{"gene":"PPP2R5A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2006,"finding":"PP2A regulatory subunit B56α selectively associates with the N terminus of c-Myc, directs intact PP2A holoenzymes to c-Myc, resulting in dramatic reduction of c-Myc levels through dephosphorylation of stabilizing phospho-Serine 62, thereby enhancing c-Myc ubiquitin-mediated degradation. shRNA knockdown of B56α results in c-Myc overexpression and elevated S62 phosphorylation.","method":"Co-immunoprecipitation, shRNA knockdown, immunoblotting, luciferase reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional knockdown validation, replicated across multiple studies in different cell types","pmids":["16537924"],"is_preprint":false},{"year":2000,"finding":"PKR (double-stranded RNA-dependent protein kinase) directly phosphorylates B56α; this phosphorylation increases PP2A trimeric holoenzyme activity in an in vitro dephosphorylation assay. PKR interaction with B56α is dependent on PKR catalytic activity, as shown by in vitro binding assays and co-immunoprecipitation.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, in vitro kinase assay, in vitro phosphatase assay, cotransfection luciferase assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of phosphorylation and activity assays with multiple orthogonal methods in a single study","pmids":["10866685"],"is_preprint":false},{"year":2007,"finding":"B56α is an in vivo binding partner of ankyrin-B in cardiomyocytes; the interaction requires a 13-residue motif at the B56α C-terminus not present in other B56 family members. Reduced ankyrin-B expression in ankyrin-B(+/-) cardiomyocytes causes disorganized B56α distribution, rescuable by exogenous ankyrin-B, establishing ankyrin-B as the targeting component for PP2A-B56α in heart.","method":"Co-immunoprecipitation, co-localization immunofluorescence, deletion/mutagenesis mapping, ankyrin-B(+/-) rescue experiments","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with structural mapping and genetic rescue using multiple orthogonal methods in a single study","pmids":["17416611"],"is_preprint":false},{"year":2009,"finding":"miR-1 overexpression selectively decreases expression of PP2A regulatory subunit B56α in rat ventricular myocytes, disrupting localization of PP2A activity to L-type Ca2+ channels and RyR2, leading to CaMKII-dependent hyperphosphorylation of RyR2 at S2814 and arrhythmogenic Ca2+ oscillations. Effects were reversed by CaMKII inhibitor KN93.","method":"Adenoviral miR-1 overexpression, electrophysiology, Ca2+ imaging, quantitative immunoblotting, pharmacological rescue with KN93","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts with specific pharmacological rescue in a single study","pmids":["19131648"],"is_preprint":false},{"year":2010,"finding":"B56α subcellular localization is controlled by CRM1-mediated nuclear export via a functional nuclear export signal (NES) at the C-terminus (aa 451-469); mutagenesis of L461A causes nuclear retention of full-length B56α. B56α transiently expressed induces nuclear export of the PP2A catalytic subunit, blocked by the L461A NES mutation. B56α also co-localizes with PP2A-A subunit at centrosomes, with centrosome targeting requiring the A-subunit binding sequences. FRAP revealed dynamic and immobile pools of B56α-GFP.","method":"CRM1 inhibition (leptomycin B), siRNA knockdown, site-directed mutagenesis (L461A), FRAP, co-localization imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis combined with pharmacological and siRNA approaches plus FRAP in a single study","pmids":["20378546"],"is_preprint":false},{"year":2010,"finding":"B56α overexpression in 3T3-L1 adipocytes significantly decreased HSL Ser660 phosphorylation, while B56α knockdown increased hormone-stimulated HSL activation and lipolysis, establishing B56α/PP2A as a negative regulator of hormone-sensitive lipase and adipose lipolysis.","method":"Adenovirus-mediated overexpression and knockdown in 3T3-L1 adipocytes, phospho-specific immunoblotting, lipolysis assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — bidirectional gain/loss of function with defined biochemical readout, single lab, single study","pmids":["20534721"],"is_preprint":false},{"year":2013,"finding":"PKCα directly phosphorylates B56α at Ser41 in vitro; phosphorylation at Ser41 markedly increases B56α's potency as a PP2A inhibitor. A phosphomimetic S41D mutant reduces PP2A activity in HEK293 cells and increases endoplasmic reticulum Ca2+ release by 23% compared to wild-type B56α. Purified PP2A dimer (C and A subunits) can dephosphorylate PKCα-phosphorylated B56α.","method":"In vitro kinase assay with purified PKCα, in vitro phosphatase assay, phosphomimetic mutagenesis (S41D), transfection in HEK293, Fluo-4 Ca2+ fluorescence measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of phosphorylation plus mutagenesis plus functional cellular readout in a single study","pmids":["24225947"],"is_preprint":false},{"year":2014,"finding":"Transgenic 2-fold overexpression of B56α in mouse cardiomyocytes enhances PP2A activity localized mainly in cytoplasm and myofilament fractions, reduces basal phosphorylation of cardiac troponin I and myosin-binding protein C by 26% and 35% respectively, increases basal contractility, decreases L-type Ca2+ current density after isoproterenol, and reduces phospholamban Ser16 phosphorylation after β-adrenergic stimulation.","method":"Transgenic mouse model, subcellular fractionation with PP2A activity assay, phospho-specific immunoblotting, cardiomyocyte isolation, whole-heart contractility measurements, patch-clamp electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple biochemical and functional readouts in a single rigorous study","pmids":["25320082"],"is_preprint":false},{"year":2015,"finding":"B56α acts as an autoinhibitory subunit that suppresses excess PP2A activity in the heart. B56α(+/-) mice show increased PP2A activity, decreased RyR2 phosphorylation, reduced Ca2+ waves and sparks, slower heart rates, conduction defects, and increased parasympathetic sensitivity. In vivo B56α expression in the absence of changes in other subunit abundance decreases basal phosphatase activity and suppresses parasympathetic heart rate regulation.","method":"B56α(+/-) and B56α in vivo overexpression mouse models, PP2A activity assay, phospho-specific immunoblotting, Ca2+ spark/wave imaging, ECG, pharmacological challenge","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (knockout and overexpression) with multiple orthogonal functional and biochemical readouts","pmids":["26198358"],"is_preprint":false},{"year":2011,"finding":"PP2A-B56α overexpression suppresses c-MYC protein levels in melanoma cells and induces oncogene-induced senescence (OIS), while B56α depletion in normal human melanocytes upregulates c-MYC protein and suppresses BRAF(V600E)-induced senescence, establishing PP2A-B56α as a functional regulator of c-MYC stability and OIS in melanocytic cells.","method":"B56α overexpression and siRNA knockdown in melanoma cells and normal melanocytes, immunoblotting for c-MYC, senescence assays (SA-β-gal), viral-mediated BRAF(V600E) expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional gain/loss of function with defined molecular and cellular phenotypes, single lab","pmids":["21822300"],"is_preprint":false},{"year":2012,"finding":"B56α mediates all-trans retinoic acid (atRA)-induced dephosphorylation of eNOS at Ser1179 and decreased NO production in bovine aortic endothelial cells; atRA increases B56α mRNA and protein expression (but not PP2A Cα), and siRNA knockdown of B56α reverses atRA-induced inhibition of eNOS-Ser1179 phosphorylation and NO production.","method":"siRNA knockdown of PP2A-B56α, okadaic acid pharmacology, phospho-specific immunoblotting, NO measurement, real-time PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA loss-of-function with specific biochemical readout, single lab, single study","pmids":["23237802"],"is_preprint":false},{"year":2016,"finding":"Metformin activates PP2A complexes containing the B56α subunit, which inhibits JAK2V617F kinase activity as a negative regulator; the B56α-containing PP2A complex also functions as a positive regulator of JAK2V617F by inhibiting AMPK, establishing B56α-PP2A as a bidirectional regulator in this signaling axis.","method":"Pharmacological PP2A activation, AMPK inhibition, kinase activity assay, cell growth assay in MPN cell lines","journal":"Experimental hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological approach without direct B56α-specific manipulation, single lab, single study","pmids":["27576133"],"is_preprint":false},{"year":2023,"finding":"CIP2A directly binds the PP2A-B56α trimer, displaces the PP2A-A scaffolding subunit, and forms a CIP2A-B56α-PP2Ac pseudotrimer, thereby inhibiting PP2A-B56α. CIP2A also blocks the LxxIxE-motif substrate-binding pocket on B56α, competing with substrate binding. CRISPR/Cas9 single amino acid mutagenesis of the CIP2A N-terminal head domain blunted MYC expression and MEK phosphorylation and abrogated triple-negative breast cancer tumor growth in vivo.","method":"Cryo-EM structure at 3.58 Å, biochemical binding assays, CRISPR/Cas9 mutagenesis, in vivo xenograft tumor growth assay, immunoblotting","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical validation and in vivo CRISPR mutagenesis with functional readout in a single rigorous study","pmids":["36854761"],"is_preprint":false},{"year":2022,"finding":"eIF3a translationally inhibits PPP2R5A (B56α), a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair; suppression of PPP2R5A results in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity.","method":"Co-IP, RIP (RNA immunoprecipitation), luciferase reporter assay, flow cytometry, TUNEL, comet assay, western blot, xenograft model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, luciferase, Co-IP, functional assays) in a single study, single lab","pmids":["35187743"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of PPP2R5A (B56α) in complex with HIV-1 Vif-CBFβ-elongin B-elongin C at 3.58 Å shows PPP2R5A binds across the Vif molecule at a distinct interface partially overlapping with those for APOBEC3 substrates. Vif blocks a canonical PPP2R5A substrate-binding site, indicating dual mechanisms of PP2A suppression: degradation-dependent and degradation-independent inhibition of phosphatase activity.","method":"Cryo-EM structure determination, biochemical binding assays, cellular ubiquitination/degradation assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with biochemical and cellular validation in a single rigorous study","pmids":["38789685"],"is_preprint":false},{"year":2021,"finding":"B56α is specifically induced during adipocyte differentiation and mediates PP2A-directed dephosphorylation of GSK3β, thereby blocking Wnt pathway activity and driving adipocyte differentiation. Inducible B56α knockout mice fail to develop gonadal adipose tissue normally and show a shift from adipocyte to osteoblast fate. B56α expression is driven by the adipocyte transcription factor PPARγ.","method":"Inducible B56α knockout mouse, in vitro adipocyte differentiation assays, phospho-specific immunoblotting for GSK3β, Wnt reporter assay, PPARγ ChIP/promoter analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockout with defined biochemical substrate (GSK3β dephosphorylation) and multiple functional readouts, single lab","pmids":["34232566"],"is_preprint":false},{"year":2006,"finding":"Sustained JNK activation in cardiomyocytes causes a 70% decrease in B56α protein and mRNA, converting B56α mRNA from a stable to a rapidly degraded labile form. The RNA-binding protein AUF1 is increased 4-fold in JNK-activated cells and binds B56α 3'-UTR adenylate-uridylate-rich elements with nanomolar affinity, establishing AUF1-mediated mRNA destabilization as a mechanism downstream of stress-activated MAPK signaling.","method":"Established JNK activation model in cardiomyocytes, real-time PCR mRNA decay time-course, gel mobility shift assay (EMSA), AUF1 immunoblotting","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA decay kinetics combined with EMSA demonstrating AUF1-B56α 3'-UTR binding, single lab, multiple methods","pmids":["16603688"],"is_preprint":false},{"year":2022,"finding":"Phosphorylation of B56α at Ser41 by PKC is required for PKC-activated enhancement of myocyte contraction and Ca2+ signaling; transgenic mice expressing the non-phosphorylatable S41A mutant show blunted PP2A inhibition, attenuated sarcomere shortening and Ca2+ transient increases after PMA, reduced MyBP-C phosphorylation, and altered L-type Ca2+ channel activation/inactivation kinetics compared to wild-type.","method":"Transgenic mouse model (S41A mutant), PP2A activity assay, patch-clamp electrophysiology, Ca2+ transient measurement, phospho-specific immunoblotting","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mutagenesis model with multiple orthogonal functional and biochemical readouts, confirmed in context of earlier in vitro kinase study (PMID 24225947)","pmids":["35119335"],"is_preprint":false},{"year":2024,"finding":"KRASG12D induces CIP2A expression and sequesters B56α away from the active PP2A holoenzyme in a CIP2A-dependent manner, leading to increased c-MYC S62 phosphorylation. Knockout of B56α in vivo promotes KRASG12D-driven acinar-to-ductal metaplasia and PanIN formation. Pharmacological re-activation of PP2A with SMAPs attenuates ADM ex vivo.","method":"KRAS mutant cell models, co-immunoprecipitation, phospho-specific immunoblotting, B56α knockout in KrasG12D mouse model, ex vivo acinar culture with SMAP treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout in vivo combined with Co-IP and pharmacological rescue, multiple orthogonal approaches in a single study","pmids":["39443726"],"is_preprint":false},{"year":2026,"finding":"PP2A-B56α dephosphorylates the S62 residue on N-Myc in neuroblastoma, promoting its proteasomal degradation; S62 phosphosite mutation on N-Myc abrogates PP2A-B56α-mediated effects on N-Myc stability, cell viability, and colony formation. In vivo xenograft tumor growth inhibition by PP2A activator DT-061 is accompanied by reduced N-Myc protein expression.","method":"PP2A activator (DT-061) treatment, proteasome inhibitor rescue (MG-132), competitive antagonist (DT-766), N-Myc S62A phosphosite mutagenesis, cell viability assay, colony formation assay, xenograft mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphosite mutagenesis combined with pharmacological rescue and in vivo validation, multiple orthogonal methods","pmids":["41707997"],"is_preprint":false},{"year":2025,"finding":"Suppression of PP2A-B56α in EGFR-mutant non-small cell lung cancer results in decreased epithelial marker expression, increased mesenchymal markers, and acquisition of migratory and invasive phenotypes both in vitro and in vivo; B56α overexpression rescues these migratory phenotypes.","method":"B56α knockdown and overexpression, EMT marker immunoblotting, in vitro migration/invasion assays, in vivo metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional gain/loss of function with in vitro and in vivo functional readouts, single lab","pmids":["41965447"],"is_preprint":false},{"year":2023,"finding":"PP2A reactivation using PP2A-activating drugs synergizes with venetoclax in AML through PP2A complexes containing the B56α regulatory subunit; mechanistically, PP2A reactivation simultaneously inhibits antiapoptotic BCL2 and reduces MCL1 protein stability through extracellular signal-regulated kinase (ERK) signaling inhibition. B56α expression level dictates response to the combination therapy.","method":"Gene editing (B56α-specific manipulation), pharmacological PP2A activation with three structurally distinct drugs, AML cell lines, primary AML cells, xenograft models, immunoblotting for BCL2/MCL1/ERK","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene editing combined with three distinct pharmacological agents and in vivo validation with defined molecular mechanisms, replicated across multiple models","pmids":["36455198"],"is_preprint":false},{"year":2025,"finding":"Quantitative phosphoproteomics identified >25 hyperphosphorylated proteins harboring B56 binding motifs as putative direct substrates of PP2A-B56α in response to β-adrenergic signaling in vivo. Loss of B56α in cardiomyocytes blunts acute isoproterenol-induced increases in intracellular calcium transient amplitude, and B56α-deficient mice are protected from isoproterenol-induced systolic dysfunction despite comparable hypertrophy.","method":"Quantitative phosphoproteomics of B56α-deficient and wild-type hearts after isoproterenol injection, in vitro Ca2+ transient measurement in cardiomyocytes, in vivo sustained isoproterenol infusion model with echocardiography","journal":"Journal of molecular and cellular cardiology plus","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics with motif analysis plus in vitro and in vivo functional validation, multiple orthogonal approaches in a single study","pmids":["40485773"],"is_preprint":false},{"year":2019,"finding":"B56α localizes to myofilaments under resting conditions and translocates to the cytosol in response to acute β-adrenergic receptor stimulation; homozygous Ppp2r5a-disrupted mice show reduced PP2A catalytic activity, attenuated inotropic response to dobutamine, and blunted hypertrophic response to sustained isoproterenol infusion despite normal basal cardiac phenotype.","method":"Ppp2r5a targeted knockout mouse (heterozygous and homozygous), echocardiography, gravimetric and histological analyses, PP2A activity assay, western blotting, acute and sustained β-AR stimulation protocols","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined genetic mouse model with multiple functional and biochemical endpoints under two distinct challenge conditions","pmids":["30203051"],"is_preprint":false},{"year":2025,"finding":"PP2A B56α subunit interacts with the METTL3 methyltransferase domain (MTD) and facilitates METTL3 enzymatic activity, increasing NLRP3 mRNA m6A methylation and NLRP3 mRNA stability in HBx-expressing hepatocytes, thereby promoting pyroptosis and lipid accumulation.","method":"Co-immunoprecipitation, METTL3 knockdown and catalytic inactivation, m6A methylation assays, western blot, in vivo HBx-transgenic mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with functional knockdown validating B56α-METTL3 interaction, single lab, single study","pmids":["41053025"],"is_preprint":false}],"current_model":"PPP2R5A/B56α is a regulatory subunit that directs the PP2A heterotrimer to specific substrates and subcellular locations: it targets PP2A to c-Myc (dephosphorylating S62 to promote proteasomal degradation), N-Myc, GSK3β (blocking Wnt signaling during adipogenesis), HSL (inhibiting adipose lipolysis), eNOS-Ser1179, RyR2, myofilament proteins, and ATM/ATR; its own activity is modulated by PKR- and PKCα-mediated phosphorylation (at Ser41) that enhance PP2A inhibition, by CRM1-dependent nuclear export via a C-terminal NES, by ankyrin-B-dependent targeting to cardiac subcellular domains, and by the oncoprotein CIP2A which structurally displaces the PP2A-A subunit and blocks the B56α substrate-binding pocket to form an inhibitory pseudotrimer; additionally, HIV-1 Vif degrades PPP2R5A through cullin-RING ubiquitin ligase recruitment while also blocking its substrate-binding site in a degradation-independent manner."},"narrative":{"mechanistic_narrative":"PPP2R5A (B56α) is a substrate- and localization-targeting regulatory subunit of the PP2A holoenzyme that directs phosphatase activity toward defined substrates to control oncogenic signaling, cardiac excitation-contraction, and adipocyte fate [PMID:16537924, PMID:26198358, PMID:34232566]. A central function is restraint of Myc-family oncoproteins: B56α binds the c-Myc N-terminus and directs PP2A to dephosphorylate the stabilizing phospho-Ser62, driving ubiquitin-mediated c-Myc degradation, with loss of B56α elevating c-Myc and bypassing oncogene-induced senescence [PMID:16537924, PMID:21822300]; the same Ser62-directed mechanism governs N-Myc stability in neuroblastoma [PMID:41707997]. This tumor-suppressive axis is disabled in cancer by the oncoprotein CIP2A, which displaces the PP2A-A scaffold to form an inhibitory CIP2A-B56α-PP2Ac pseudotrimer and occludes the LxxIxE substrate-binding pocket, a mechanism exploited downstream of oncogenic KRAS to sequester B56α and raise c-Myc S62 phosphorylation [PMID:36854761, PMID:39443726]. B56α also dephosphorylates GSK3β to block Wnt signaling and drive adipocyte over osteoblast fate downstream of PPARγ [PMID:34232566], and dephosphorylates ATM/ATR to terminate DNA-damage signaling after repair [PMID:35187743]. In the heart, B56α functions as an autoinhibitory subunit that suppresses excess PP2A activity, is targeted to myofilament and cardiac membrane domains by ankyrin-B, and tunes phosphorylation of RyR2, troponin I, myosin-binding protein C, and phospholamban to control contractility, calcium handling, and the response to β-adrenergic stimulation [PMID:17416611, PMID:25320082, PMID:26198358, PMID:30203051]. B56α activity and abundance are themselves regulated: PKR and PKCα phosphorylate it (PKCα at Ser41) to enhance PP2A inhibition with consequences for cardiac contraction [PMID:10866685, PMID:24225947, PMID:35119335]; CRM1 exports it from the nucleus via a C-terminal NES [PMID:20378546]; and its mRNA is destabilized by AUF1 downstream of JNK signaling [PMID:16603688]. HIV-1 Vif suppresses B56α both by recruiting a cullin-RING ligase for degradation and by structurally blocking its substrate-binding site [PMID:38789685].","teleology":[{"year":2000,"claim":"Established that B56α is not a static targeting subunit but is itself a regulated node, with kinase input modulating PP2A holoenzyme output.","evidence":"Yeast two-hybrid, in vitro kinase/phosphatase assays showing PKR phosphorylates B56α and alters PP2A activity","pmids":["10866685"],"confidence":"High","gaps":["In vitro phosphorylation site not mapped to a defined residue","Cellular consequence of PKR-B56α phosphorylation not established"]},{"year":2006,"claim":"Defined the canonical substrate-directing function of B56α by showing it tethers PP2A to c-Myc and dephosphorylates the stabilizing S62 to control Myc levels.","evidence":"Reciprocal Co-IP and shRNA knockdown with phospho-S62 immunoblotting","pmids":["16537924"],"confidence":"High","gaps":["Did not address whether other B56 isoforms share this substrate","Did not establish in vivo tumor relevance"]},{"year":2006,"claim":"Showed B56α abundance is post-transcriptionally controlled, linking stress-activated MAPK signaling to PP2A regulatory subunit availability.","evidence":"JNK activation model with mRNA decay kinetics and EMSA demonstrating AUF1 binding to the B56α 3'-UTR","pmids":["16603688"],"confidence":"Medium","gaps":["AUF1 binding shown in vitro; direct in vivo destabilization not proven","Downstream phosphatase consequences of B56α loss not measured"]},{"year":2007,"claim":"Identified the molecular determinant that confines B56α-PP2A to cardiac subcellular domains, explaining spatial specificity of PP2A action.","evidence":"Co-IP, deletion mapping of a C-terminal motif, and ankyrin-B(+/-) rescue in cardiomyocytes","pmids":["17416611"],"confidence":"High","gaps":["Substrates accessed via ankyrin-B targeting not directly identified","Generality beyond heart untested"]},{"year":2010,"claim":"Resolved how B56α partitions between nuclear, cytoplasmic, and centrosomal pools, defining the structural elements controlling its localization.","evidence":"Leptomycin B, siRNA, L461A NES mutagenesis, and FRAP imaging","pmids":["20378546"],"confidence":"High","gaps":["Functional substrate consequences of nuclear vs cytoplasmic pools not defined","Centrosomal role of B56α not mechanistically explored"]},{"year":2010,"claim":"Extended B56α function into metabolic control by identifying HSL as a target and B56α-PP2A as a brake on lipolysis.","evidence":"Bidirectional overexpression/knockdown in 3T3-L1 adipocytes with phospho-HSL and lipolysis assays","pmids":["20534721"],"confidence":"Medium","gaps":["Direct dephosphorylation of HSL by B56α-PP2A not reconstituted","Single lab, single cell model"]},{"year":2009,"claim":"Connected B56α abundance to arrhythmogenesis by showing miR-1 loss of B56α mislocalizes PP2A from calcium-handling machinery.","evidence":"Adenoviral miR-1, electrophysiology, Ca2+ imaging, KN93 rescue in ventricular myocytes","pmids":["19131648"],"confidence":"High","gaps":["miR-1 effect on B56α is indirect; direct targeting not proven","RyR2 dephosphorylation by B56α-PP2A inferred, not reconstituted"]},{"year":2011,"claim":"Established B56α-mediated c-MYC suppression as a tumor-suppressive barrier by linking it to oncogene-induced senescence in melanocytes.","evidence":"Bidirectional B56α manipulation with BRAF(V600E) and SA-β-gal senescence assays","pmids":["21822300"],"confidence":"Medium","gaps":["Direct PP2A activity on c-MYC in this context not measured","Single lab"]},{"year":2012,"claim":"Broadened B56α substrate scope to endothelial signaling, identifying eNOS-Ser1179 as a target controlling NO output.","evidence":"siRNA knockdown, okadaic acid pharmacology, phospho-eNOS immunoblotting and NO measurement","pmids":["23237802"],"confidence":"Medium","gaps":["Direct B56α-eNOS interaction not demonstrated","Single lab, single study"]},{"year":2013,"claim":"Mapped a specific phosphoswitch on B56α, showing PKCα phosphorylation at Ser41 converts it into a potent PP2A inhibitor with cellular calcium consequences.","evidence":"In vitro kinase/phosphatase assays with purified PKCα, S41D phosphomimetic, Fluo-4 Ca2+ imaging in HEK293","pmids":["24225947"],"confidence":"High","gaps":["In vivo relevance addressed only later","Mechanism by which Ser41 phosphorylation inhibits PP2A not structurally defined"]},{"year":2014,"claim":"Demonstrated in vivo that B56α levels set cardiac contractility and myofilament phosphorylation, validating B56α-PP2A as a dosage-sensitive cardiac regulator.","evidence":"Transgenic B56α-overexpressing mice with subcellular fractionation, phospho-immunoblotting, contractility and patch-clamp readouts","pmids":["25320082"],"confidence":"High","gaps":["Direct substrate dephosphorylation not reconstituted in vitro","Overexpression model may not reflect physiological dosage"]},{"year":2015,"claim":"Reframed B56α as an autoinhibitory subunit suppressing excess cardiac PP2A activity, with knockout producing calcium and conduction phenotypes.","evidence":"B56α(+/-) and overexpression mouse models, PP2A activity, Ca2+ spark/wave imaging, ECG, pharmacological challenge","pmids":["26198358"],"confidence":"High","gaps":["Mechanism of autoinhibition not structurally resolved","Relationship to substrate-directing role not reconciled"]},{"year":2019,"claim":"Showed B56α dynamically relocalizes upon β-adrenergic stimulation and is required for the inotropic and hypertrophic stress response in vivo.","evidence":"Ppp2r5a knockout mice with echocardiography, PP2A activity, and acute/sustained β-AR stimulation","pmids":["30203051"],"confidence":"High","gaps":["Substrates driving stress-response phenotypes not enumerated here","Translocation trigger not mechanistically defined"]},{"year":2021,"claim":"Identified GSK3β as a developmental substrate and placed B56α in a PPARγ-driven program governing adipocyte versus osteoblast cell fate.","evidence":"Inducible B56α knockout mice, adipocyte differentiation, phospho-GSK3β, Wnt reporter, PPARγ ChIP","pmids":["34232566"],"confidence":"High","gaps":["Direct GSK3β dephosphorylation by B56α-PP2A not reconstituted","Whether Wnt block is solely GSK3β-mediated unresolved"]},{"year":2022,"claim":"Linked B56α to genome maintenance, showing it dephosphorylates ATM/ATR to terminate DNA-damage signaling and that its translational suppression sensitizes cells to irinotecan.","evidence":"Co-IP, RIP, luciferase, comet/TUNEL assays, xenografts showing eIF3a-mediated translational control of B56α","pmids":["35187743"],"confidence":"Medium","gaps":["Direct B56α-PP2A dephosphorylation of ATM/ATR not biochemically reconstituted","Single lab"]},{"year":2022,"claim":"Provided in vivo confirmation that PKC phosphorylation of B56α Ser41 is required for PKC-driven enhancement of cardiac contraction and calcium signaling.","evidence":"Transgenic S41A non-phosphorylatable mutant mice with PP2A activity, patch-clamp, Ca2+ transients, phospho-immunoblotting","pmids":["35119335"],"confidence":"High","gaps":["Other potential phosphosites on B56α not addressed","Substrate-level consequences only partially mapped"]},{"year":2023,"claim":"Defined the structural basis by which the oncoprotein CIP2A inactivates B56α-PP2A, forming a pseudotrimer that displaces the A subunit and blocks the substrate pocket.","evidence":"Cryo-EM at 3.58 Å, biochemical binding, CRISPR/Cas9 mutagenesis, in vivo xenografts in TNBC","pmids":["36854761"],"confidence":"High","gaps":["Whether all B56α substrates are equally blocked unresolved","Regulation of CIP2A-B56α assembly not defined"]},{"year":2023,"claim":"Established B56α expression level as a determinant of therapeutic response, with PP2A reactivation synergizing with venetoclax through BCL2/MCL1/ERK in AML.","evidence":"Gene editing of B56α, three distinct PP2A-activating drugs, primary AML cells and xenografts","pmids":["36455198"],"confidence":"High","gaps":["Direct B56α substrates in the BCL2/MCL1 axis not pinpointed","Mechanism connecting PP2A to MCL1 stability inferred via ERK"]},{"year":2024,"claim":"Showed oncogenic KRAS hijacks the CIP2A mechanism to sequester B56α from active PP2A, raising c-MYC S62 phosphorylation and promoting pancreatic preneoplasia.","evidence":"KRAS mutant models, Co-IP, B56α knockout in KrasG12D mice, ex vivo SMAP rescue","pmids":["39443726"],"confidence":"High","gaps":["Quantitative contribution of B56α sequestration vs other PP2A losses unclear","Whether SMAP rescue acts specifically through B56α untested"]},{"year":2024,"claim":"Defined how HIV-1 Vif suppresses B56α by both targeting it for cullin-RING-mediated degradation and structurally occluding its substrate-binding site.","evidence":"Cryo-EM of B56α-Vif-CBFβ-elongin BC at 3.58 Å, binding and degradation assays","pmids":["38789685"],"confidence":"High","gaps":["Cellular substrates affected by Vif-mediated B56α loss not enumerated","Physiological consequence for HIV replication not detailed here"]},{"year":2025,"claim":"Identified B56α as required for EMT restraint in EGFR-mutant lung cancer, with loss conferring migratory and invasive phenotypes.","evidence":"Bidirectional B56α manipulation with EMT markers and in vitro/in vivo migration assays","pmids":["41965447"],"confidence":"Medium","gaps":["Direct B56α substrates controlling EMT not identified","Single lab"]},{"year":2025,"claim":"Used unbiased phosphoproteomics to enumerate candidate B56α cardiac substrates and confirmed B56α shapes the β-adrenergic calcium and systolic response in vivo.","evidence":"Quantitative phosphoproteomics with B56-motif analysis in B56α-deficient hearts plus Ca2+ transient and echocardiography","pmids":["40485773"],"confidence":"High","gaps":["Candidate substrates not individually validated as direct","Motif presence does not prove direct dephosphorylation"]},{"year":2025,"claim":"Revealed a non-canonical B56α function as a positive cofactor for the m6A methyltransferase METTL3, promoting NLRP3 mRNA methylation and pyroptosis.","evidence":"Co-IP, METTL3 knockdown/catalytic inactivation, m6A assays, HBx-transgenic mice","pmids":["41053025"],"confidence":"Medium","gaps":["Whether this role is PP2A-dependent or independent unclear","Direct B56α-METTL3 interaction shown by Co-IP only, single study"]},{"year":2026,"claim":"Generalized the Myc-degradation mechanism to N-Myc, showing B56α-PP2A dephosphorylates N-Myc S62 to limit neuroblastoma growth.","evidence":"DT-061/DT-766 pharmacology, MG-132 rescue, N-Myc S62A mutagenesis, xenografts","pmids":["41707997"],"confidence":"High","gaps":["Direct B56α-N-Myc binding not structurally mapped","Specificity of DT-061 for B56α-PP2A not isolated"]},{"year":null,"claim":"How B56α reconciles its dual roles as a substrate-directing subunit and an autoinhibitory dampener of PP2A activity, and what governs substrate selection across its many described targets, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phosphorylation/localization state to substrate choice","Most candidate substrates lack reconstituted direct dephosphorylation","Tissue-specific substrate repertoires not comprehensively defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,13,15,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005815","term_label":"microtubule organizing 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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"},{"mim_id":"601645","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), GAMMA; PPP2R5C","url":"https://www.omim.org/entry/601645"},{"mim_id":"601644","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), BETA; PPP2R5B","url":"https://www.omim.org/entry/601644"},{"mim_id":"601643","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B (B56), ALPHA; PPP2R5A","url":"https://www.omim.org/entry/601643"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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overexpression and elevated S62 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, immunoblotting, luciferase reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional knockdown validation, replicated across multiple studies in different cell types\",\n      \"pmids\": [\"16537924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PKR (double-stranded RNA-dependent protein kinase) directly phosphorylates B56α; this phosphorylation increases PP2A trimeric holoenzyme activity in an in vitro dephosphorylation assay. PKR interaction with B56α is dependent on PKR catalytic activity, as shown by in vitro binding assays and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, in vitro kinase assay, in vitro phosphatase assay, cotransfection luciferase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of phosphorylation and activity assays with multiple orthogonal methods in a single study\",\n      \"pmids\": [\"10866685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"B56α is an in vivo binding partner of ankyrin-B in cardiomyocytes; the interaction requires a 13-residue motif at the B56α C-terminus not present in other B56 family members. Reduced ankyrin-B expression in ankyrin-B(+/-) cardiomyocytes causes disorganized B56α distribution, rescuable by exogenous ankyrin-B, establishing ankyrin-B as the targeting component for PP2A-B56α in heart.\",\n      \"method\": \"Co-immunoprecipitation, co-localization immunofluorescence, deletion/mutagenesis mapping, ankyrin-B(+/-) rescue experiments\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with structural mapping and genetic rescue using multiple orthogonal methods in a single study\",\n      \"pmids\": [\"17416611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"miR-1 overexpression selectively decreases expression of PP2A regulatory subunit B56α in rat ventricular myocytes, disrupting localization of PP2A activity to L-type Ca2+ channels and RyR2, leading to CaMKII-dependent hyperphosphorylation of RyR2 at S2814 and arrhythmogenic Ca2+ oscillations. Effects were reversed by CaMKII inhibitor KN93.\",\n      \"method\": \"Adenoviral miR-1 overexpression, electrophysiology, Ca2+ imaging, quantitative immunoblotting, pharmacological rescue with KN93\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts with specific pharmacological rescue in a single study\",\n      \"pmids\": [\"19131648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B56α subcellular localization is controlled by CRM1-mediated nuclear export via a functional nuclear export signal (NES) at the C-terminus (aa 451-469); mutagenesis of L461A causes nuclear retention of full-length B56α. B56α transiently expressed induces nuclear export of the PP2A catalytic subunit, blocked by the L461A NES mutation. B56α also co-localizes with PP2A-A subunit at centrosomes, with centrosome targeting requiring the A-subunit binding sequences. FRAP revealed dynamic and immobile pools of B56α-GFP.\",\n      \"method\": \"CRM1 inhibition (leptomycin B), siRNA knockdown, site-directed mutagenesis (L461A), FRAP, co-localization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis combined with pharmacological and siRNA approaches plus FRAP in a single study\",\n      \"pmids\": [\"20378546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B56α overexpression in 3T3-L1 adipocytes significantly decreased HSL Ser660 phosphorylation, while B56α knockdown increased hormone-stimulated HSL activation and lipolysis, establishing B56α/PP2A as a negative regulator of hormone-sensitive lipase and adipose lipolysis.\",\n      \"method\": \"Adenovirus-mediated overexpression and knockdown in 3T3-L1 adipocytes, phospho-specific immunoblotting, lipolysis assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — bidirectional gain/loss of function with defined biochemical readout, single lab, single study\",\n      \"pmids\": [\"20534721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PKCα directly phosphorylates B56α at Ser41 in vitro; phosphorylation at Ser41 markedly increases B56α's potency as a PP2A inhibitor. A phosphomimetic S41D mutant reduces PP2A activity in HEK293 cells and increases endoplasmic reticulum Ca2+ release by 23% compared to wild-type B56α. Purified PP2A dimer (C and A subunits) can dephosphorylate PKCα-phosphorylated B56α.\",\n      \"method\": \"In vitro kinase assay with purified PKCα, in vitro phosphatase assay, phosphomimetic mutagenesis (S41D), transfection in HEK293, Fluo-4 Ca2+ fluorescence measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of phosphorylation plus mutagenesis plus functional cellular readout in a single study\",\n      \"pmids\": [\"24225947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transgenic 2-fold overexpression of B56α in mouse cardiomyocytes enhances PP2A activity localized mainly in cytoplasm and myofilament fractions, reduces basal phosphorylation of cardiac troponin I and myosin-binding protein C by 26% and 35% respectively, increases basal contractility, decreases L-type Ca2+ current density after isoproterenol, and reduces phospholamban Ser16 phosphorylation after β-adrenergic stimulation.\",\n      \"method\": \"Transgenic mouse model, subcellular fractionation with PP2A activity assay, phospho-specific immunoblotting, cardiomyocyte isolation, whole-heart contractility measurements, patch-clamp electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple biochemical and functional readouts in a single rigorous study\",\n      \"pmids\": [\"25320082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B56α acts as an autoinhibitory subunit that suppresses excess PP2A activity in the heart. B56α(+/-) mice show increased PP2A activity, decreased RyR2 phosphorylation, reduced Ca2+ waves and sparks, slower heart rates, conduction defects, and increased parasympathetic sensitivity. In vivo B56α expression in the absence of changes in other subunit abundance decreases basal phosphatase activity and suppresses parasympathetic heart rate regulation.\",\n      \"method\": \"B56α(+/-) and B56α in vivo overexpression mouse models, PP2A activity assay, phospho-specific immunoblotting, Ca2+ spark/wave imaging, ECG, pharmacological challenge\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (knockout and overexpression) with multiple orthogonal functional and biochemical readouts\",\n      \"pmids\": [\"26198358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PP2A-B56α overexpression suppresses c-MYC protein levels in melanoma cells and induces oncogene-induced senescence (OIS), while B56α depletion in normal human melanocytes upregulates c-MYC protein and suppresses BRAF(V600E)-induced senescence, establishing PP2A-B56α as a functional regulator of c-MYC stability and OIS in melanocytic cells.\",\n      \"method\": \"B56α overexpression and siRNA knockdown in melanoma cells and normal melanocytes, immunoblotting for c-MYC, senescence assays (SA-β-gal), viral-mediated BRAF(V600E) expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional gain/loss of function with defined molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"21822300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"B56α mediates all-trans retinoic acid (atRA)-induced dephosphorylation of eNOS at Ser1179 and decreased NO production in bovine aortic endothelial cells; atRA increases B56α mRNA and protein expression (but not PP2A Cα), and siRNA knockdown of B56α reverses atRA-induced inhibition of eNOS-Ser1179 phosphorylation and NO production.\",\n      \"method\": \"siRNA knockdown of PP2A-B56α, okadaic acid pharmacology, phospho-specific immunoblotting, NO measurement, real-time PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA loss-of-function with specific biochemical readout, single lab, single study\",\n      \"pmids\": [\"23237802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Metformin activates PP2A complexes containing the B56α subunit, which inhibits JAK2V617F kinase activity as a negative regulator; the B56α-containing PP2A complex also functions as a positive regulator of JAK2V617F by inhibiting AMPK, establishing B56α-PP2A as a bidirectional regulator in this signaling axis.\",\n      \"method\": \"Pharmacological PP2A activation, AMPK inhibition, kinase activity assay, cell growth assay in MPN cell lines\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological approach without direct B56α-specific manipulation, single lab, single study\",\n      \"pmids\": [\"27576133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIP2A directly binds the PP2A-B56α trimer, displaces the PP2A-A scaffolding subunit, and forms a CIP2A-B56α-PP2Ac pseudotrimer, thereby inhibiting PP2A-B56α. CIP2A also blocks the LxxIxE-motif substrate-binding pocket on B56α, competing with substrate binding. CRISPR/Cas9 single amino acid mutagenesis of the CIP2A N-terminal head domain blunted MYC expression and MEK phosphorylation and abrogated triple-negative breast cancer tumor growth in vivo.\",\n      \"method\": \"Cryo-EM structure at 3.58 Å, biochemical binding assays, CRISPR/Cas9 mutagenesis, in vivo xenograft tumor growth assay, immunoblotting\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical validation and in vivo CRISPR mutagenesis with functional readout in a single rigorous study\",\n      \"pmids\": [\"36854761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eIF3a translationally inhibits PPP2R5A (B56α), a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair; suppression of PPP2R5A results in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity.\",\n      \"method\": \"Co-IP, RIP (RNA immunoprecipitation), luciferase reporter assay, flow cytometry, TUNEL, comet assay, western blot, xenograft model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, luciferase, Co-IP, functional assays) in a single study, single lab\",\n      \"pmids\": [\"35187743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of PPP2R5A (B56α) in complex with HIV-1 Vif-CBFβ-elongin B-elongin C at 3.58 Å shows PPP2R5A binds across the Vif molecule at a distinct interface partially overlapping with those for APOBEC3 substrates. Vif blocks a canonical PPP2R5A substrate-binding site, indicating dual mechanisms of PP2A suppression: degradation-dependent and degradation-independent inhibition of phosphatase activity.\",\n      \"method\": \"Cryo-EM structure determination, biochemical binding assays, cellular ubiquitination/degradation assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with biochemical and cellular validation in a single rigorous study\",\n      \"pmids\": [\"38789685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B56α is specifically induced during adipocyte differentiation and mediates PP2A-directed dephosphorylation of GSK3β, thereby blocking Wnt pathway activity and driving adipocyte differentiation. Inducible B56α knockout mice fail to develop gonadal adipose tissue normally and show a shift from adipocyte to osteoblast fate. B56α expression is driven by the adipocyte transcription factor PPARγ.\",\n      \"method\": \"Inducible B56α knockout mouse, in vitro adipocyte differentiation assays, phospho-specific immunoblotting for GSK3β, Wnt reporter assay, PPARγ ChIP/promoter analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockout with defined biochemical substrate (GSK3β dephosphorylation) and multiple functional readouts, single lab\",\n      \"pmids\": [\"34232566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sustained JNK activation in cardiomyocytes causes a 70% decrease in B56α protein and mRNA, converting B56α mRNA from a stable to a rapidly degraded labile form. The RNA-binding protein AUF1 is increased 4-fold in JNK-activated cells and binds B56α 3'-UTR adenylate-uridylate-rich elements with nanomolar affinity, establishing AUF1-mediated mRNA destabilization as a mechanism downstream of stress-activated MAPK signaling.\",\n      \"method\": \"Established JNK activation model in cardiomyocytes, real-time PCR mRNA decay time-course, gel mobility shift assay (EMSA), AUF1 immunoblotting\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA decay kinetics combined with EMSA demonstrating AUF1-B56α 3'-UTR binding, single lab, multiple methods\",\n      \"pmids\": [\"16603688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Phosphorylation of B56α at Ser41 by PKC is required for PKC-activated enhancement of myocyte contraction and Ca2+ signaling; transgenic mice expressing the non-phosphorylatable S41A mutant show blunted PP2A inhibition, attenuated sarcomere shortening and Ca2+ transient increases after PMA, reduced MyBP-C phosphorylation, and altered L-type Ca2+ channel activation/inactivation kinetics compared to wild-type.\",\n      \"method\": \"Transgenic mouse model (S41A mutant), PP2A activity assay, patch-clamp electrophysiology, Ca2+ transient measurement, phospho-specific immunoblotting\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mutagenesis model with multiple orthogonal functional and biochemical readouts, confirmed in context of earlier in vitro kinase study (PMID 24225947)\",\n      \"pmids\": [\"35119335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRASG12D induces CIP2A expression and sequesters B56α away from the active PP2A holoenzyme in a CIP2A-dependent manner, leading to increased c-MYC S62 phosphorylation. Knockout of B56α in vivo promotes KRASG12D-driven acinar-to-ductal metaplasia and PanIN formation. Pharmacological re-activation of PP2A with SMAPs attenuates ADM ex vivo.\",\n      \"method\": \"KRAS mutant cell models, co-immunoprecipitation, phospho-specific immunoblotting, B56α knockout in KrasG12D mouse model, ex vivo acinar culture with SMAP treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in vivo combined with Co-IP and pharmacological rescue, multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"39443726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PP2A-B56α dephosphorylates the S62 residue on N-Myc in neuroblastoma, promoting its proteasomal degradation; S62 phosphosite mutation on N-Myc abrogates PP2A-B56α-mediated effects on N-Myc stability, cell viability, and colony formation. In vivo xenograft tumor growth inhibition by PP2A activator DT-061 is accompanied by reduced N-Myc protein expression.\",\n      \"method\": \"PP2A activator (DT-061) treatment, proteasome inhibitor rescue (MG-132), competitive antagonist (DT-766), N-Myc S62A phosphosite mutagenesis, cell viability assay, colony formation assay, xenograft mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphosite mutagenesis combined with pharmacological rescue and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"41707997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Suppression of PP2A-B56α in EGFR-mutant non-small cell lung cancer results in decreased epithelial marker expression, increased mesenchymal markers, and acquisition of migratory and invasive phenotypes both in vitro and in vivo; B56α overexpression rescues these migratory phenotypes.\",\n      \"method\": \"B56α knockdown and overexpression, EMT marker immunoblotting, in vitro migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional gain/loss of function with in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"41965447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PP2A reactivation using PP2A-activating drugs synergizes with venetoclax in AML through PP2A complexes containing the B56α regulatory subunit; mechanistically, PP2A reactivation simultaneously inhibits antiapoptotic BCL2 and reduces MCL1 protein stability through extracellular signal-regulated kinase (ERK) signaling inhibition. B56α expression level dictates response to the combination therapy.\",\n      \"method\": \"Gene editing (B56α-specific manipulation), pharmacological PP2A activation with three structurally distinct drugs, AML cell lines, primary AML cells, xenograft models, immunoblotting for BCL2/MCL1/ERK\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene editing combined with three distinct pharmacological agents and in vivo validation with defined molecular mechanisms, replicated across multiple models\",\n      \"pmids\": [\"36455198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Quantitative phosphoproteomics identified >25 hyperphosphorylated proteins harboring B56 binding motifs as putative direct substrates of PP2A-B56α in response to β-adrenergic signaling in vivo. Loss of B56α in cardiomyocytes blunts acute isoproterenol-induced increases in intracellular calcium transient amplitude, and B56α-deficient mice are protected from isoproterenol-induced systolic dysfunction despite comparable hypertrophy.\",\n      \"method\": \"Quantitative phosphoproteomics of B56α-deficient and wild-type hearts after isoproterenol injection, in vitro Ca2+ transient measurement in cardiomyocytes, in vivo sustained isoproterenol infusion model with echocardiography\",\n      \"journal\": \"Journal of molecular and cellular cardiology plus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics with motif analysis plus in vitro and in vivo functional validation, multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"40485773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B56α localizes to myofilaments under resting conditions and translocates to the cytosol in response to acute β-adrenergic receptor stimulation; homozygous Ppp2r5a-disrupted mice show reduced PP2A catalytic activity, attenuated inotropic response to dobutamine, and blunted hypertrophic response to sustained isoproterenol infusion despite normal basal cardiac phenotype.\",\n      \"method\": \"Ppp2r5a targeted knockout mouse (heterozygous and homozygous), echocardiography, gravimetric and histological analyses, PP2A activity assay, western blotting, acute and sustained β-AR stimulation protocols\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic mouse model with multiple functional and biochemical endpoints under two distinct challenge conditions\",\n      \"pmids\": [\"30203051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP2A B56α subunit interacts with the METTL3 methyltransferase domain (MTD) and facilitates METTL3 enzymatic activity, increasing NLRP3 mRNA m6A methylation and NLRP3 mRNA stability in HBx-expressing hepatocytes, thereby promoting pyroptosis and lipid accumulation.\",\n      \"method\": \"Co-immunoprecipitation, METTL3 knockdown and catalytic inactivation, m6A methylation assays, western blot, in vivo HBx-transgenic mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with functional knockdown validating B56α-METTL3 interaction, single lab, single study\",\n      \"pmids\": [\"41053025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2R5A/B56α is a regulatory subunit that directs the PP2A heterotrimer to specific substrates and subcellular locations: it targets PP2A to c-Myc (dephosphorylating S62 to promote proteasomal degradation), N-Myc, GSK3β (blocking Wnt signaling during adipogenesis), HSL (inhibiting adipose lipolysis), eNOS-Ser1179, RyR2, myofilament proteins, and ATM/ATR; its own activity is modulated by PKR- and PKCα-mediated phosphorylation (at Ser41) that enhance PP2A inhibition, by CRM1-dependent nuclear export via a C-terminal NES, by ankyrin-B-dependent targeting to cardiac subcellular domains, and by the oncoprotein CIP2A which structurally displaces the PP2A-A subunit and blocks the B56α substrate-binding pocket to form an inhibitory pseudotrimer; additionally, HIV-1 Vif degrades PPP2R5A through cullin-RING ubiquitin ligase recruitment while also blocking its substrate-binding site in a degradation-independent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2R5A (B56\\u03b1) is a substrate- and localization-targeting regulatory subunit of the PP2A holoenzyme that directs phosphatase activity toward defined substrates to control oncogenic signaling, cardiac excitation-contraction, and adipocyte fate [#0, #8, #15]. A central function is restraint of Myc-family oncoproteins: B56\\u03b1 binds the c-Myc N-terminus and directs PP2A to dephosphorylate the stabilizing phospho-Ser62, driving ubiquitin-mediated c-Myc degradation, with loss of B56\\u03b1 elevating c-Myc and bypassing oncogene-induced senescence [#0, #9]; the same Ser62-directed mechanism governs N-Myc stability in neuroblastoma [#19]. This tumor-suppressive axis is disabled in cancer by the oncoprotein CIP2A, which displaces the PP2A-A scaffold to form an inhibitory CIP2A-B56\\u03b1-PP2Ac pseudotrimer and occludes the LxxIxE substrate-binding pocket, a mechanism exploited downstream of oncogenic KRAS to sequester B56\\u03b1 and raise c-Myc S62 phosphorylation [#12, #18]. B56\\u03b1 also dephosphorylates GSK3\\u03b2 to block Wnt signaling and drive adipocyte over osteoblast fate downstream of PPAR\\u03b3 [#15], and dephosphorylates ATM/ATR to terminate DNA-damage signaling after repair [#13]. In the heart, B56\\u03b1 functions as an autoinhibitory subunit that suppresses excess PP2A activity, is targeted to myofilament and cardiac membrane domains by ankyrin-B, and tunes phosphorylation of RyR2, troponin I, myosin-binding protein C, and phospholamban to control contractility, calcium handling, and the response to \\u03b2-adrenergic stimulation [#2, #7, #8, #23]. B56\\u03b1 activity and abundance are themselves regulated: PKR and PKC\\u03b1 phosphorylate it (PKC\\u03b1 at Ser41) to enhance PP2A inhibition with consequences for cardiac contraction [#1, #6, #17]; CRM1 exports it from the nucleus via a C-terminal NES [#4]; and its mRNA is destabilized by AUF1 downstream of JNK signaling [#16]. HIV-1 Vif suppresses B56\\u03b1 both by recruiting a cullin-RING ligase for degradation and by structurally blocking its substrate-binding site [#14].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that B56\\u03b1 is not a static targeting subunit but is itself a regulated node, with kinase input modulating PP2A holoenzyme output.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro kinase/phosphatase assays showing PKR phosphorylates B56\\u03b1 and alters PP2A activity\",\n      \"pmids\": [\"10866685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro phosphorylation site not mapped to a defined residue\", \"Cellular consequence of PKR-B56\\u03b1 phosphorylation not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the canonical substrate-directing function of B56\\u03b1 by showing it tethers PP2A to c-Myc and dephosphorylates the stabilizing S62 to control Myc levels.\",\n      \"evidence\": \"Reciprocal Co-IP and shRNA knockdown with phospho-S62 immunoblotting\",\n      \"pmids\": [\"16537924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether other B56 isoforms share this substrate\", \"Did not establish in vivo tumor relevance\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed B56\\u03b1 abundance is post-transcriptionally controlled, linking stress-activated MAPK signaling to PP2A regulatory subunit availability.\",\n      \"evidence\": \"JNK activation model with mRNA decay kinetics and EMSA demonstrating AUF1 binding to the B56\\u03b1 3'-UTR\",\n      \"pmids\": [\"16603688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AUF1 binding shown in vitro; direct in vivo destabilization not proven\", \"Downstream phosphatase consequences of B56\\u03b1 loss not measured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the molecular determinant that confines B56\\u03b1-PP2A to cardiac subcellular domains, explaining spatial specificity of PP2A action.\",\n      \"evidence\": \"Co-IP, deletion mapping of a C-terminal motif, and ankyrin-B(+/-) rescue in cardiomyocytes\",\n      \"pmids\": [\"17416611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates accessed via ankyrin-B targeting not directly identified\", \"Generality beyond heart untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how B56\\u03b1 partitions between nuclear, cytoplasmic, and centrosomal pools, defining the structural elements controlling its localization.\",\n      \"evidence\": \"Leptomycin B, siRNA, L461A NES mutagenesis, and FRAP imaging\",\n      \"pmids\": [\"20378546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional substrate consequences of nuclear vs cytoplasmic pools not defined\", \"Centrosomal role of B56\\u03b1 not mechanistically explored\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended B56\\u03b1 function into metabolic control by identifying HSL as a target and B56\\u03b1-PP2A as a brake on lipolysis.\",\n      \"evidence\": \"Bidirectional overexpression/knockdown in 3T3-L1 adipocytes with phospho-HSL and lipolysis assays\",\n      \"pmids\": [\"20534721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of HSL by B56\\u03b1-PP2A not reconstituted\", \"Single lab, single cell model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected B56\\u03b1 abundance to arrhythmogenesis by showing miR-1 loss of B56\\u03b1 mislocalizes PP2A from calcium-handling machinery.\",\n      \"evidence\": \"Adenoviral miR-1, electrophysiology, Ca2+ imaging, KN93 rescue in ventricular myocytes\",\n      \"pmids\": [\"19131648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"miR-1 effect on B56\\u03b1 is indirect; direct targeting not proven\", \"RyR2 dephosphorylation by B56\\u03b1-PP2A inferred, not reconstituted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established B56\\u03b1-mediated c-MYC suppression as a tumor-suppressive barrier by linking it to oncogene-induced senescence in melanocytes.\",\n      \"evidence\": \"Bidirectional B56\\u03b1 manipulation with BRAF(V600E) and SA-\\u03b2-gal senescence assays\",\n      \"pmids\": [\"21822300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PP2A activity on c-MYC in this context not measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened B56\\u03b1 substrate scope to endothelial signaling, identifying eNOS-Ser1179 as a target controlling NO output.\",\n      \"evidence\": \"siRNA knockdown, okadaic acid pharmacology, phospho-eNOS immunoblotting and NO measurement\",\n      \"pmids\": [\"23237802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct B56\\u03b1-eNOS interaction not demonstrated\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped a specific phosphoswitch on B56\\u03b1, showing PKC\\u03b1 phosphorylation at Ser41 converts it into a potent PP2A inhibitor with cellular calcium consequences.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays with purified PKC\\u03b1, S41D phosphomimetic, Fluo-4 Ca2+ imaging in HEK293\",\n      \"pmids\": [\"24225947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance addressed only later\", \"Mechanism by which Ser41 phosphorylation inhibits PP2A not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in vivo that B56\\u03b1 levels set cardiac contractility and myofilament phosphorylation, validating B56\\u03b1-PP2A as a dosage-sensitive cardiac regulator.\",\n      \"evidence\": \"Transgenic B56\\u03b1-overexpressing mice with subcellular fractionation, phospho-immunoblotting, contractility and patch-clamp readouts\",\n      \"pmids\": [\"25320082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate dephosphorylation not reconstituted in vitro\", \"Overexpression model may not reflect physiological dosage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reframed B56\\u03b1 as an autoinhibitory subunit suppressing excess cardiac PP2A activity, with knockout producing calcium and conduction phenotypes.\",\n      \"evidence\": \"B56\\u03b1(+/-) and overexpression mouse models, PP2A activity, Ca2+ spark/wave imaging, ECG, pharmacological challenge\",\n      \"pmids\": [\"26198358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of autoinhibition not structurally resolved\", \"Relationship to substrate-directing role not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed B56\\u03b1 dynamically relocalizes upon \\u03b2-adrenergic stimulation and is required for the inotropic and hypertrophic stress response in vivo.\",\n      \"evidence\": \"Ppp2r5a knockout mice with echocardiography, PP2A activity, and acute/sustained \\u03b2-AR stimulation\",\n      \"pmids\": [\"30203051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates driving stress-response phenotypes not enumerated here\", \"Translocation trigger not mechanistically defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified GSK3\\u03b2 as a developmental substrate and placed B56\\u03b1 in a PPAR\\u03b3-driven program governing adipocyte versus osteoblast cell fate.\",\n      \"evidence\": \"Inducible B56\\u03b1 knockout mice, adipocyte differentiation, phospho-GSK3\\u03b2, Wnt reporter, PPAR\\u03b3 ChIP\",\n      \"pmids\": [\"34232566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GSK3\\u03b2 dephosphorylation by B56\\u03b1-PP2A not reconstituted\", \"Whether Wnt block is solely GSK3\\u03b2-mediated unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked B56\\u03b1 to genome maintenance, showing it dephosphorylates ATM/ATR to terminate DNA-damage signaling and that its translational suppression sensitizes cells to irinotecan.\",\n      \"evidence\": \"Co-IP, RIP, luciferase, comet/TUNEL assays, xenografts showing eIF3a-mediated translational control of B56\\u03b1\",\n      \"pmids\": [\"35187743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct B56\\u03b1-PP2A dephosphorylation of ATM/ATR not biochemically reconstituted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided in vivo confirmation that PKC phosphorylation of B56\\u03b1 Ser41 is required for PKC-driven enhancement of cardiac contraction and calcium signaling.\",\n      \"evidence\": \"Transgenic S41A non-phosphorylatable mutant mice with PP2A activity, patch-clamp, Ca2+ transients, phospho-immunoblotting\",\n      \"pmids\": [\"35119335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other potential phosphosites on B56\\u03b1 not addressed\", \"Substrate-level consequences only partially mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the structural basis by which the oncoprotein CIP2A inactivates B56\\u03b1-PP2A, forming a pseudotrimer that displaces the A subunit and blocks the substrate pocket.\",\n      \"evidence\": \"Cryo-EM at 3.58 \\u00c5, biochemical binding, CRISPR/Cas9 mutagenesis, in vivo xenografts in TNBC\",\n      \"pmids\": [\"36854761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all B56\\u03b1 substrates are equally blocked unresolved\", \"Regulation of CIP2A-B56\\u03b1 assembly not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established B56\\u03b1 expression level as a determinant of therapeutic response, with PP2A reactivation synergizing with venetoclax through BCL2/MCL1/ERK in AML.\",\n      \"evidence\": \"Gene editing of B56\\u03b1, three distinct PP2A-activating drugs, primary AML cells and xenografts\",\n      \"pmids\": [\"36455198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct B56\\u03b1 substrates in the BCL2/MCL1 axis not pinpointed\", \"Mechanism connecting PP2A to MCL1 stability inferred via ERK\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed oncogenic KRAS hijacks the CIP2A mechanism to sequester B56\\u03b1 from active PP2A, raising c-MYC S62 phosphorylation and promoting pancreatic preneoplasia.\",\n      \"evidence\": \"KRAS mutant models, Co-IP, B56\\u03b1 knockout in KrasG12D mice, ex vivo SMAP rescue\",\n      \"pmids\": [\"39443726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of B56\\u03b1 sequestration vs other PP2A losses unclear\", \"Whether SMAP rescue acts specifically through B56\\u03b1 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how HIV-1 Vif suppresses B56\\u03b1 by both targeting it for cullin-RING-mediated degradation and structurally occluding its substrate-binding site.\",\n      \"evidence\": \"Cryo-EM of B56\\u03b1-Vif-CBF\\u03b2-elongin BC at 3.58 \\u00c5, binding and degradation assays\",\n      \"pmids\": [\"38789685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrates affected by Vif-mediated B56\\u03b1 loss not enumerated\", \"Physiological consequence for HIV replication not detailed here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified B56\\u03b1 as required for EMT restraint in EGFR-mutant lung cancer, with loss conferring migratory and invasive phenotypes.\",\n      \"evidence\": \"Bidirectional B56\\u03b1 manipulation with EMT markers and in vitro/in vivo migration assays\",\n      \"pmids\": [\"41965447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct B56\\u03b1 substrates controlling EMT not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used unbiased phosphoproteomics to enumerate candidate B56\\u03b1 cardiac substrates and confirmed B56\\u03b1 shapes the \\u03b2-adrenergic calcium and systolic response in vivo.\",\n      \"evidence\": \"Quantitative phosphoproteomics with B56-motif analysis in B56\\u03b1-deficient hearts plus Ca2+ transient and echocardiography\",\n      \"pmids\": [\"40485773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Candidate substrates not individually validated as direct\", \"Motif presence does not prove direct dephosphorylation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-canonical B56\\u03b1 function as a positive cofactor for the m6A methyltransferase METTL3, promoting NLRP3 mRNA methylation and pyroptosis.\",\n      \"evidence\": \"Co-IP, METTL3 knockdown/catalytic inactivation, m6A assays, HBx-transgenic mice\",\n      \"pmids\": [\"41053025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this role is PP2A-dependent or independent unclear\", \"Direct B56\\u03b1-METTL3 interaction shown by Co-IP only, single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized the Myc-degradation mechanism to N-Myc, showing B56\\u03b1-PP2A dephosphorylates N-Myc S62 to limit neuroblastoma growth.\",\n      \"evidence\": \"DT-061/DT-766 pharmacology, MG-132 rescue, N-Myc S62A mutagenesis, xenografts\",\n      \"pmids\": [\"41707997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct B56\\u03b1-N-Myc binding not structurally mapped\", \"Specificity of DT-061 for B56\\u03b1-PP2A not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How B56\\u03b1 reconciles its dual roles as a substrate-directing subunit and an autoinhibitory dampener of PP2A activity, and what governs substrate selection across its many described targets, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phosphorylation/localization state to substrate choice\", \"Most candidate substrates lack reconstituted direct dephosphorylation\", \"Tissue-specific substrate repertoires not comprehensively defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 13, 15, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 15, 18]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7, 8, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"PP2A heterotrimer (B56\\u03b1 regulatory subunit)\",\n      \"CIP2A-B56\\u03b1-PP2Ac pseudotrimer\"\n    ],\n    \"partners\": [\n      \"MYC\",\n      \"MYCN\",\n      \"GSK3B\",\n      \"CIP2A\",\n      \"ANK2\",\n      \"EIF3A\",\n      \"METTL3\",\n      \"PRKCA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}