Affinage

PPP2R5A

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

Length
486 aa
Mass
56.2 kDa
Annotated
2026-04-28
42 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP2R5A (B56α) is a regulatory B subunit of the protein phosphatase 2A (PP2A) holoenzyme that directs substrate specificity, subcellular targeting, and phosphatase activity across multiple tissues and signaling contexts. In the PP2A heterotrimer, B56α recruits PP2A to dephosphorylate c-Myc and N-Myc at Ser62, promoting their ubiquitin-mediated proteasomal degradation (PMID:16537924, PMID:41707997), and dephosphorylates GSK3β to suppress Wnt signaling and drive adipocyte differentiation (PMID:34232566); in cardiomyocytes, ankyrin-B targets B56α to membrane compartments where it modulates phosphorylation of RyR2, L-type Ca²⁺ channels, troponin I, and myosin-binding protein C, thereby tuning excitation–contraction coupling and β-adrenergic responsiveness (PMID:17416611, PMID:25320082, PMID:26198358, PMID:30203051). B56α activity is regulated by PKC α-mediated phosphorylation at Ser41, which enhances an autoinhibitory suppression of PP2A catalytic activity (PMID:24225947, PMID:35119335), by CRM1-dependent nuclear export via a C-terminal NES (PMID:20378546), and by inhibitory sequestration through the oncoprotein CIP2A, which displaces the PP2A-A scaffolding subunit and occludes the LxxIxE substrate-binding pocket to form an inhibitory pseudotrimer (PMID:36854761, PMID:39443726). HIV-1 Vif co-opts a cullin-RING E3 ligase to degrade B56α and simultaneously blocks its substrate-binding site, contributing to G2/M cell cycle arrest (PMID:38789685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Establishing that B56α is not merely a passive scaffold but is itself a regulated target: PKR directly phosphorylates B56α, increasing PP2A holoenzyme activity and downstream eIF4E dephosphorylation, revealing that kinase-mediated modification of the regulatory subunit can tune PP2A output.

    Evidence Yeast two-hybrid, in vitro kinase assay, co-immunoprecipitation, and dephosphorylation assays

    PMID:10866685

    Open questions at the time
    • Physiological context of PKR-B56α signaling beyond interferon responses remains undefined
    • PKR phosphorylation site on B56α not mapped
  2. 2006 High

    Identifying the first substrate recruitment function: B56α directly associates with the c-Myc N-terminus, directing PP2A to dephosphorylate Ser62 and promote Myc degradation, establishing B56α as a tumor-suppressive substrate-targeting subunit.

    Evidence Co-immunoprecipitation, shRNA knockdown with phospho-Ser62 and Myc protein-level readouts

    PMID:16537924

    Open questions at the time
    • Structural basis for c-Myc recognition by B56α not determined
    • Whether B56α directly dephosphorylates other Myc family members was untested
  3. 2006 Medium

    Revealing post-transcriptional regulation of B56α abundance: JNK activation destabilizes B56α mRNA via AUF1 binding to AU-rich elements in the 3′-UTR, providing a mechanism by which stress signaling can reduce B56α protein and alter PP2A substrate targeting in cardiomyocytes.

    Evidence mRNA stability assays and gel-shift for AUF1-B56α 3′-UTR interaction in JNK-activated cardiomyocytes

    PMID:16603688

    Open questions at the time
    • AUF1 binding validated by gel-shift only; in vivo confirmation lacking
    • Whether JNK-mediated B56α loss contributes to cardiac pathology not demonstrated
  4. 2007 High

    Defining how B56α reaches its cardiac substrates: ankyrin-B binds a unique 13-residue C-terminal motif of B56α to target PP2A to cardiomyocyte membrane compartments; disruption of this interaction disorganizes B56α distribution and alters local phosphatase activity.

    Evidence Co-IP, deletion mapping, ankyrin-B heterozygous knockout with rescue in primary cardiomyocytes

    PMID:17416611

    Open questions at the time
    • Crystal structure of ankyrin-B–B56α interface not solved
    • Whether ankyrin-B targeting is required for all cardiac substrates of B56α is unclear
  5. 2009 High

    Linking B56α loss to arrhythmogenesis: miR-1-mediated downregulation of B56α displaces PP2A from RyR2 and L-type Ca²⁺ channels, causing CaMKII-dependent RyR2 hyperphosphorylation and arrhythmogenic Ca²⁺ oscillations, placing B56α at the nexus of microRNA regulation and cardiac arrhythmia.

    Evidence Adenoviral miR-1 overexpression, electrophysiology, Ca²⁺ imaging, pharmacological CaMKII inhibition in rat ventricular myocytes

    PMID:19131648

    Open questions at the time
    • Direct demonstration that miR-1 targets B56α 3′-UTR (e.g., luciferase reporter) not shown in this study
    • Contribution of other miR-1 targets to the phenotype not excluded
  6. 2010 High

    Resolving B56α subcellular distribution mechanism and a metabolic substrate: B56α is exported from the nucleus via a CRM1-dependent C-terminal NES (residues 451–469) and localizes to centrosomes through A-subunit interaction; separately, B56α-containing PP2A dephosphorylates HSL at Ser660 in adipocytes, suppressing lipolysis.

    Evidence NES mutagenesis (L461A), leptomycin B treatment, FRAP for localization; gain- and loss-of-function with phospho-HSL readout in 3T3-L1 adipocytes

    PMID:20378546 PMID:20534721

    Open questions at the time
    • Whether NES-mediated export is dynamically regulated in vivo is unknown
    • HSL dephosphorylation by B56α-PP2A not confirmed with purified enzyme
  7. 2013 High

    Pinpointing the inhibitory phosphorylation site: PKCα phosphorylates B56α at Ser41, markedly enhancing B56α's autoinhibitory effect on PP2A catalytic activity and altering ER Ca²⁺ release, identifying Ser41 as a molecular switch controlling PP2A output.

    Evidence In vitro kinase assay, phosphomimetic S41D and non-phosphorylatable mutants in HEK293 cells, PP2A activity assay, Ca²⁺ measurements

    PMID:24225947

    Open questions at the time
    • Structural mechanism by which Ser41 phosphorylation induces autoinhibition not resolved
    • In vivo significance of Ser41 not yet demonstrated at this point
  8. 2014 High

    Demonstrating in vivo cardiac consequences of B56α gain-of-function: cardiomyocyte-directed B56α overexpression in mice enhances cytoplasmic/myofilament PP2A activity, reduces basal troponin I and MyBP-C phosphorylation, increases basal contractility, and blunts β-adrenergic responses.

    Evidence Transgenic mouse overexpression, PP2A activity with subcellular fractionation, echocardiography, patch-clamp

    PMID:25320082

    Open questions at the time
    • Whether altered contractility is solely due to troponin I/MyBP-C dephosphorylation or involves additional substrates
    • Long-term cardiac remodeling consequences not assessed
  9. 2015 High

    Establishing the paradoxical autoinhibitory model: B56α heterozygous knockout mice show increased PP2A activity, revealing that B56α not only targets substrates but also constrains excess phosphatase activity, with physiological consequences including reduced RyR2 phosphorylation and bradycardia.

    Evidence B56α heterozygous knockout mice, PP2A activity assay, ECG, Ca²⁺ imaging, phospho-RyR2 Western blot

    PMID:26198358

    Open questions at the time
    • Molecular mechanism of autoinhibition (intramolecular vs. allosteric) not defined
    • Whether autoinhibition extends to non-cardiac tissues untested
  10. 2019 High

    Revealing stimulus-dependent relocalization: under resting conditions B56α localizes to myofilaments; β-adrenergic stimulation triggers translocation to the cytosol, and full B56α knockout attenuates both inotropic and hypertrophic cardiac responses.

    Evidence Ppp2r5a knockout mice, subcellular fractionation, echocardiography, cardiac histology

    PMID:30203051

    Open questions at the time
    • Signal triggering translocation (direct phosphorylation, scaffold release) not identified
    • Whether translocation involves Ser41 phosphorylation not tested
  11. 2022 High

    Validating Ser41 as the critical in vivo switch: transgenic mice expressing non-phosphorylatable S41A B56α are resistant to PKC-mediated PP2A inhibition, confirming that PKC–B56α–PP2A signaling specifically through Ser41 controls L-type Ca²⁺ channel kinetics and contractile protein phosphorylation.

    Evidence Transgenic S41A B56α mutant mice, PP2A activity assay, Ca²⁺ transients, patch-clamp, phospho-MyBP-C Western blot

    PMID:35119335

    Open questions at the time
    • Whether Ser41 phosphorylation modulates B56α interactions with non-cardiac substrates unknown
    • Identity of the phosphatase that reverses Ser41 phosphorylation in vivo not confirmed
  12. 2021 High

    Extending B56α tumor-suppressive function to differentiation: PPARγ-driven B56α expression during adipogenesis directs PP2A to dephosphorylate GSK3β, blocking Wnt signaling; inducible B56α knockout mice show impaired adipose development and a fate switch toward osteoblasts.

    Evidence Inducible knockout mouse, phospho-GSK3β Western blot, adipocyte differentiation and in vivo adipose analysis

    PMID:34232566

    Open questions at the time
    • Whether GSK3β is a direct B56α-PP2A substrate (in vitro reconstitution) not shown
    • Role of B56α in brown/beige adipocyte differentiation not examined
  13. 2023 High

    Revealing the structural mechanism of oncogenic PP2A inhibition: cryo-EM shows CIP2A displaces the A subunit from B56α–PP2Ac, forming an inhibitory pseudotrimer, and occludes the LxxIxE substrate-binding groove; disrupting this interface suppresses MYC expression and breast cancer xenograft growth.

    Evidence Cryo-EM structure, biochemical binding assays, CRISPR mutagenesis, in vivo xenograft

    PMID:36854761

    Open questions at the time
    • Whether all CIP2A-sensitive substrates use LxxIxE motifs is untested
    • Dynamics of A-subunit displacement in cells not characterized
  14. 2024 High

    Revealing viral co-option: cryo-EM at 3.58 Å shows HIV-1 Vif binds B56α at a site partially overlapping APOBEC3 interfaces and occludes the substrate-binding pocket, suppressing PP2A activity through both degradation-dependent and degradation-independent mechanisms to induce G2/M arrest.

    Evidence Cryo-EM structure, biochemical binding assays, cellular degradation assays

    PMID:38789685

    Open questions at the time
    • Relative contribution of degradation vs. substrate-site blockade to cell cycle arrest not quantified
    • Whether Vif targets other B56 family members in vivo unclear
  15. 2024 High

    Connecting CIP2A–B56α axis to KRAS-driven tumorigenesis: KRASG12D induces CIP2A, which sequesters B56α from PP2A and prevents c-MYC Ser62 dephosphorylation; B56α knockout accelerates pancreatic acinar-to-ductal metaplasia.

    Evidence B56α knockout mice crossed with KRASG12D pancreatic cancer model, Co-IP, pharmacological PP2A reactivation

    PMID:39443726

    Open questions at the time
    • Whether pharmacological PP2A reactivation restores B56α-specific holoenzyme or acts through other B subunits
    • Contribution of substrates beyond c-MYC not defined
  16. 2025 Medium

    Systematic substrate identification: phosphoproteomics of B56α-deficient hearts after β-adrenergic stimulation identified >25 hyperphosphorylated proteins with B56 binding motifs as candidate direct substrates, and B56α loss blunted acute Ca²⁺ transients but protected against sustained β-adrenergic systolic dysfunction.

    Evidence Quantitative phosphoproteomics, B56α knockout mice, Ca²⁺ imaging, echocardiography

    PMID:40485773

    Open questions at the time
    • Putative substrates identified by motif and hyperphosphorylation; direct dephosphorylation not validated for individual candidates
    • Mechanism of protection from sustained isoproterenol-induced dysfunction not elucidated
  17. 2025 Medium

    A non-canonical interaction: B56α binds METTL3 and facilitates m6A methylation of NLRP3 mRNA, promoting pyroptosis in HBx-expressing hepatocytes — a function independent of classic PP2A phosphatase activity.

    Evidence Co-IP, MeRIP-seq, siRNA knockdown in hepatocyte models

    PMID:41053025

    Open questions at the time
    • Whether B56α enhances METTL3 activity directly or through PP2A-mediated dephosphorylation not distinguished
    • Single study; independent replication needed
    • Phosphatase-independent vs. phosphatase-dependent mechanism not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis of B56α's autoinhibitory function, how stimulus-dependent translocation from myofilaments to cytosol is regulated, the full in vivo substrate repertoire beyond validated targets (c-Myc, N-Myc, GSK3β, RyR2, HSL, troponin I, MyBP-C), and whether the METTL3 interaction represents a phosphatase-independent scaffolding role.
  • No structural model of B56α autoinhibitory conformation exists
  • Translocation signal unknown
  • Most putative cardiac substrates from phosphoproteomics unvalidated individually

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0140096 catalytic activity, acting on a protein 6
Localization
GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 1 R-HSA-1640170 Cell Cycle 1
Partners
ANK2CIP2AEIF2AK2MYCMYCNPPP2CAPPP2R1APRKCA
Complex memberships
CIP2A-B56α-PP2Ac pseudotrimerPP2A holoenzyme (AC-B56α trimer)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PP2A regulatory subunit B56α (PPP2R5A) selectively associates with the N terminus of c-Myc, directing intact PP2A holoenzymes to c-Myc and causing dephosphorylation of c-Myc serine 62, which enhances c-Myc ubiquitin-mediated degradation. shRNA knockdown of B56α increases c-Myc levels, c-Myc Ser62 phosphorylation, and c-Myc function. Co-immunoprecipitation, shRNA knockdown, Western blot for phospho-Ser62 c-Myc Molecular and cellular biology High 16537924
2000 PKR (double-stranded RNA-dependent protein kinase) directly phosphorylates B56α (PPP2R5A) in vitro, and this phosphorylation increases PP2A trimeric holoenzyme activity. Interaction is dependent on PKR catalytic activity, confirmed by in vitro binding and co-immunoprecipitation. PKR phosphorylation of B56α also reduces eIF4E phosphorylation via increased PP2A activity. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, in vitro kinase assay, in vitro dephosphorylation assay, cotransfection luciferase assay Molecular and cellular biology High 10866685
2007 B56α (PPP2R5A) is an in vivo binding partner of ankyrin-B in cardiomyocytes. A 13-residue motif in the B56α C-terminus (not present in other B56 family members) mediates ankyrin-B association. Reduced ankyrin-B expression in ankyrin-B+/- cardiomyocytes causes disorganized B56α distribution, rescuable by exogenous ankyrin-B, establishing ankyrin-B as a critical targeting component for PP2A-B56α in the heart. Co-immunoprecipitation, co-localization in primary cardiomyocytes, deletion/domain mapping, ankyrin-B heterozygous knockout with rescue American journal of physiology. Heart and circulatory physiology High 17416611
2009 miR-1 overexpression in rat ventricular myocytes selectively decreases expression of the PP2A regulatory subunit B56α (PPP2R5A), disrupting localization of PP2A activity to the L-type Ca2+ channel and RyR2. This causes CaMKII-dependent hyperphosphorylation of RyR2 at S2814, increased Ca2+ spark frequency, and arrhythmogenic Ca2+ oscillations. Effects are reversed by CaMKII inhibitor KN93. Adenoviral miR-1 overexpression, electrophysiology, Ca2+ imaging, quantitative immunoblotting, pharmacological inhibition Circulation research High 19131648
2010 B56α (PPP2R5A) localizes primarily in the cytoplasm via CRM1-mediated nuclear export. A functional nuclear export signal (NES) at the C-terminus (amino acids 451–469) is required; L461A NES mutation causes nuclear retention. B56α expression induces nuclear export of the PP2A catalytic subunit, blocked by the L461A mutation. B56α also co-localizes with the PP2A A subunit at centrosomes via sequences that bind the A subunit. FRAP reveals dynamic and immobile pools. siRNA knockdown of CRM1, leptomycin B treatment, site-directed mutagenesis (L461A), FRAP, co-localization, subcellular fractionation The Journal of biological chemistry High 20378546
2013 PKCα directly phosphorylates B56α (PPP2R5A) at Ser41 in vitro. This phosphorylation markedly increases the potency of B56α to inhibit PP2A activity. A phosphomimetic S41D mutant also reduces PP2A activity in HEK293 cells and increases ER Ca2+ release. The dimeric PP2A holoenzyme (C+A subunits) can dephosphorylate PKCα-phosphorylated B56α. In vitro kinase assay, phosphomimetic and non-phosphorylatable mutant expression in HEK293 cells, PP2A activity assay, Ca2+ fluorescence measurements The Journal of biological chemistry High 24225947
2014 Cardiomyocyte-directed overexpression of B56α in transgenic mice results in enhanced PP2A activity localized mainly to the cytoplasm and myofilament fraction, reduced basal phosphorylation of cardiac troponin I and myosin-binding protein C (by 26% and 35% respectively), and increased basal contractility. β-adrenergic stimulation is impaired in these mice, with reduced phospholamban Ser16 phosphorylation and decreased L-type Ca2+ current density after isoproterenol. Transgenic mouse overexpression, PP2A activity assay with subcellular fractionation, echocardiography, patch-clamp, Western blot for phosphoproteins The Journal of biological chemistry High 25320082
2015 B56α (PPP2R5A) has an autoinhibitory role suppressing excess PP2A activity in the heart. B56α+/- mice show increased PP2A activity, slower heart rates, increased heart rate variability, conduction defects, reduced RyR2 phosphorylation and decreased Ca2+ waves/sparks. In vivo B56α expression in the absence of altered other PP2A subunit abundance decreases basal phosphatase activity and increases RyR2 phosphorylation. B56α heterozygous knockout mice, PP2A activity assay, ECG, Ca2+ imaging, Western blot for phospho-RyR2 Science signaling High 26198358
2010 B56α (PPP2R5A) overexpression or knockdown in 3T3-L1 adipocytes regulates hormone-sensitive lipase (HSL) Ser660 phosphorylation. B56α overexpression decreases HSL Ser660 phosphorylation, while B56α knockdown increases HSL activation and lipolysis, establishing PP2A-B56α as a negative regulator of adipose lipolysis by dephosphorylating HSL. Adenovirus-mediated B56α overexpression and knockdown in 3T3-L1 adipocytes, lipolysis assay, Western blot for phospho-HSL Endocrinology Medium 20534721
2012 All-trans retinoic acid increases B56α (PPP2R5A) expression and PP2A activity in bovine aortic endothelial cells, leading to dephosphorylation of eNOS at Ser1179 and decreased NO production. siRNA knockdown of B56α reverses retinoic acid-induced inhibition of eNOS phosphorylation and NO production. siRNA knockdown of B56α, PP2A activity assay, Western blot for phospho-eNOS, NO production measurement Biochemical and biophysical research communications Medium 23237802
2006 Sustained JNK activation in cardiomyocytes decreases B56α (PPP2R5A) protein and mRNA levels by ~70%, converting B56α mRNA from a stable to a rapidly degraded labile form. The RNA-binding protein AUF1, which is induced 4-fold by JNK activation, binds with nanomolar affinity to adenylate-uridylate-rich elements in the B56α 3'-UTR, providing a mechanism for JNK-mediated destabilization of B56α mRNA. JNK activation model, real-time PCR mRNA stability assays, gel mobility shift assay for AUF1-B56α 3'-UTR interaction American journal of physiology. Heart and circulatory physiology Medium 16603688
2023 CIP2A directly binds the PP2A-B56α trimer and: (1) displaces the PP2A-A scaffolding subunit to form a CIP2A-B56α-PP2Ac pseudotrimer, and (2) blocks the LxxIxE-motif substrate-binding pocket on B56α, preventing substrate access. CIP2A N-terminal head domain interaction with B56α stabilizes CIP2A protein. CRISPR/Cas9 mutagenesis of this head domain blunts MYC expression and MEK phosphorylation and abrogates triple-negative breast cancer tumor growth in vivo. Cryo-EM structure, biochemical binding assays, CRISPR/Cas9 mutagenesis, in vivo xenograft model Nature communications High 36854761
2022 PKC activation (via PMA) inhibits PP2A activity in wild-type cardiomyocytes but not in transgenic mice expressing the non-phosphorylatable S41A B56α mutant, demonstrating that PKC-mediated enhancement of myocyte contraction and intracellular Ca2+ signaling is specifically mediated through phosphorylation of B56α at Ser41. PKC-B56α-PP2A signaling modulates L-type Ca2+ channel activation/inactivation kinetics and myosin-binding protein C phosphorylation. Transgenic mouse with S41A B56α mutant, PP2A activity assay, Ca2+ transient measurements, patch-clamp electrophysiology, Western blot for phospho-MyBP-C American journal of physiology. Heart and circulatory physiology High 35119335
2024 HIV-1 Vif recruits PPP2R5A (B56α) for ubiquitin-mediated degradation via a cullin-RING-E3 ligase complex. Cryo-EM structure at 3.58 Å shows PPP2R5A binds across the Vif molecule at a distinct interface partially overlapping with APOBEC3 binding sites. Vif also blocks the canonical PPP2R5A substrate-binding site, suppressing phosphatase activity through both degradation-dependent and degradation-independent mechanisms, contributing to G2/M cell cycle arrest. Cryo-EM structure at 3.58 Å, biochemical binding assays, cellular degradation assays Nature structural & molecular biology High 38789685
2021 B56α (PPP2R5A) is specifically induced during adipocyte differentiation and mediates PP2A dephosphorylation of GSK3β, thereby blocking Wnt signaling and driving adipocyte differentiation. Inducible B56α knockout mice show impaired gonadal adipose tissue development and a fate switch toward osteoblasts. B56α expression is driven by the adipocyte transcription factor PPARγ. Inducible knockout mouse, Western blot for phospho-GSK3β, adipocyte differentiation assay, in vivo adipose tissue analysis EMBO reports High 34232566
2022 PPP2R5A (B56α) directly dephosphorylates ATM/ATR. eIF3a translationally inhibits PPP2R5A, causing chronic ATM/ATR phosphorylation and activation, which impairs DNA repair and enhances irinotecan sensitivity. Suppression of PPP2R5A resulted in chronic ATM/ATR phosphorylation. Co-IP, RIP assay, luciferase reporter for translation, siRNA knockdown, Western blot for phospho-ATM/ATR, xenograft model Cell proliferation Medium 35187743
2019 B56α (PPP2R5A) localizes to myofilaments under resting conditions in cardiomyocytes and translocates to the cytosol in response to acute β-adrenergic receptor stimulation. Loss of B56α in Ppp2r5a-disrupted mice reduces PP2A catalytic activity, attenuates the inotropic response to dobutamine, and blunts hypertrophic responses to sustained isoproterenol infusion. Ppp2r5a knockout mice (HET and HOM), echocardiography, subcellular fractionation for localization, Western blot, cardiac histology Cardiovascular research High 30203051
2023 PP2A reactivation via B56α-containing complexes synergizes with venetoclax in AML by simultaneously inhibiting antiapoptotic BCL2 (directly) and decreasing MCL1 protein stability via suppression of ERK signaling. Gene editing and pharmacological approaches confirmed that the therapeutic synergy specifically requires PP2A complexes containing the B56α regulatory subunit. CRISPR gene editing, pharmacological PP2A activators, AML cell lines, primary cells, xenograft models, Western blot for BCL2/MCL1/p-ERK Blood High 36455198
2016 Metformin activates PP2A complexes containing the B56α subunit to inhibit oncogenic JAK2V617F activity in myeloproliferative neoplasm cells. The B56α-containing PP2A complex also functions as a positive regulator of JAK2V617F by inhibiting AMPK, revealing a dual regulatory role. Pharmacological PP2A activation, siRNA knockdown of B56α, Western blot for JAK2V617F activity, cell growth assays Experimental hematology Medium 27576133
2024 KRASG12D induces expression of CIP2A, which sequesters B56α away from the active PP2A holoenzyme in a CIP2A-dependent manner, preventing c-MYC dephosphorylation and driving c-MYC-dependent pancreatic tumorigenesis. B56α knockout accelerates KRASG12D-driven acinar-to-ductal metaplasia and PanIN formation in vivo. B56α knockout mice crossed with KRASG12D model, co-immunoprecipitation for complex disruption, pharmacological PP2A activators (SMAPs), Western blot for phospho-c-MYC Oncogene High 39443726
2025 Quantitative phosphoproteomics of B56α-deficient mouse hearts after isoproterenol stimulation identified >25 hyperphosphorylated proteins harboring a B56 binding motif as putative direct substrates. Loss of B56α blunts acute isoproterenol-induced intracellular calcium transient amplitude in cardiomyocytes in vitro, and protects mice from systolic dysfunction during sustained isoproterenol infusion in vivo. Quantitative phosphoproteomics, B56α knockout mice, intracellular Ca2+ imaging in cardiomyocytes, echocardiography Journal of molecular and cellular cardiology plus Medium 40485773
2025 B56α (PPP2R5A) interacts with the METTL3 methyltransferase domain, facilitating METTL3 enzymatic activity and increasing m6A methylation of NLRP3 mRNA, thereby promoting NLRP3-dependent pyroptosis and lipid accumulation in HBx-expressing hepatocytes. Co-immunoprecipitation, METTL3 catalytic inactivation, m6A-seq/MeRIP, siRNA knockdown, Western blot Cell death & disease Medium 41053025
2026 PP2A-B56α directly dephosphorylates N-Myc Ser62 in neuroblastoma cells, driving N-Myc proteasomal degradation. Mutation of the N-Myc S62 phosphosite abrogates PP2A-B56α-mediated reduction in N-Myc expression. PP2A reactivation reduces cell viability and colony formation and inhibits xenograft tumor growth. PP2A activator DT-061, proteasome inhibitor MG-132, S62A N-Myc phosphosite mutation, Western blot, xenograft model The Journal of biological chemistry Medium 41707997
2017 PPP2R5A (B56α) is a direct target of miR-218 validated by dual luciferase reporter assay. miR-218 overexpression inhibits PPP2R5A expression, activates Wnt/β-catenin signaling, and promotes cisplatin resistance in oral cancer cells. PPP2R5A overexpression rescues β-catenin signaling and restores cisplatin sensitivity. Dual luciferase reporter assay, ectopic expression and knockdown, cell viability assay, apoptosis assay Oncology reports Medium 28849187

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 234 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 39 21822300
2023 Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nature communications 32 36854761
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
2023 Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation. Blood 21 36455198
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
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
2022 eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response. Cell proliferation 6 35187743
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 1 40737850
2025 Suppression of PP2A-B56α Drives EMT in EGFR Mutant Non-Small Cell Lung Cancer. bioRxiv : the preprint server for biology 1 40791476
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
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 0 41053025
2024 KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development. bioRxiv : the preprint server for biology 0 38826439
2023 Decidual derived exosomal miR-99a-5p targets Ppp2r5a to inhibit trophoblast invasion in response to CeO2NPs exposure. Particle and fibre toxicology 0 37081566