Affinage

PPP2R5A

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform · UniProt Q15172

Length
486 aa
Mass
56.2 kDa
Annotated
2026-06-10
42 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2000 High

    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

    PMID:10866685

    Open questions at the time
    • In vitro phosphorylation site not mapped to a defined residue
    • Cellular consequence of PKR-B56α phosphorylation not established
  2. 2006 High

    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

    PMID:16537924

    Open questions at the time
    • Did not address whether other B56 isoforms share this substrate
    • Did not establish in vivo tumor relevance
  3. 2006 Medium

    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

    PMID:16603688

    Open questions at the time
    • AUF1 binding shown in vitro; direct in vivo destabilization not proven
    • Downstream phosphatase consequences of B56α loss not measured
  4. 2007 High

    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

    PMID:17416611

    Open questions at the time
    • Substrates accessed via ankyrin-B targeting not directly identified
    • Generality beyond heart untested
  5. 2010 High

    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

    PMID:20378546

    Open questions at the time
    • Functional substrate consequences of nuclear vs cytoplasmic pools not defined
    • Centrosomal role of B56α not mechanistically explored
  6. 2010 Medium

    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

    PMID:20534721

    Open questions at the time
    • Direct dephosphorylation of HSL by B56α-PP2A not reconstituted
    • Single lab, single cell model
  7. 2009 High

    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

    PMID:19131648

    Open questions at the time
    • miR-1 effect on B56α is indirect; direct targeting not proven
    • RyR2 dephosphorylation by B56α-PP2A inferred, not reconstituted
  8. 2011 Medium

    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

    PMID:21822300

    Open questions at the time
    • Direct PP2A activity on c-MYC in this context not measured
    • Single lab
  9. 2012 Medium

    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

    PMID:23237802

    Open questions at the time
    • Direct B56α-eNOS interaction not demonstrated
    • Single lab, single study
  10. 2013 High

    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

    PMID:24225947

    Open questions at the time
    • In vivo relevance addressed only later
    • Mechanism by which Ser41 phosphorylation inhibits PP2A not structurally defined
  11. 2014 High

    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

    PMID:25320082

    Open questions at the time
    • Direct substrate dephosphorylation not reconstituted in vitro
    • Overexpression model may not reflect physiological dosage
  12. 2015 High

    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

    PMID:26198358

    Open questions at the time
    • Mechanism of autoinhibition not structurally resolved
    • Relationship to substrate-directing role not reconciled
  13. 2019 High

    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

    PMID:30203051

    Open questions at the time
    • Substrates driving stress-response phenotypes not enumerated here
    • Translocation trigger not mechanistically defined
  14. 2021 High

    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

    PMID:34232566

    Open questions at the time
    • Direct GSK3β dephosphorylation by B56α-PP2A not reconstituted
    • Whether Wnt block is solely GSK3β-mediated unresolved
  15. 2022 Medium

    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

    PMID:35187743

    Open questions at the time
    • Direct B56α-PP2A dephosphorylation of ATM/ATR not biochemically reconstituted
    • Single lab
  16. 2022 High

    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

    PMID:35119335

    Open questions at the time
    • Other potential phosphosites on B56α not addressed
    • Substrate-level consequences only partially mapped
  17. 2023 High

    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

    PMID:36854761

    Open questions at the time
    • Whether all B56α substrates are equally blocked unresolved
    • Regulation of CIP2A-B56α assembly not defined
  18. 2023 High

    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

    PMID:36455198

    Open questions at the time
    • Direct B56α substrates in the BCL2/MCL1 axis not pinpointed
    • Mechanism connecting PP2A to MCL1 stability inferred via ERK
  19. 2024 High

    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

    PMID:39443726

    Open questions at the time
    • Quantitative contribution of B56α sequestration vs other PP2A losses unclear
    • Whether SMAP rescue acts specifically through B56α untested
  20. 2024 High

    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

    PMID:38789685

    Open questions at the time
    • Cellular substrates affected by Vif-mediated B56α loss not enumerated
    • Physiological consequence for HIV replication not detailed here
  21. 2025 Medium

    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

    PMID:41965447

    Open questions at the time
    • Direct B56α substrates controlling EMT not identified
    • Single lab
  22. 2025 High

    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

    PMID:40485773

    Open questions at the time
    • Candidate substrates not individually validated as direct
    • Motif presence does not prove direct dephosphorylation
  23. 2025 Medium

    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

    PMID:41053025

    Open questions at the time
    • Whether this role is PP2A-dependent or independent unclear
    • Direct B56α-METTL3 interaction shown by Co-IP only, single study
  24. 2026 High

    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

    PMID:41707997

    Open questions at the time
    • Direct B56α-N-Myc binding not structurally mapped
    • Specificity of DT-061 for B56α-PP2A not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 1
Partners
ANK2CIP2AEIF3AGSK3BMETTL3MYCMYCNPRKCA
Complex memberships
CIP2A-B56α-PP2Ac pseudotrimerPP2A heterotrimer (B56α regulatory subunit)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Co-immunoprecipitation, shRNA knockdown, immunoblotting, luciferase reporter assay Molecular and cellular biology High 16537924
2000 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. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, in vitro kinase assay, in vitro phosphatase assay, cotransfection luciferase assay Molecular and cellular biology High 10866685
2007 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. Co-immunoprecipitation, co-localization immunofluorescence, deletion/mutagenesis mapping, ankyrin-B(+/-) rescue experiments American journal of physiology. Heart and circulatory physiology High 17416611
2009 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. Adenoviral miR-1 overexpression, electrophysiology, Ca2+ imaging, quantitative immunoblotting, pharmacological rescue with KN93 Circulation research High 19131648
2010 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. CRM1 inhibition (leptomycin B), siRNA knockdown, site-directed mutagenesis (L461A), FRAP, co-localization imaging The Journal of biological chemistry High 20378546
2010 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. Adenovirus-mediated overexpression and knockdown in 3T3-L1 adipocytes, phospho-specific immunoblotting, lipolysis assay Endocrinology Medium 20534721
2013 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. In vitro kinase assay with purified PKCα, in vitro phosphatase assay, phosphomimetic mutagenesis (S41D), transfection in HEK293, Fluo-4 Ca2+ fluorescence measurement The Journal of biological chemistry High 24225947
2014 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. Transgenic mouse model, subcellular fractionation with PP2A activity assay, phospho-specific immunoblotting, cardiomyocyte isolation, whole-heart contractility measurements, patch-clamp electrophysiology The Journal of biological chemistry High 25320082
2015 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. B56α(+/-) and B56α in vivo overexpression mouse models, PP2A activity assay, phospho-specific immunoblotting, Ca2+ spark/wave imaging, ECG, pharmacological challenge Science signaling High 26198358
2011 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. 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 Oncogene Medium 21822300
2012 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. siRNA knockdown of PP2A-B56α, okadaic acid pharmacology, phospho-specific immunoblotting, NO measurement, real-time PCR Biochemical and biophysical research communications Medium 23237802
2016 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. Pharmacological PP2A activation, AMPK inhibition, kinase activity assay, cell growth assay in MPN cell lines Experimental hematology Low 27576133
2023 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. Cryo-EM structure at 3.58 Å, biochemical binding assays, CRISPR/Cas9 mutagenesis, in vivo xenograft tumor growth assay, immunoblotting Nature communications High 36854761
2022 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. Co-IP, RIP (RNA immunoprecipitation), luciferase reporter assay, flow cytometry, TUNEL, comet assay, western blot, xenograft model Cell proliferation Medium 35187743
2024 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. Cryo-EM structure determination, biochemical binding assays, cellular ubiquitination/degradation assays Nature structural & molecular biology High 38789685
2021 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. Inducible B56α knockout mouse, in vitro adipocyte differentiation assays, phospho-specific immunoblotting for GSK3β, Wnt reporter assay, PPARγ ChIP/promoter analysis EMBO reports High 34232566
2006 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. Established JNK activation model in cardiomyocytes, real-time PCR mRNA decay time-course, gel mobility shift assay (EMSA), AUF1 immunoblotting American journal of physiology. Heart and circulatory physiology Medium 16603688
2022 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. Transgenic mouse model (S41A mutant), PP2A activity assay, patch-clamp electrophysiology, Ca2+ transient measurement, phospho-specific immunoblotting American journal of physiology. Heart and circulatory physiology High 35119335
2024 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. KRAS mutant cell models, co-immunoprecipitation, phospho-specific immunoblotting, B56α knockout in KrasG12D mouse model, ex vivo acinar culture with SMAP treatment Oncogene High 39443726
2026 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. 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 The Journal of biological chemistry High 41707997
2025 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. B56α knockdown and overexpression, EMT marker immunoblotting, in vitro migration/invasion assays, in vivo metastasis model Oncogene Medium 41965447
2023 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. 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 Blood High 36455198
2025 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. 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 of molecular and cellular cardiology plus High 40485773
2019 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. Ppp2r5a targeted knockout mouse (heterozygous and homozygous), echocardiography, gravimetric and histological analyses, PP2A activity assay, western blotting, acute and sustained β-AR stimulation protocols Cardiovascular research High 30203051
2025 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. Co-immunoprecipitation, METTL3 knockdown and catalytic inactivation, m6A methylation assays, western blot, in vivo HBx-transgenic mouse model Cell death & disease Medium 41053025

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Molecular and cellular biology 236 16537924
2009 miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circulation research 230 19131648
2008 A tumor suppressor role for PP2A-B56alpha through negative regulation of c-Myc and other key oncoproteins. Cancer metastasis reviews 100 18246411
2000 The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR. Molecular and cellular biology 95 10866685
2007 Molecular basis for PP2A regulatory subunit B56alpha targeting in cardiomyocytes. American journal of physiology. Heart and circulatory physiology 75 17416611
1996 Assignment of human protein phosphatase 2A regulatory subunit genes b56alpha, b56beta, b56gamma, b56delta, and b56epsilon (PPP2R5A-PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 --> p12. Genomics 58 8812429
2015 Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart. Science signaling 47 26198358
2014 Cardiac function is regulated by B56α-mediated targeting of protein phosphatase 2A (PP2A) to contractile relevant substrates. The Journal of biological chemistry 43 25320082
2017 MicroRNA-218 promotes cisplatin resistance in oral cancer via the PPP2R5A/Wnt signaling pathway. Oncology reports 41 28849187
2013 Protein phosphatase 2A is regulated by protein kinase Cα (PKCα)-dependent phosphorylation of its targeting subunit B56α at Ser41. The Journal of biological chemistry 41 24225947
2011 PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene 41 21822300
2023 Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nature communications 32 36854761
2023 Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation. Blood 23 36455198
2010 Nuclear export and centrosome targeting of the protein phosphatase 2A subunit B56alpha: role of B56alpha in nuclear export of the catalytic subunit. The Journal of biological chemistry 23 20378546
2006 JNK activation decreases PP2A regulatory subunit B56alpha expression and mRNA stability and increases AUF1 expression in cardiomyocytes. American journal of physiology. Heart and circulatory physiology 23 16603688
2017 PPP2R5A: A multirole protein phosphatase subunit in regulating cancer development. Cancer letters 21 29175459
2017 The tumor suppressor phosphatase PP2A-B56α regulates stemness and promotes the initiation of malignancies in a novel murine model. PloS one 21 29190822
2010 B56alpha/protein phosphatase 2A inhibits adipose lipolysis in high-fat diet-induced obese mice. Endocrinology 20 20534721
2016 Metformin inhibits JAK2V617F activity in MPN cells by activating AMPK and PP2A complexes containing the B56α subunit. Experimental hematology 19 27576133
2012 B56α subunit of protein phosphatase 2A mediates retinoic acid-induced decreases in phosphorylation of endothelial nitric oxide synthase at serine 1179 and nitric oxide production in bovine aortic endothelial cells. Biochemical and biophysical research communications 15 23237802
2019 Role of type 2A phosphatase regulatory subunit B56α in regulating cardiac responses to β-adrenergic stimulation in vivo. Cardiovascular research 13 30203051
2022 Activation of PKC results in improved contractile effects and Ca2+ cycling by inhibition of PP2A-B56α. American journal of physiology. Heart and circulatory physiology 7 35119335
2022 eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response. Cell proliferation 7 35187743
2004 Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat. Clinical and experimental hypertension (New York, N.Y. : 1993) 7 15132302
2024 KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development. Oncogene 6 39443726
2020 Splice of Life for Cancer: Missplicing of PPP2R5A by Mutant SF3B1 Leads to MYC Stabilization and Tumorigenesis. Cancer discovery 5 32482664
2024 Structural insights into PPP2R5A degradation by HIV-1 Vif. Nature structural & molecular biology 4 38789685
2022 Impaired myocellular Ca2+ cycling in protein phosphatase PP2A-B56α KO mice is normalized by β-adrenergic stimulation. The Journal of biological chemistry 4 35963431
2021 The B56α subunit of PP2A is necessary for mesenchymal stem cell commitment to adipocyte. EMBO reports 4 34232566
2019 Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56α. BioMed research international 4 31641668
2025 A phosphoproteomic study uncovers the importance of PP2A-B56α in liver injury precipitated by NLRP3 activation during MC-LR exposure. Ecotoxicology and environmental safety 3 40737850
2023 Decidual derived exosomal miR-99a-5p targets Ppp2r5a to inhibit trophoblast invasion in response to CeO2NPs exposure. Particle and fibre toxicology 2 37081566
2025 Suppression of PP2A-B56α Drives EMT in EGFR Mutant Non-Small Cell Lung Cancer. bioRxiv : the preprint server for biology 1 40791476
2025 Hepatic steatosis and pyroptosis are induced by the hepatitis B virus X protein via B56α-METTL3 interaction-mediated m6A modification of the NLRP3 mRNA. Cell death & disease 1 41053025
2024 Loss of protein phosphatase 2A regulatory subunit PPP2R5A is associated with increased incidence of stress-induced proarrhythmia. Frontiers in cardiovascular medicine 1 38863902
2022 Myocardial overexpression of protein phosphatase 2A-B56α improves resistance against ischemia-reperfusion injury. Journal of molecular and cellular cardiology plus 1 39803363
2026 The protein phosphatase 2A-B56α complex regulates N-Myc degradation in neuroblastoma. The Journal of biological chemistry 0 41707997
2026 Suppression of PP2A-B56α drives EMT in EGFR mutant non-small cell lung cancer. Oncogene 0 41965447
2025 PP2A-B56α is a key determinant of cardiac protein phosphorylation and functional responses to β-adrenergic signalling. Journal of molecular and cellular cardiology plus 0 40485773
2025 Dual compartment utility of BRET-based biosensors for PPP2R5A/B56α, a cancer-associated B regulatory subunit of PP2A. BioTechniques 0 40579746
2025 Activation of PP2A-B56α leads to aberrant EGFR signaling and proliferative phenotypes in PDAC. bioRxiv : the preprint server for biology 0 40766646
2024 KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development. bioRxiv : the preprint server for biology 0 38826439

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