNEL apoptosis assay, behavioral testing","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific cardiac and neuromuscular phenotype and subcellular localization data, single lab","pmids":["24425002"],"is_preprint":false},{"year":2017,"finding":"PP2A-B56γ is required for stability of BubR1 during nocodazole-induced spindle assembly checkpoint (SAC) arrest. In primary cells lacking B56γ, BubR1 is prematurely degraded and cells proceed through mitosis, resulting in abnormal chromosomal segregation. Inactivation of B56γ alone (without affecting other B56 family members) is sufficient to affect SAC efficiency.","method":"B56γ knockout primary cells, nocodazole arrest, Western blot (BubR1 levels), chromosome segregation analysis, fluorescence imaging of B56 subunit localization","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific SAC phenotype and molecular readout (BubR1 degradation), single lab","pmids":["28562161"],"is_preprint":false},{"year":2003,"finding":"B56γ1 and B56γ2 (but not B56γ3) localize to the Golgi complex (cis-Golgi) in melanoma cells, and the PP2A catalytic subunit co-fractionates with B56γ in the Golgi-enriched fraction. A truncated variant Δγ1 preferentially localizes to the trans-Golgi. Cells stably expressing Δγ1 show faster vesicle transport from ER to plasma membrane and elevated directional migration, suggesting B56γ-containing PP2A holoenzymes suppress vesicle transport.","method":"Immunofluorescence, subcellular fractionation/sucrose gradient, FLAG-tagged protein localization, vesicle transport assay, cell migration assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — fractionation-based localization with functional transport and migration assays, single lab, no direct substrate identified","pmids":["12547706"],"is_preprint":false},{"year":2007,"finding":"Liprin-α1 interacts with PP2A B56γ as a novel binding partner identified by tandem affinity purification and mass spectrometry. B56γ-liprin-α1 complexes are distinct from PP2A complexes containing B56γ (i.e., liprin-α1 does not directly contribute to cell transformation). Suppression of liprin-α1 alters cell morphology.","method":"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, RNAi knockdown","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification confirmed by Co-IP, functional morphology readout, single lab","pmids":["18235218"],"is_preprint":false},{"year":2022,"finding":"Liprin-α1 contains an LxxIxE short linear motif (SLiM) in its N-terminal region that interacts specifically with B56γ regulatory subunits of PP2A. Two point mutations in the SLiM strongly reduce the interaction. B56γ mediates the interaction of liprin-α1 with the heterotrimeric PP2A holoenzyme. B56γ localizes to plasma membrane-associated platforms (PMAPs) in migrating breast cancer cells in a liprin-α1-dependent manner. Silencing B56γ inhibits cell spreading, invasion, motility, and lamellipodia dynamics to a similar extent as silencing liprin-α1.","method":"Co-immunoprecipitation, mutagenesis of SLiM motif, subcellular fractionation, live-cell imaging, RNAi knockdown, invasion assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, SLiM mutagenesis, localization experiments with functional consequence (motility, invasion), single lab with multiple orthogonal methods","pmids":["36171301"],"is_preprint":false},{"year":2020,"finding":"The B56γ subunit of PP2A is the host factor bound by the HTLV-1 retroviral integrase (IN). Cryo-EM and X-ray crystallography structures reveal a tetrameric IN assembly bound to two molecules of B56γ via a conserved short linear motif on the integrase.","method":"X-ray crystallography, single-particle cryo-EM, structural determination of complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM and X-ray crystal structures of the protein complex, rigorous structural validation","pmids":["33028863"],"is_preprint":false},{"year":2018,"finding":"B56γ is transactivated by AP-1, which is regulated by ER stress-induced CREBH signaling in HBx-expressing hepatic cells. B56γ dephosphorylates p-Thr55-p53, triggering p53/p21 pathway-dependent G1 cell cycle arrest and apoptosis of HBx-expressing hepatocytes.","method":"Western blot, co-immunoprecipitation, gene knockdown/overexpression, cell cycle analysis, luciferase reporter assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dephosphorylation assay, cell cycle and apoptosis readouts with specific molecular mechanism, single lab","pmids":["29988038"],"is_preprint":false},{"year":2022,"finding":"B56γ inhibits HBV/HBx-dependent hepatocarcinogenesis by mediating dephosphorylation of AKT at Thr308 and Ser473. B56γ overexpression and site-directed mutagenesis mimicking dephosphorylation (AKTT308A, AKTS473A) inhibited cell growth, migration, and invasion in HBx-expressing HCC cells.","method":"Western blot, site-directed mutagenesis, co-immunoprecipitation, overexpression, xenograft mouse model, cell migration/invasion assays","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis mimicking dephosphorylation, in vivo xenograft, multiple functional assays, single lab","pmids":["35811356"],"is_preprint":false},{"year":2022,"finding":"B56γ-mediated direct dephosphorylation of Drp1 at Ser616 inhibits the interaction between p-Drp1Ser616 and Rab7, thereby inhibiting mitophagy and increasing mitochondria-dependent apoptosis in HCC cells under chemotherapy treatment.","method":"Co-immunoprecipitation, Western blot (dephosphorylation), B56γ overexpression/knockdown, xenograft mouse model, flow cytometry (apoptosis), mitochondria-lysosome contact site imaging","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dephosphorylation assay, co-IP of Drp1-Rab7 interaction, in vivo xenograft, multiple functional assays, single lab","pmids":["35697120"],"is_preprint":false},{"year":2003,"finding":"A truncated isoform of B56γ (Δγ1) in metastatic melanoma BL6 cells impairs the cell-cycle checkpoint, leading to increased polyploidy and reduced apoptosis after irradiation, and promotes metastasis. Expression of Δγ1 in F10 cells reproduced the checkpoint aberration and enhanced metastatic ability.","method":"Gene transfection, irradiation, cell cycle analysis, apoptosis assay, in vivo tumor transplant and metastasis assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic expression in isogenic cell lines, in vivo metastasis assay, cell cycle readout, single lab","pmids":["12507892"],"is_preprint":false},{"year":2004,"finding":"A truncated B56γ variant (Δγ1) reduces irradiation-induced Mdm2 phosphorylation, which blocks irradiation-stimulated p53 accumulation and p53-target gene (Bax) induction, contributing to melanoma cell radioresistance.","method":"Stable transfection, Western blot (Mdm2 and p53 phosphorylation), RT-PCR (p53/Bax mRNA), apoptosis assay, in vivo irradiation","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Western blot-based mechanism in stably transfected cells, single lab, single method per endpoint, indirect mechanism (no direct dephosphorylation assay)","pmids":["15024700"],"is_preprint":false},{"year":2021,"finding":"Mice with both B56δ and B56γ inactivated (double knockout) arrest fetal development around E12 with hearts having a single outflow vessel, demonstrating strong genetic interaction between B56δ and B56γ that is necessary for heart development. Individual knockouts of B56δ or B56γ alone are not lethal.","method":"CRISPR/Cas9n knockout mouse generation, embryo phenotyping, cardiac histology","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockout, clear developmental phenotype, single lab","pmids":["35415460"],"is_preprint":false},{"year":2010,"finding":"The transcription factor NRL directly binds the NRL-response element on the Ppp2r5c promoter (validated by EMSA and chromatin immunoprecipitation) and enhances Ppp2r5c transcriptional activity during mouse photoreceptor development.","method":"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP directly demonstrating NRL binding to Ppp2r5c promoter, single lab","pmids":["21078119"],"is_preprint":false},{"year":2026,"finding":"PP2A-B56γ selectively dephosphorylates the ribosome biogenesis regulator Ebp1 at Ser335 in neurons exposed to polystyrene nanoplastics, reducing Ebp1 nucleolar localization, suppressing 47S pre-rRNA transcription, and inducing nucleolar stress that activates the p53/p21 pathway and promotes neuronal senescence. Pharmacological PP2A inhibition (LB-100) prevented these effects.","method":"In vitro dephosphorylation assay, mouse exposure model, immunofluorescence (Ebp1 nucleolar localization), pre-rRNA transcription assay, Western blot (p53/p21), pharmacological rescue with LB-100, co-culture system","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dephosphorylation assay with specific substrate and site, in vivo model, pharmacological rescue, single lab with multiple orthogonal methods","pmids":["42097318"],"is_preprint":false},{"year":2025,"finding":"De novo missense variants in PPP2R5C cause a neurodevelopmental disorder (Houge-Janssens syndrome spectrum). Variants affect either substrate binding, C-subunit binding, or both, and variably reduce catalytic activity of the phosphatase. Total loss-of-function variants can be inherited from non-symptomatic parents, indicating dominant-negative mechanism on substrate dephosphorylation is the likely pathogenic mechanism.","method":"Patient variant analysis, structural mapping onto PP2A crystal structure, PP2A catalytic activity assays, clinical phenotyping of 26 individuals","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — activity assays on multiple patient variants, structural mapping, large patient cohort, single study","pmids":["39978342"],"is_preprint":false},{"year":2026,"finding":"PPP2R5C (B56γ) interacts with Tau protein, reducing Tau levels and phosphorylation via ULK1-dependent autophagolysosomal activation and PP2A regulation. PPP2R5C reduction precedes Tau hyperphosphorylation in Tau Braak-staged brains.","method":"Co-immunoprecipitation, immunohistochemistry of staged brain tissue, exosome proteomics (LC-MS/MS), Western blot","journal":"Cell reports. Medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP showing interaction with Tau, mechanistic pathway proposed but not fully reconstituted, single lab, limited mechanistic follow-up in abstract","pmids":["41720088"],"is_preprint":false}],"current_model":"PPP2R5C (B56γ) is the substrate-targeting regulatory subunit of PP2A heterotrimeric phosphatase complexes; upon DNA damage, ATM phosphorylates B56γ3 at Ser510 (blocking MDM2-mediated ubiquitination and degradation) while also phosphorylating p53 at Ser15 to recruit B56γ-PP2A, which dephosphorylates p53 at Thr55 to stabilize p53 and activate p21-dependent growth arrest; B56γ additionally dephosphorylates AKT, Drp1 at Ser616, Ebp1 at Ser335, and CREB/ATF1, suppresses NF-κB in T cells via IKK dephosphorylation, supports cell migration through liprin-α1-mediated recruitment to plasma membrane platforms, localizes to the Golgi to regulate vesicle transport, is required for spindle assembly checkpoint integrity (BubR1 stability) and cardiac development, and serves as the host receptor for deltaretroviral integrase via a conserved short linear motif, with cancer-associated mutations in its HEAT repeat 1 or substrate-binding domain disrupting AC core assembly or substrate recognition to abrogate tumor suppressor function."},"narrative":{"mechanistic_narrative":"PPP2R5C (B56γ) is a substrate-targeting regulatory subunit of the PP2A heterotrimeric phosphatase that operates as a context-dependent tumor suppressor by directing catalytic activity onto specific phosphoprotein substrates [PMID:17245430, PMID:15466190]. Its central role is in the DNA-damage response: ATM-dependent phosphorylation of p53 at Ser15 recruits B56γ, which dephosphorylates p53 at Thr55 to stabilize the protein, drive p21 transcription, and impose G1 arrest, while ATM also phosphorylates B56γ itself at Ser510 to block MDM2-mediated ubiquitination and stabilize the subunit [PMID:17245430, PMID:17967874, PMID:21460856, PMID:29988038]. B56γ engages the PP2A AC core through its first HEAT repeat and contacts substrates through a separate substrate-binding domain, so cancer-associated mutations fall into two mechanistic classes—loss of AC-core assembly (e.g. C39R) abolishing all activity, or loss of specific substrate contacts (e.g. F395C) selectively crippling p53-dependent suppression [PMID:20473327, PMID:22315229, PMID:23723076]. Beyond p53, B56γ-PP2A dephosphorylates AKT (Thr308/Ser473), Drp1 at Ser616 to restrain mitophagy, Ebp1 at Ser335 to govern nucleolar ribosome biogenesis, and CREB/ATF1, and it negatively regulates NF-κB in T-cell receptor signaling by opposing IKK phosphorylation [PMID:24719332, PMID:20730097, PMID:35811356, PMID:35697120, PMID:42097318]. The subunit is recruited to plasma-membrane platforms via an LxxIxE short linear motif in liprin-α1 to support cell spreading, invasion, and migration, localizes isoform-specifically to the Golgi to modulate vesicle transport, and maintains spindle-assembly-checkpoint integrity by stabilizing BubR1 [PMID:28562161, PMID:12547706, PMID:36171301]. B56γ is required for cardiac development, acting in genetic concert with B56δ [PMID:24425002, PMID:35415460], and is exploited as the host receptor for HTLV-1 retroviral integrase through a conserved SLiM, as resolved by structural studies [PMID:33028863]. De novo missense variants in PPP2R5C cause a neurodevelopmental disorder in the Houge-Janssens syndrome spectrum, with a likely dominant-negative effect on substrate dephosphorylation [PMID:39978342].","teleology":[{"year":2007,"claim":"Established that B56γ is the PP2A subunit responsible for dephosphorylating p53 at Thr55 during the DNA-damage response, linking PP2A to p53 stabilization and apoptosis.","evidence":"RNAi knockdown, reciprocal Co-IP, and apoptosis/transformation readouts in damaged cells","pmids":["17245430"],"confidence":"High","gaps":["Did not define how the B56γ-p53 interaction is regulated","No structural basis for substrate recognition"]},{"year":2007,"claim":"Showed that ATM-driven p53 Ser15 phosphorylation is the trigger that recruits B56γ, explaining how damage signaling is converted into targeted dephosphorylation and growth arrest.","evidence":"Co-IP with phospho-site mutant p53, cell-cycle and anchorage-independent growth assays, ATM inhibition","pmids":["17967874"],"confidence":"High","gaps":["Did not address regulation of B56γ protein levels","p53-independent functions not separated"]},{"year":2011,"claim":"Resolved how B56γ itself is controlled, showing ATM phosphorylates B56γ at Ser510 to block MDM2-mediated degradation and upregulate the subunit upon damage.","evidence":"In vitro kinase assay, ubiquitination assay, Ser510 mutagenesis, transformation assays","pmids":["21460856"],"confidence":"High","gaps":["MDM2 ubiquitination site on B56γ not mapped","In vivo relevance of Ser510 not tested in animals"]},{"year":2010,"claim":"Defined a discrete substrate-binding domain by showing a lung-cancer mutation F395C selectively abolishes p53 binding and p21 activation, separating p53-dependent from p53-independent tumor suppression.","evidence":"Cancer-variant mutagenesis, Co-IP, dephosphorylation and p21 luciferase reporter assays","pmids":["20473327"],"confidence":"High","gaps":["Identity of p53-independent substrates not established","No structural model of the domain"]},{"year":2012,"claim":"Mapped HEAT repeat 1 as the AC-core docking site and showed mutation C39R there disrupts holoenzyme assembly, abolishing all suppressor activity.","evidence":"Co-IP, HEAT-repeat mutagenesis, dephosphorylation and transformation assays","pmids":["22315229"],"confidence":"High","gaps":["No reconstitution of the assembled holoenzyme","Did not enumerate p53-independent substrates lost"]},{"year":2013,"claim":"Consolidated a two-class mutational model in which cancer-derived variants either lose AC-core binding (global loss) or lose specific substrate contacts (selective loss).","evidence":"Co-IP and functional assays across multiple cancer-derived mutants","pmids":["23723076"],"confidence":"Medium","gaps":["No in vitro reconstitution","Unknown p53-independent substrates remain unidentified"]},{"year":2004,"claim":"Placed B56γ-PP2A as the key target of SV40 small-t transforming activity, by showing its knockdown substitutes for ST in fully transforming human cells.","evidence":"shRNA knockdown, full transformation assay, expression profiling","pmids":["15466190"],"confidence":"High","gaps":["Substrates mediating transformation not pinpointed","Mechanism of ST inhibition of B56γ not detailed here"]},{"year":2010,"claim":"Extended substrate range beyond p53 by showing B56γ-PP2A opposes ATM/CK1-2 phosphorylation of CREB and ATF1.","evidence":"Phosphorylation assays with B56γ manipulation and CK1/2 inhibition","pmids":["20730097"],"confidence":"Medium","gaps":["No in vitro reconstitution of direct dephosphorylation","Functional consequence on CREB/ATF1 targets unresolved"]},{"year":2014,"claim":"Identified B56γ as a brake on NF-κB in T-cell receptor signaling, opposing IKK/IκBα phosphorylation and limiting IL-2 and proliferation.","evidence":"siRNA screen with NF-κB reporter, phosphorylation Western blots, cytokine and proliferation assays","pmids":["24719332"],"confidence":"Medium","gaps":["Direct substrate within the IKK module not reconstituted","Single cell-line context (Jurkat/T cells)"]},{"year":2007,"claim":"Discovered liprin-α1 as a B56γ binding partner distinct from its transforming PP2A complexes, implicating B56γ in cell morphology.","evidence":"Tandem affinity purification/MS, Co-IP, RNAi","pmids":["18235218"],"confidence":"Medium","gaps":["Molecular basis of the interaction not defined at this stage","Functional pathway downstream of morphology change unknown"]},{"year":2022,"claim":"Defined the liprin-α1 interaction mechanistically as an LxxIxE SLiM that docks B56γ, recruiting the PP2A holoenzyme to plasma-membrane platforms to drive spreading, invasion, and motility.","evidence":"SLiM mutagenesis, reciprocal Co-IP, fractionation, live-cell imaging, invasion assay","pmids":["36171301"],"confidence":"High","gaps":["Membrane-platform substrates dephosphorylated by B56γ not identified","Tested mainly in breast cancer cells"]},{"year":2003,"claim":"Identified isoform-specific Golgi localization of B56γ and linked B56γ-PP2A to suppression of ER-to-membrane vesicle transport and directional migration.","evidence":"Immunofluorescence, sucrose-gradient fractionation, vesicle transport and migration assays","pmids":["12547706"],"confidence":"Medium","gaps":["No Golgi substrate identified","Truncated Δγ1 variant complicates interpretation"]},{"year":2017,"claim":"Showed B56γ is specifically required to stabilize BubR1 and maintain the spindle-assembly checkpoint, with its loss causing premature mitotic progression and missegregation.","evidence":"B56γ knockout primary cells, nocodazole arrest, BubR1 Western blot, segregation analysis","pmids":["28562161"],"confidence":"Medium","gaps":["Direct dephosphorylation target stabilizing BubR1 not defined","Whether BubR1 is a direct B56γ substrate untested"]},{"year":2020,"claim":"Provided atomic structures showing HTLV-1 integrase hijacks B56γ as a host factor via a conserved SLiM, defining a viral interface on the PP2A subunit.","evidence":"X-ray crystallography and single-particle cryo-EM of the integrase–B56γ complex","pmids":["33028863"],"confidence":"High","gaps":["Functional consequence of integrase binding for viral integration not detailed here","Whether binding redirects PP2A activity unknown"]},{"year":2018,"claim":"Connected upstream transcriptional control to function, showing AP-1/CREBH ER-stress signaling transactivates B56γ, which then dephosphorylates p-Thr55-p53 to enforce arrest and apoptosis in HBx-expressing hepatocytes.","evidence":"Luciferase reporter, Co-IP, knockdown/overexpression, cell-cycle/apoptosis assays","pmids":["29988038"],"confidence":"Medium","gaps":["Direct AP-1 binding to promoter not structurally mapped here","Context limited to HBx hepatocytes"]},{"year":2022,"claim":"Expanded the suppressor substrate set in liver cancer, showing B56γ dephosphorylates AKT (Thr308/Ser473) to inhibit HBx-driven growth, migration, and invasion.","evidence":"Phospho-mimetic mutagenesis, Co-IP, xenograft, migration/invasion assays","pmids":["35811356"],"confidence":"Medium","gaps":["Direct in vitro dephosphorylation of AKT not reconstituted","HBx-specific context"]},{"year":2022,"claim":"Linked B56γ to mitochondrial quality control by showing dephosphorylation of Drp1 Ser616 disrupts Drp1-Rab7 coupling, inhibiting mitophagy and enhancing apoptosis under chemotherapy.","evidence":"Co-IP of Drp1-Rab7, dephosphorylation Western blot, xenograft, apoptosis flow cytometry, contact-site imaging","pmids":["35697120"],"confidence":"Medium","gaps":["Single tumor context (HCC)","Whether the holoenzyme acts directly at mitochondria unresolved"]},{"year":2002,"claim":"First in vivo evidence linking B56γ to development, showing lung overexpression disrupts distal differentiation with loss of beta-catenin, implicating Wnt modulation.","evidence":"Transgenic mouse, in situ hybridization, IHC, beta-catenin Western blot","pmids":["12003782"],"confidence":"Medium","gaps":["Direct beta-catenin dephosphorylation not shown","Overexpression rather than physiological loss"]},{"year":2014,"claim":"Demonstrated a developmental requirement in heart and neuromuscular function via B56γ knockout causing ventricular septal defects and cardiomyocyte apoptosis.","evidence":"Knockout mouse, histology, IHC, TUNEL, behavioral testing","pmids":["24425002"],"confidence":"Medium","gaps":["Cardiac substrates of B56γ not identified","Mechanism of apoptosis not defined"]},{"year":2021,"claim":"Revealed redundancy in development by showing combined B56γ/B56δ loss is embryonic-lethal with single-outflow-vessel hearts, while single knockouts survive.","evidence":"CRISPR/Cas9n double-knockout mice, embryo phenotyping, cardiac histology","pmids":["35415460"],"confidence":"Medium","gaps":["Shared substrate underlying redundancy unknown","Outflow-tract mechanism not defined"]},{"year":2010,"claim":"Identified a transcriptional input by showing NRL directly binds the Ppp2r5c promoter to drive expression during photoreceptor development.","evidence":"EMSA, ChIP, luciferase reporter","pmids":["21078119"],"confidence":"Medium","gaps":["Functional role of B56γ in photoreceptors not tested","Downstream substrates unknown"]},{"year":2025,"claim":"Established PPP2R5C as a disease gene, showing de novo missense variants cause a neurodevelopmental disorder through impaired substrate or C-subunit binding and a likely dominant-negative effect.","evidence":"Patient variant cohort, structural mapping, PP2A catalytic activity assays","pmids":["39978342"],"confidence":"Medium","gaps":["Specific neuronal substrates driving phenotype not defined","Dominant-negative mechanism not directly reconstituted"]},{"year":2026,"claim":"Added a nucleolar/senescence axis, showing B56γ dephosphorylates Ebp1 Ser335 to suppress rRNA transcription and trigger p53/p21-dependent neuronal senescence under nanoplastic stress.","evidence":"In vitro dephosphorylation, mouse exposure model, nucleolar imaging, pre-rRNA assay, LB-100 rescue","pmids":["42097318"],"confidence":"Medium","gaps":["Generalizability beyond nanoplastic stress unknown","Single study"]},{"year":null,"claim":"The full catalogue of B56γ-specific substrates underlying its p53-independent suppressor, developmental, and neurodevelopmental functions remains incomplete, and no reconstituted structural model explains how the assembled holoenzyme selects most of its targets.","evidence":"No single study in the timeline resolves substrate selection across contexts","pmids":[],"confidence":"Low","gaps":["p53-independent substrates largely unidentified","No structure of B56γ holoenzyme bound to a physiological substrate","Disease dominant-negative mechanism not reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a 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The PP2A-PPP2R5C holoenzyme may specifically dephosphorylate and activate TP53 and play a role in DNA damage-induced inhibition of cell proliferation. PP2A-PPP2R5C may also regulate the ERK signaling pathway through ERK dephosphorylation","subcellular_location":"Nucleus; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/Q13362/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP2R5C","classification":"Not Classified","n_dependent_lines":75,"n_total_lines":1208,"dependency_fraction":0.062086092715231786},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP2R5C","total_profiled":1310},"omim":[{"mim_id":"621185","title":"HOUGE-JANSSENS SYNDROME 4; HJS4","url":"https://www.omim.org/entry/621185"},{"mim_id":"620181","title":"GRAM DOMAIN-CONTAINING PROTEIN 2A; GRAMD2A","url":"https://www.omim.org/entry/620181"},{"mim_id":"616355","title":"HOUGE-JANSSENS SYNDROME 1; HJS1","url":"https://www.omim.org/entry/616355"},{"mim_id":"601647","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), EPSILON; PPP2R5E","url":"https://www.omim.org/entry/601647"},{"mim_id":"601646","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), DELTA; PPP2R5D","url":"https://www.omim.org/entry/601646"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP2R5C"},"hgnc":{"alias_symbol":["B56G","PR61G","B56gamma"],"prev_symbol":[]},"alphafold":{"accession":"Q13362","domains":[{"cath_id":"1.20.930","chopping":"23-107_128-182","consensus_level":"medium","plddt":93.9696,"start":23,"end":182}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13362","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13362-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13362-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP2R5C","jax_strain_url":"https://www.jax.org/strain/search?query=PPP2R5C"},"sequence":{"accession":"Q13362","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13362.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13362/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13362"}},"corpus_meta":[{"pmid":"17245430","id":"PMC_17245430","title":"A 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Ablation of B56γ by RNAi abolishes Thr55 dephosphorylation, reduces p53 stabilization, Bax expression, and cell apoptosis. Endogenous B56γ protein level and association with p53 increase after DNA damage.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, Western blot, cell proliferation and transformation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi with specific phenotypic readout, replicated in multiple subsequent studies\",\n      \"pmids\": [\"17245430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATM-dependent phosphorylation of p53 at Ser15 is required for the enhanced interaction between B56γ and p53 after DNA damage. This Ser15-phosphorylation-mediated p53-B56γ interaction is required for B56γ3-induced G1 cell cycle arrest and inhibition of anchorage-independent growth.\",\n      \"method\": \"Co-immunoprecipitation, mutant p53 constructs, cell cycle analysis, anchorage-independent growth assays, ATM inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal functional assays, mutagenesis of key phospho-site, single lab\",\n      \"pmids\": [\"17967874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATM directly phosphorylates B56γ3 at Ser510 after DNA damage, leading to increased B56γ3-PP2A complex formation and directed PP2A phosphatase activity toward p53, activating tumor-suppressive functions. Under normal growth conditions, B56γ3 is targeted for ubiquitination and degradation by MDM2, and ATM-mediated phosphorylation at Ser510 blocks MDM2-mediated B56γ3 ubiquitination, upregulating B56γ3 protein levels.\",\n      \"method\": \"In vitro kinase assay, Co-IP, ubiquitination assay, mutagenesis (Ser510 substitution), cell proliferation and transformation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, Co-IP, ubiquitination assay, functional transformation assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21460856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A B56γ mutation F395C identified in lung cancer disrupts the B56γ-p53 interaction, abolishes p53 Thr55 dephosphorylation, prevents transcriptional activation of p21, and eliminates the p53-dependent tumor-suppressive function of B56γ-PP2A. A domain of B56γ required for p53 interaction was identified, distinguishing p53-dependent from p53-independent tumor suppressive functions.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, dephosphorylation assays, luciferase reporter (p21 transcription), cell transformation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of cancer-associated variant, Co-IP, functional assays for substrate dephosphorylation and transcriptional output, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20473327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HEAT repeat 1 of B56γ is required for interaction with the PP2A AC core (scaffolding A and catalytic C subunits) and for B56γ-PP2A tumor-suppressive function. A tumor-associated mutation C39R within HEAT repeat 1 disrupts the AC core interaction, abolishing both p53-dependent and p53-independent tumor suppression.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, dephosphorylation assays, cell proliferation and transformation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis with structural basis (HEAT repeat), Co-IP, multiple functional assays, single lab with orthogonal methods\",\n      \"pmids\": [\"22315229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"B56γ tumor-associated mutations from human cancer samples lose tumor-suppressive activity by two distinct mechanisms: disruption of interaction with the PP2A AC core (abolishing all substrate dephosphorylation), or disruption of specific substrate interactions (p53 and unknown proteins), causing partial loss of either p53-dependent or p53-independent tumor suppression.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of cancer-derived variants, p53 dephosphorylation assay, cell proliferation and transformation assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional assays on multiple cancer-derived mutants, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"23723076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Knockdown of PP2A B56γ subunit can substitute for SV40 small tumor antigen (ST) expression to fully transform human cells (expressing LT, hTERT, and Ras-V12), establishing B56γ-PP2A as the relevant target of ST's transforming activity. ST promotes cell transformation through integrin signaling, src phosphorylation, and NF-κB activation.\",\n      \"method\": \"shRNA knockdown, transformation assay, gene expression profiling, pharmacological inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis by B56γ knockdown substituting for ST, full transformation assay, replicated across multiple studies confirming PP2A-B56γ as ST target\",\n      \"pmids\": [\"15466190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"B56γ is a negative regulator of NF-κB in TCR signaling in T cells. B56γ silencing induced increased IKK and IκBα phosphorylation upon TCR stimulation, enhanced NF-κB activity and target gene expression (including IL-2), and increased T cell proliferation. B56γ was identified by siRNA screen in Jurkat cells using an NF-κB-responsive reporter.\",\n      \"method\": \"siRNA screen, NF-κB luciferase reporter, Western blot (IKK and IκBα phosphorylation), cytokine quantification, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen with reporter, confirmed by phosphorylation assays and functional readouts, single lab, no direct substrate dephosphorylation reconstituted\",\n      \"pmids\": [\"24719332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PP2A with B56γ targeting subunit antagonizes ATM- and CK1/2-dependent phosphorylation of CREB and ATF1 in cells. B56γ-PP2A opposes phosphorylation at the conserved ATM/CK cluster on both transcription factors.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, B56γ overexpression/knockdown, CK1/2 inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation assays in cellulo with B56γ manipulation, single lab, no in vitro reconstitution of direct dephosphorylation\",\n      \"pmids\": [\"20730097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Transgenic overexpression of B56γ in the lung (using SP-C promoter) disrupts distal lung differentiation and causes neonatal death, associated with loss of beta-catenin, suggesting B56γ modulates PP2A action on the Wnt/beta-catenin signaling pathway during lung airway morphogenesis.\",\n      \"method\": \"Transgenic mouse model, in situ hybridization, immunohistochemistry, beta-catenin Western blot\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic loss-of-function with specific developmental phenotype and molecular readout (beta-catenin loss), single lab\",\n      \"pmids\": [\"12003782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PP2A-B56γ knockout mice develop incomplete ventricular septal defects and decreased ventricular cardiomyocytes, with cardiomyocyte apoptosis during mid-to-late gestation. B56γ is expressed in the nucleus of alpha-actinin-positive cardiomyocytes containing Z-bands during cardiac development. Mice also show decreased neuromuscular coordination and gripping strength, indicating a role in neuromuscular function.\",\n      \"method\": \"Transgenic knockout mouse, histology, immunohistochemistry, TUNEL apoptosis assay, behavioral testing\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific cardiac and neuromuscular phenotype and subcellular localization data, single lab\",\n      \"pmids\": [\"24425002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PP2A-B56γ is required for stability of BubR1 during nocodazole-induced spindle assembly checkpoint (SAC) arrest. In primary cells lacking B56γ, BubR1 is prematurely degraded and cells proceed through mitosis, resulting in abnormal chromosomal segregation. Inactivation of B56γ alone (without affecting other B56 family members) is sufficient to affect SAC efficiency.\",\n      \"method\": \"B56γ knockout primary cells, nocodazole arrest, Western blot (BubR1 levels), chromosome segregation analysis, fluorescence imaging of B56 subunit localization\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific SAC phenotype and molecular readout (BubR1 degradation), single lab\",\n      \"pmids\": [\"28562161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"B56γ1 and B56γ2 (but not B56γ3) localize to the Golgi complex (cis-Golgi) in melanoma cells, and the PP2A catalytic subunit co-fractionates with B56γ in the Golgi-enriched fraction. A truncated variant Δγ1 preferentially localizes to the trans-Golgi. Cells stably expressing Δγ1 show faster vesicle transport from ER to plasma membrane and elevated directional migration, suggesting B56γ-containing PP2A holoenzymes suppress vesicle transport.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation/sucrose gradient, FLAG-tagged protein localization, vesicle transport assay, cell migration assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — fractionation-based localization with functional transport and migration assays, single lab, no direct substrate identified\",\n      \"pmids\": [\"12547706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Liprin-α1 interacts with PP2A B56γ as a novel binding partner identified by tandem affinity purification and mass spectrometry. B56γ-liprin-α1 complexes are distinct from PP2A complexes containing B56γ (i.e., liprin-α1 does not directly contribute to cell transformation). Suppression of liprin-α1 alters cell morphology.\",\n      \"method\": \"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, RNAi knockdown\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification confirmed by Co-IP, functional morphology readout, single lab\",\n      \"pmids\": [\"18235218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Liprin-α1 contains an LxxIxE short linear motif (SLiM) in its N-terminal region that interacts specifically with B56γ regulatory subunits of PP2A. Two point mutations in the SLiM strongly reduce the interaction. B56γ mediates the interaction of liprin-α1 with the heterotrimeric PP2A holoenzyme. B56γ localizes to plasma membrane-associated platforms (PMAPs) in migrating breast cancer cells in a liprin-α1-dependent manner. Silencing B56γ inhibits cell spreading, invasion, motility, and lamellipodia dynamics to a similar extent as silencing liprin-α1.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of SLiM motif, subcellular fractionation, live-cell imaging, RNAi knockdown, invasion assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, SLiM mutagenesis, localization experiments with functional consequence (motility, invasion), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36171301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The B56γ subunit of PP2A is the host factor bound by the HTLV-1 retroviral integrase (IN). Cryo-EM and X-ray crystallography structures reveal a tetrameric IN assembly bound to two molecules of B56γ via a conserved short linear motif on the integrase.\",\n      \"method\": \"X-ray crystallography, single-particle cryo-EM, structural determination of complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM and X-ray crystal structures of the protein complex, rigorous structural validation\",\n      \"pmids\": [\"33028863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"B56γ is transactivated by AP-1, which is regulated by ER stress-induced CREBH signaling in HBx-expressing hepatic cells. B56γ dephosphorylates p-Thr55-p53, triggering p53/p21 pathway-dependent G1 cell cycle arrest and apoptosis of HBx-expressing hepatocytes.\",\n      \"method\": \"Western blot, co-immunoprecipitation, gene knockdown/overexpression, cell cycle analysis, luciferase reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dephosphorylation assay, cell cycle and apoptosis readouts with specific molecular mechanism, single lab\",\n      \"pmids\": [\"29988038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B56γ inhibits HBV/HBx-dependent hepatocarcinogenesis by mediating dephosphorylation of AKT at Thr308 and Ser473. B56γ overexpression and site-directed mutagenesis mimicking dephosphorylation (AKTT308A, AKTS473A) inhibited cell growth, migration, and invasion in HBx-expressing HCC cells.\",\n      \"method\": \"Western blot, site-directed mutagenesis, co-immunoprecipitation, overexpression, xenograft mouse model, cell migration/invasion assays\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis mimicking dephosphorylation, in vivo xenograft, multiple functional assays, single lab\",\n      \"pmids\": [\"35811356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B56γ-mediated direct dephosphorylation of Drp1 at Ser616 inhibits the interaction between p-Drp1Ser616 and Rab7, thereby inhibiting mitophagy and increasing mitochondria-dependent apoptosis in HCC cells under chemotherapy treatment.\",\n      \"method\": \"Co-immunoprecipitation, Western blot (dephosphorylation), B56γ overexpression/knockdown, xenograft mouse model, flow cytometry (apoptosis), mitochondria-lysosome contact site imaging\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dephosphorylation assay, co-IP of Drp1-Rab7 interaction, in vivo xenograft, multiple functional assays, single lab\",\n      \"pmids\": [\"35697120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A truncated isoform of B56γ (Δγ1) in metastatic melanoma BL6 cells impairs the cell-cycle checkpoint, leading to increased polyploidy and reduced apoptosis after irradiation, and promotes metastasis. Expression of Δγ1 in F10 cells reproduced the checkpoint aberration and enhanced metastatic ability.\",\n      \"method\": \"Gene transfection, irradiation, cell cycle analysis, apoptosis assay, in vivo tumor transplant and metastasis assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic expression in isogenic cell lines, in vivo metastasis assay, cell cycle readout, single lab\",\n      \"pmids\": [\"12507892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A truncated B56γ variant (Δγ1) reduces irradiation-induced Mdm2 phosphorylation, which blocks irradiation-stimulated p53 accumulation and p53-target gene (Bax) induction, contributing to melanoma cell radioresistance.\",\n      \"method\": \"Stable transfection, Western blot (Mdm2 and p53 phosphorylation), RT-PCR (p53/Bax mRNA), apoptosis assay, in vivo irradiation\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Western blot-based mechanism in stably transfected cells, single lab, single method per endpoint, indirect mechanism (no direct dephosphorylation assay)\",\n      \"pmids\": [\"15024700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mice with both B56δ and B56γ inactivated (double knockout) arrest fetal development around E12 with hearts having a single outflow vessel, demonstrating strong genetic interaction between B56δ and B56γ that is necessary for heart development. Individual knockouts of B56δ or B56γ alone are not lethal.\",\n      \"method\": \"CRISPR/Cas9n knockout mouse generation, embryo phenotyping, cardiac histology\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockout, clear developmental phenotype, single lab\",\n      \"pmids\": [\"35415460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The transcription factor NRL directly binds the NRL-response element on the Ppp2r5c promoter (validated by EMSA and chromatin immunoprecipitation) and enhances Ppp2r5c transcriptional activity during mouse photoreceptor development.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP directly demonstrating NRL binding to Ppp2r5c promoter, single lab\",\n      \"pmids\": [\"21078119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PP2A-B56γ selectively dephosphorylates the ribosome biogenesis regulator Ebp1 at Ser335 in neurons exposed to polystyrene nanoplastics, reducing Ebp1 nucleolar localization, suppressing 47S pre-rRNA transcription, and inducing nucleolar stress that activates the p53/p21 pathway and promotes neuronal senescence. Pharmacological PP2A inhibition (LB-100) prevented these effects.\",\n      \"method\": \"In vitro dephosphorylation assay, mouse exposure model, immunofluorescence (Ebp1 nucleolar localization), pre-rRNA transcription assay, Western blot (p53/p21), pharmacological rescue with LB-100, co-culture system\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dephosphorylation assay with specific substrate and site, in vivo model, pharmacological rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42097318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo missense variants in PPP2R5C cause a neurodevelopmental disorder (Houge-Janssens syndrome spectrum). Variants affect either substrate binding, C-subunit binding, or both, and variably reduce catalytic activity of the phosphatase. Total loss-of-function variants can be inherited from non-symptomatic parents, indicating dominant-negative mechanism on substrate dephosphorylation is the likely pathogenic mechanism.\",\n      \"method\": \"Patient variant analysis, structural mapping onto PP2A crystal structure, PP2A catalytic activity assays, clinical phenotyping of 26 individuals\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — activity assays on multiple patient variants, structural mapping, large patient cohort, single study\",\n      \"pmids\": [\"39978342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PPP2R5C (B56γ) interacts with Tau protein, reducing Tau levels and phosphorylation via ULK1-dependent autophagolysosomal activation and PP2A regulation. PPP2R5C reduction precedes Tau hyperphosphorylation in Tau Braak-staged brains.\",\n      \"method\": \"Co-immunoprecipitation, immunohistochemistry of staged brain tissue, exosome proteomics (LC-MS/MS), Western blot\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP showing interaction with Tau, mechanistic pathway proposed but not fully reconstituted, single lab, limited mechanistic follow-up in abstract\",\n      \"pmids\": [\"41720088\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2R5C (B56γ) is the substrate-targeting regulatory subunit of PP2A heterotrimeric phosphatase complexes; upon DNA damage, ATM phosphorylates B56γ3 at Ser510 (blocking MDM2-mediated ubiquitination and degradation) while also phosphorylating p53 at Ser15 to recruit B56γ-PP2A, which dephosphorylates p53 at Thr55 to stabilize p53 and activate p21-dependent growth arrest; B56γ additionally dephosphorylates AKT, Drp1 at Ser616, Ebp1 at Ser335, and CREB/ATF1, suppresses NF-κB in T cells via IKK dephosphorylation, supports cell migration through liprin-α1-mediated recruitment to plasma membrane platforms, localizes to the Golgi to regulate vesicle transport, is required for spindle assembly checkpoint integrity (BubR1 stability) and cardiac development, and serves as the host receptor for deltaretroviral integrase via a conserved short linear motif, with cancer-associated mutations in its HEAT repeat 1 or substrate-binding domain disrupting AC core assembly or substrate recognition to abrogate tumor suppressor function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2R5C (B56\\u03b3) is a substrate-targeting regulatory subunit of the PP2A heterotrimeric phosphatase that operates as a context-dependent tumor suppressor by directing catalytic activity onto specific phosphoprotein substrates [#0, #6]. Its central role is in the DNA-damage response: ATM-dependent phosphorylation of p53 at Ser15 recruits B56\\u03b3, which dephosphorylates p53 at Thr55 to stabilize the protein, drive p21 transcription, and impose G1 arrest, while ATM also phosphorylates B56\\u03b3 itself at Ser510 to block MDM2-mediated ubiquitination and stabilize the subunit [#0, #1, #2, #16]. B56\\u03b3 engages the PP2A AC core through its first HEAT repeat and contacts substrates through a separate substrate-binding domain, so cancer-associated mutations fall into two mechanistic classes\\u2014loss of AC-core assembly (e.g. C39R) abolishing all activity, or loss of specific substrate contacts (e.g. F395C) selectively crippling p53-dependent suppression [#3, #4, #5]. Beyond p53, B56\\u03b3-PP2A dephosphorylates AKT (Thr308/Ser473), Drp1 at Ser616 to restrain mitophagy, Ebp1 at Ser335 to govern nucleolar ribosome biogenesis, and CREB/ATF1, and it negatively regulates NF-\\u03baB in T-cell receptor signaling by opposing IKK phosphorylation [#7, #8, #17, #18, #23]. The subunit is recruited to plasma-membrane platforms via an LxxIxE short linear motif in liprin-\\u03b11 to support cell spreading, invasion, and migration, localizes isoform-specifically to the Golgi to modulate vesicle transport, and maintains spindle-assembly-checkpoint integrity by stabilizing BubR1 [#11, #12, #14]. B56\\u03b3 is required for cardiac development, acting in genetic concert with B56\\u03b4 [#10, #21], and is exploited as the host receptor for HTLV-1 retroviral integrase through a conserved SLiM, as resolved by structural studies [#15]. De novo missense variants in PPP2R5C cause a neurodevelopmental disorder in the Houge-Janssens syndrome spectrum, with a likely dominant-negative effect on substrate dephosphorylation [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that B56\\u03b3 is the PP2A subunit responsible for dephosphorylating p53 at Thr55 during the DNA-damage response, linking PP2A to p53 stabilization and apoptosis.\",\n      \"evidence\": \"RNAi knockdown, reciprocal Co-IP, and apoptosis/transformation readouts in damaged cells\",\n      \"pmids\": [\"17245430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how the B56\\u03b3-p53 interaction is regulated\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that ATM-driven p53 Ser15 phosphorylation is the trigger that recruits B56\\u03b3, explaining how damage signaling is converted into targeted dephosphorylation and growth arrest.\",\n      \"evidence\": \"Co-IP with phospho-site mutant p53, cell-cycle and anchorage-independent growth assays, ATM inhibition\",\n      \"pmids\": [\"17967874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulation of B56\\u03b3 protein levels\", \"p53-independent functions not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how B56\\u03b3 itself is controlled, showing ATM phosphorylates B56\\u03b3 at Ser510 to block MDM2-mediated degradation and upregulate the subunit upon damage.\",\n      \"evidence\": \"In vitro kinase assay, ubiquitination assay, Ser510 mutagenesis, transformation assays\",\n      \"pmids\": [\"21460856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MDM2 ubiquitination site on B56\\u03b3 not mapped\", \"In vivo relevance of Ser510 not tested in animals\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a discrete substrate-binding domain by showing a lung-cancer mutation F395C selectively abolishes p53 binding and p21 activation, separating p53-dependent from p53-independent tumor suppression.\",\n      \"evidence\": \"Cancer-variant mutagenesis, Co-IP, dephosphorylation and p21 luciferase reporter assays\",\n      \"pmids\": [\"20473327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of p53-independent substrates not established\", \"No structural model of the domain\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped HEAT repeat 1 as the AC-core docking site and showed mutation C39R there disrupts holoenzyme assembly, abolishing all suppressor activity.\",\n      \"evidence\": \"Co-IP, HEAT-repeat mutagenesis, dephosphorylation and transformation assays\",\n      \"pmids\": [\"22315229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstitution of the assembled holoenzyme\", \"Did not enumerate p53-independent substrates lost\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Consolidated a two-class mutational model in which cancer-derived variants either lose AC-core binding (global loss) or lose specific substrate contacts (selective loss).\",\n      \"evidence\": \"Co-IP and functional assays across multiple cancer-derived mutants\",\n      \"pmids\": [\"23723076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution\", \"Unknown p53-independent substrates remain unidentified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed B56\\u03b3-PP2A as the key target of SV40 small-t transforming activity, by showing its knockdown substitutes for ST in fully transforming human cells.\",\n      \"evidence\": \"shRNA knockdown, full transformation assay, expression profiling\",\n      \"pmids\": [\"15466190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates mediating transformation not pinpointed\", \"Mechanism of ST inhibition of B56\\u03b3 not detailed here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended substrate range beyond p53 by showing B56\\u03b3-PP2A opposes ATM/CK1-2 phosphorylation of CREB and ATF1.\",\n      \"evidence\": \"Phosphorylation assays with B56\\u03b3 manipulation and CK1/2 inhibition\",\n      \"pmids\": [\"20730097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of direct dephosphorylation\", \"Functional consequence on CREB/ATF1 targets unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified B56\\u03b3 as a brake on NF-\\u03baB in T-cell receptor signaling, opposing IKK/I\\u03baB\\u03b1 phosphorylation and limiting IL-2 and proliferation.\",\n      \"evidence\": \"siRNA screen with NF-\\u03baB reporter, phosphorylation Western blots, cytokine and proliferation assays\",\n      \"pmids\": [\"24719332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate within the IKK module not reconstituted\", \"Single cell-line context (Jurkat/T cells)\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovered liprin-\\u03b11 as a B56\\u03b3 binding partner distinct from its transforming PP2A complexes, implicating B56\\u03b3 in cell morphology.\",\n      \"evidence\": \"Tandem affinity purification/MS, Co-IP, RNAi\",\n      \"pmids\": [\"18235218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the interaction not defined at this stage\", \"Functional pathway downstream of morphology change unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the liprin-\\u03b11 interaction mechanistically as an LxxIxE SLiM that docks B56\\u03b3, recruiting the PP2A holoenzyme to plasma-membrane platforms to drive spreading, invasion, and motility.\",\n      \"evidence\": \"SLiM mutagenesis, reciprocal Co-IP, fractionation, live-cell imaging, invasion assay\",\n      \"pmids\": [\"36171301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane-platform substrates dephosphorylated by B56\\u03b3 not identified\", \"Tested mainly in breast cancer cells\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified isoform-specific Golgi localization of B56\\u03b3 and linked B56\\u03b3-PP2A to suppression of ER-to-membrane vesicle transport and directional migration.\",\n      \"evidence\": \"Immunofluorescence, sucrose-gradient fractionation, vesicle transport and migration assays\",\n      \"pmids\": [\"12547706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No Golgi substrate identified\", \"Truncated \\u0394\\u03b31 variant complicates interpretation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed B56\\u03b3 is specifically required to stabilize BubR1 and maintain the spindle-assembly checkpoint, with its loss causing premature mitotic progression and missegregation.\",\n      \"evidence\": \"B56\\u03b3 knockout primary cells, nocodazole arrest, BubR1 Western blot, segregation analysis\",\n      \"pmids\": [\"28562161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation target stabilizing BubR1 not defined\", \"Whether BubR1 is a direct B56\\u03b3 substrate untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided atomic structures showing HTLV-1 integrase hijacks B56\\u03b3 as a host factor via a conserved SLiM, defining a viral interface on the PP2A subunit.\",\n      \"evidence\": \"X-ray crystallography and single-particle cryo-EM of the integrase\\u2013B56\\u03b3 complex\",\n      \"pmids\": [\"33028863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of integrase binding for viral integration not detailed here\", \"Whether binding redirects PP2A activity unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected upstream transcriptional control to function, showing AP-1/CREBH ER-stress signaling transactivates B56\\u03b3, which then dephosphorylates p-Thr55-p53 to enforce arrest and apoptosis in HBx-expressing hepatocytes.\",\n      \"evidence\": \"Luciferase reporter, Co-IP, knockdown/overexpression, cell-cycle/apoptosis assays\",\n      \"pmids\": [\"29988038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AP-1 binding to promoter not structurally mapped here\", \"Context limited to HBx hepatocytes\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the suppressor substrate set in liver cancer, showing B56\\u03b3 dephosphorylates AKT (Thr308/Ser473) to inhibit HBx-driven growth, migration, and invasion.\",\n      \"evidence\": \"Phospho-mimetic mutagenesis, Co-IP, xenograft, migration/invasion assays\",\n      \"pmids\": [\"35811356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro dephosphorylation of AKT not reconstituted\", \"HBx-specific context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked B56\\u03b3 to mitochondrial quality control by showing dephosphorylation of Drp1 Ser616 disrupts Drp1-Rab7 coupling, inhibiting mitophagy and enhancing apoptosis under chemotherapy.\",\n      \"evidence\": \"Co-IP of Drp1-Rab7, dephosphorylation Western blot, xenograft, apoptosis flow cytometry, contact-site imaging\",\n      \"pmids\": [\"35697120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor context (HCC)\", \"Whether the holoenzyme acts directly at mitochondria unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First in vivo evidence linking B56\\u03b3 to development, showing lung overexpression disrupts distal differentiation with loss of beta-catenin, implicating Wnt modulation.\",\n      \"evidence\": \"Transgenic mouse, in situ hybridization, IHC, beta-catenin Western blot\",\n      \"pmids\": [\"12003782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct beta-catenin dephosphorylation not shown\", \"Overexpression rather than physiological loss\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a developmental requirement in heart and neuromuscular function via B56\\u03b3 knockout causing ventricular septal defects and cardiomyocyte apoptosis.\",\n      \"evidence\": \"Knockout mouse, histology, IHC, TUNEL, behavioral testing\",\n      \"pmids\": [\"24425002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiac substrates of B56\\u03b3 not identified\", \"Mechanism of apoptosis not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed redundancy in development by showing combined B56\\u03b3/B56\\u03b4 loss is embryonic-lethal with single-outflow-vessel hearts, while single knockouts survive.\",\n      \"evidence\": \"CRISPR/Cas9n double-knockout mice, embryo phenotyping, cardiac histology\",\n      \"pmids\": [\"35415460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared substrate underlying redundancy unknown\", \"Outflow-tract mechanism not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a transcriptional input by showing NRL directly binds the Ppp2r5c promoter to drive expression during photoreceptor development.\",\n      \"evidence\": \"EMSA, ChIP, luciferase reporter\",\n      \"pmids\": [\"21078119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of B56\\u03b3 in photoreceptors not tested\", \"Downstream substrates unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established PPP2R5C as a disease gene, showing de novo missense variants cause a neurodevelopmental disorder through impaired substrate or C-subunit binding and a likely dominant-negative effect.\",\n      \"evidence\": \"Patient variant cohort, structural mapping, PP2A catalytic activity assays\",\n      \"pmids\": [\"39978342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific neuronal substrates driving phenotype not defined\", \"Dominant-negative mechanism not directly reconstituted\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added a nucleolar/senescence axis, showing B56\\u03b3 dephosphorylates Ebp1 Ser335 to suppress rRNA transcription and trigger p53/p21-dependent neuronal senescence under nanoplastic stress.\",\n      \"evidence\": \"In vitro dephosphorylation, mouse exposure model, nucleolar imaging, pre-rRNA assay, LB-100 rescue\",\n      \"pmids\": [\"42097318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond nanoplastic stress unknown\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full catalogue of B56\\u03b3-specific substrates underlying its p53-independent suppressor, developmental, and neurodevelopmental functions remains incomplete, and no reconstituted structural model explains how the assembled holoenzyme selects most of its targets.\",\n      \"evidence\": \"No single study in the timeline resolves substrate selection across contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"p53-independent substrates largely unidentified\", \"No structure of B56\\u03b3 holoenzyme bound to a physiological substrate\", \"Disease dominant-negative mechanism not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 17, 18, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 13]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [24, 15]}\n    ],\n    \"complexes\": [\n      \"PP2A holoenzyme (B56\\u03b3-A-C heterotrimer)\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"PPP2CA\",\n      \"MDM2\",\n      \"PPP1R9A/liprin-\\u03b11\",\n      \"AKT\",\n      \"DNM1L/Drp1\",\n      \"BubR1\",\n      \"PA2G4/Ebp1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}