Affinage

PPP2R1A

Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform · UniProt P30153

Length
589 aa
Mass
65.3 kDa
Annotated
2026-06-10
55 papers in source corpus 22 papers cited in narrative 22 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

PPP2R1A (PR65/Aα) encodes the scaffold subunit of protein phosphatase 2A (PP2A), built from 15 tandem HEAT motifs that fold into an elongated left-handed superhelix whose intra-repeat ridge serves as the docking platform for the catalytic (C) and variable regulatory (B) subunits, thereby templating the assembly of functionally diverse heterotrimeric holoenzymes (PMID:9989501). Binding of the catalytic subunit depends on the HEAT repeat 11 loop, where Lys416 also mediates competitive recruitment of HSF2 (PMID:10872807), and holoenzyme assembly is negatively tuned in vivo by phosphorylation of the scaffold at S303/T268/S314, which weakens the scaffold–catalytic interaction (PMID:24465463). Through these holoenzymes PPP2R1A controls major growth-signaling outputs, restraining AKT, GSK3β, and mTOR/p70S6K substrate phosphorylation (PMID:16166293, PMID:27485451). Cancer-associated mutations corrupt scaffold function by two routes: P179R-type changes alter the scaffold conformation and impair catalytic subunit binding to cause loss of function and haploinsufficiency (PMID:16166293, PMID:31142515), whereas HEAT repeat 5/7 mutations act dominant-negatively by gaining interaction with the inhibitor TIPRL1 while retaining B56 binding, forming substrate-trapping complexes that drive tumor growth (PMID:27485451); specific variants such as W257G and R183W reprogram B56-subunit selectivity to activate SRC-JNK-c-Jun migration signaling or to dephosphorylate dCK and confer nucleoside-analogue resistance (PMID:27272709, PMID:38888850). Beyond signaling, PPP2R1A is required in vivo for WNT- and Nodal-dependent gastrulation and mesoderm formation (PMID:28619992), associates RAC1-dependently with the NHSL1-containing WAVE Shell Complex at the lamellipodial edge to sustain actin polymerization and migration persistence (PMID:37322026), and regulates inhibitory synaptogenesis and spatial learning in forebrain neurons via an EZH2–MAGL–2-AG endocannabinoid axis (PMID:40839403). De novo PPP2R1A variants cause a neurodevelopmental disorder whose severity tracks with the degree of impaired B55α binding (PMID:33106617). Scaffold activity is further modulated by post-translational modification (HAT1-mediated K541 succinylation blocks holoenzyme assembly and PCK1 dephosphorylation to reprogram hepatic gluconeogenesis/lipogenesis) (PMID:41132830) and by small molecules that bind the scaffold to either unfold it and activate PP2A or stabilize it to promote holoenzyme assembly (PMID:40588551, PMID:41795341).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    Established the structural logic of the PP2A scaffold, explaining how a single subunit can simultaneously present binding surfaces for catalytic and regulatory subunits.

    Evidence 2.3 Å X-ray crystal structure of PR65/Aα revealing 15 HEAT repeats forming a superhelical platform

    PMID:9989501

    Open questions at the time
    • Structure alone does not define which residues map to specific B-subunit families
    • No bound holoenzyme structure in this study
  2. 2000 Medium

    Mapped a discrete scaffold residue governing catalytic-subunit engagement and showed regulatory proteins can compete at that site.

    Evidence Point mutagenesis of HEAT repeat 11 (Lys416) with HSF2/catalytic-subunit binding competition assays

    PMID:10872807

    Open questions at the time
    • Single in vitro study without structural validation of the HSF2 interface
    • Physiological consequence of HSF2 competition not established
  3. 2005 High

    Linked cancer-associated Aα mutations to tumorigenesis, identifying functional haploinsufficiency that perturbs holoenzyme composition and activates AKT.

    Evidence Cancer-mutant Aα expression in human cells with binding/phosphatase assays and tumor formation in immunodeficient mice

    PMID:16166293

    Open questions at the time
    • Did not resolve which specific substrates drive transformation
    • Loss- vs gain-of-function distinction not fully separated
  4. 2009 Medium

    Defined the transcriptional control of PPP2R1A by identifying activating and repressing factors at the proximal promoter.

    Evidence Promoter dissection, EMSA, ChIP, and reporter assays for CREB, ETS-1, AP-2α, SP-1

    PMID:19750005

    Open questions at the time
    • Physiological contexts driving each factor not defined
    • No in vivo confirmation
  5. 2013 Medium

    Extended transcriptional regulation to NF-κB and DNA methylation, connecting a promoter variant to expression control.

    Evidence Promoter reporter, NF-κB binding, and methylation analysis with case-control study

    PMID:23555712

    Open questions at the time
    • Disease relevance of the variant not mechanistically established
    • Single-lab reporter system
  6. 2014 Medium

    Showed that scaffold phosphorylation is a physiological switch tuning holoenzyme assembly, relevant to cardiac PP2A activity.

    Evidence In vivo phosphosite identification (S303/T268/S314) plus phosphomimetic mutants and Co-IP in failing rat hearts

    PMID:24465463

    Open questions at the time
    • Kinase(s) responsible for these sites not identified
    • Whether phosphorylation acts on all holoenzyme types unknown
  7. 2016 High

    Resolved the dominant-negative mechanism of recurrent HEAT 5/7 mutations: gain of TIPRL1 binding creates substrate-trapping complexes that hyperactivate growth signaling.

    Evidence Co-IP, phosphatase assays, anchorage-independent growth, tumor models, and TIPRL1 silencing rescue in endometrial cancer cells

    PMID:27485451

    Open questions at the time
    • Structural basis of aberrant TIPRL1 recruitment not defined
    • Generality across all hotspot mutations not established
  8. 2016 Medium

    Connected scaffold abundance to metabolic and migratory phenotypes through mutation-specific B56 selectivity and translational control.

    Evidence W257G migration and B56-binding Co-IP assays (SRC-JNK-c-Jun); eEF-2K knockdown linking Aα synthesis to c-Myc/PKM2 and glycolysis

    PMID:27181208 PMID:27272709

    Open questions at the time
    • B56δ-specific substrate set incompletely defined
    • eEF-2K study had a published figure correction
  9. 2017 High

    Demonstrated an essential developmental role: PPP2R1A is required for gastrulation by enabling WNT and Nodal signal transduction.

    Evidence Mouse Ppp2r1a knockout with genetic rescue and embryonic marker/transcriptome analysis

    PMID:28619992

    Open questions at the time
    • Direct phosphatase substrates in WNT/Nodal signaling not identified
    • Which holoenzyme B-subunits mediate the effect unknown
  10. 2019 High

    Provided structural and in vivo proof that P179R is a conformation-altering loss-of-function mutation, with wild-type restoration reversing tumorigenicity.

    Evidence Mutant crystal structure, molecular dynamics, binding/activity assays, and in vivo rescue with PP2A reactivation

    PMID:31142515

    Open questions at the time
    • Reconciliation with dominant-negative model for other hotspots
    • In-cell mitotic consequences addressed only in a separate study
  11. 2019 Medium

    Linked P179R loss of function to mitotic fitness via reduced holoenzyme targeting and enhanced centrosome clustering after whole-genome doubling.

    Evidence CRISPR knock-in of P179R in RPE-1 cells with centrosome clustering and PP2A assembly assays

    PMID:31357169

    Open questions at the time
    • Mechanism connecting PP2A to centrosome clustering not detailed
    • Single isogenic cell system
  12. 2020 Medium

    Identified a chromatin-remodeling transcriptional cascade (BRG1-ETS1) controlling PPP2R1A and downstream endothelial eNOS/NO signaling.

    Evidence BRG1 knockdown, ChIP and Co-IP at the PR65A promoter, and NO/eNOS readouts in endothelial cells and Apoe-/- mice

    PMID:32903816

    Open questions at the time
    • Direct phosphatase target controlling eNOS phosphorylation not defined
    • Apparent opposite BRG1 effect versus leukemia context unresolved
  13. 2020 Medium

    Established genotype-phenotype logic for de novo neurodevelopmental variants, tying severity to specific B-subunit binding deficits.

    Evidence Phosphatase and B55α/striatin binding assays with clinical phenotyping across 30 individuals

    PMID:33106617

    Open questions at the time
    • Neuronal substrates underlying phenotypes not identified here
    • Mechanism of altered striatin recruitment not structurally resolved
  14. 2023 High

    Revealed a non-canonical cytoskeletal role: RAC1-dependent recruitment of PPP2R1A into the NHSL1-containing WAVE Shell Complex sustains lamellipodial actin dynamics and migration persistence.

    Evidence Differential proteomics, reciprocal Co-IP, live imaging, actin polymerization assays, and NHSL1-depletion epistasis

    PMID:37322026

    Open questions at the time
    • Whether PP2A catalytic activity is required within the WSC unknown
    • Substrates dephosphorylated at the lamellipodium not identified
  15. 2024 Medium

    Showed PPP2R1A is exploited in innate-immune evasion, recruited by viral p17 to suppress IRF3 phosphorylation and IFN-β induction.

    Evidence Co-IP of p17 with PR65A/STING/IRF3 and IFN-β reporter/phosphorylation assays

    PMID:38957619

    Open questions at the time
    • Direct dephosphorylation of IRF3 by PP2A not formally demonstrated
    • Single viral system
  16. 2024 Medium

    Defined a drug-resistance gain-of-function: R183W redirects B56δ-PP2A to inactivate dCK and blunt clofarabine cytotoxicity.

    Evidence R183W expression in carcinoma cells with dCK phosphorylation, B56δ knockdown, and pharmacologic PP2A inhibition rescues

    PMID:38888850

    Open questions at the time
    • Structural basis of altered B56δ targeting not resolved
    • Generality to other nucleoside analogues unknown
  17. 2024 Medium

    Added a leukemia-context transcriptional axis where BRG1 represses PPP2R1A to license PI3K/AKT and c-Myc/BCL-2 signaling.

    Evidence ChIP, PPP2R1A knockdown/overexpression, pathway Western blots, and xenografts in B-ALL

    PMID:39187513

    Open questions at the time
    • Opposing direction of BRG1 effect versus endothelial study not reconciled
    • Direct PP2A substrate in AKT pathway not pinpointed
  18. 2025 Medium

    Identified small-molecule modulation of the scaffold itself: sphingosine analogs bind and reversibly unfold PPP2R1A to activate PP2A while inhibiting karyopherins.

    Evidence Direct binding, unfolding and PP2A activity assays with ceramide negative control and nuclear import assays

    PMID:40588551

    Open questions at the time
    • Binding site on the scaffold not mapped
    • Selectivity over karyopherin effects in cells unclear
  19. 2025 Medium

    Demonstrated that K541 succinylation by HAT1 is a metabolic switch blocking holoenzyme assembly and PCK1 dephosphorylation to reprogram hepatic metabolism.

    Evidence Multi-omics, HAT1 knockout mice, succinylation mapping, Co-IP with PCK1, and in vivo tumor growth

    PMID:41132830

    Open questions at the time
    • Desuccinylase / dynamics of K541 modification not defined
    • Single-lab in vivo system
  20. 2025 High

    Established a neuronal mechanism whereby Ppp2r1a haploinsufficiency disrupts inhibitory synaptogenesis and learning through an EZH2-MAGL-2-AG endocannabinoid pathway.

    Evidence Forebrain conditional heterozygous knockout with electrophysiology, 2-AG measurement, EZH2/MAGL analysis, and JZL184 rescue

    PMID:40839403

    Open questions at the time
    • Direct PP2A substrate upstream of EZH2 not identified
    • Relevance to specific human PPP2R1A variants not tested
  21. 2026 Medium

    Showed scaffold stabilization as a therapeutic strategy: covalent binding at Cys317 promotes holoenzyme assembly and PP2A-mediated dephosphorylation of inflammatory signaling.

    Evidence ABPP target identification, covalent site mapping, holoenzyme assembly and phosphatase assays, and molecular dynamics

    PMID:41795341

    Open questions at the time
    • In vivo efficacy not established
    • Specificity of Cys317 engagement across the proteome not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct hotspot mutations select between loss-of-function (haploinsufficiency) and dominant-negative gain-of-function outcomes, and which specific holoenzyme-substrate pairs mediate each tissue phenotype, remains unresolved.
  • No unified structural framework reconciling P179R loss-of-function with HEAT 5/7 dominant-negative behavior
  • Direct physiological substrates for developmental, cytoskeletal, and immune roles largely unidentified
  • Mechanism linking specific B-subunit reassortment to each clinical phenotype incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-112316 Neuronal System 1 R-HSA-1266738 Developmental Biology 1 R-HSA-1640170 Cell Cycle 1
Partners
B55ΑB56/B' SUBUNITSHSF2NHSL1PCK1PP2A CATALYTIC SUBUNIT (C)STRIATINTIPRL1
Complex memberships
PP2A holoenzyme (A-B-C heterotrimer)WAVE Shell Complex (NHSL1-containing)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Crystal structure of PR65/Aα at 2.3 Å resolution revealed 15 tandemly repeated HEAT motifs forming an elongated double-layer alpha-helical scaffold with a novel left-hand superhelical conformation; the intrarepeat turns align to form a continuous ridge that constitutes the protein interaction interface for binding the catalytic and regulatory B subunits. X-ray crystallography (2.3 Å resolution crystal structure) Cell High 9989501
2000 HEAT repeat 11 intra-repeat loop, specifically lysine 416, of PR65/A is critical for binding both the PP2A catalytic subunit and HSF2; HSF2 competes with the catalytic subunit for binding to PR65 at this residue, identifying a molecular basis for HSF2 as a PP2A regulatory protein. Point mutagenesis of PR65 HEAT repeat 11 loop; binding competition assays between HSF2 and catalytic subunit Biochemical and biophysical research communications Medium 10872807
2005 Cancer-associated PPP2R1A (Aα) mutants exhibit defects in binding to other PP2A subunits and impair phosphatase activity; partial suppression of endogenous Aα activates the AKT pathway and permits tumor formation in immunodeficient mice, indicating that cancer-associated Aα mutations contribute to tumorigenesis through functional haploinsufficiency that disturbs PP2A holoenzyme composition. Introduction of cancer-associated Aα mutants into immortalized human cells; binding assays; phosphatase activity assays; tumor formation in immunodeficient mice Cancer research High 16166293
2009 Transcription of PP2A-Aα (PPP2R1A) is regulated by multiple transcription factors (CREB, ETS-1, AP-2α, SP-1) binding to cis-elements in the proximal promoter; SP-1 negatively regulates while CREB, ETS-1, and AP-2α positively regulate promoter activity. Promoter dissection; gel mobility shift assay; in vitro mutagenesis; reporter gene assay; ChIP assay PloS one Medium 19750005
2013 The PPP2R1A promoter contains a functional variant (-241 -/G) that influences NF-κB DNA-binding affinity; NF-κB regulates PPP2R1A transcription through this variant, and CpG island methylation in the promoter region also modulates PPP2R1A expression. Promoter reporter assay; NF-κB binding assay; methylation analysis; case-control study PloS one Medium 23555712
2014 PP2A Aα scaffold subunit (PR65A) is phosphorylated in vivo at residues S303, T268, and S314 in cardiac tissue; phosphomimetic substitutions at these sites inhibit interaction of PR65A with the PP2A catalytic subunit and reduce PP2A holoenzyme signaling; failing hearts have less phosphorylated PR65A and increased PP2A activity. In vivo phosphorylation site identification; HEK cell transfection with phosphomimetic and non-phosphorylated PR65A mutants; co-immunoprecipitation; 2D-DIGE phospho-protein profiling; Western blot from Dahl rat failing hearts PloS one Medium 24465463
2016 eEF-2 kinase restricts synthesis (translation) of PP2A-Aα (PPP2R1A); knockdown of eEF-2K increases PP2A-Aα protein synthesis, which promotes ubiquitin-proteasomal degradation of c-Myc and downregulates pyruvate kinase M2, reducing glycolysis (Warburg effect). eEF-2K knockdown in cancer cells; metabolic assays (glucose uptake, lactate, ATP); PP2A-A protein synthesis measurement; c-Myc and PKM2 Western blot; in vitro and in vivo tumor models Oncogene Medium 27181208
2016 Recurrent PPP2R1A cancer mutations (in HEAT repeats 5 and 7) act in a dominant-negative manner by gaining interaction with the PP2A inhibitor TIPRL1 while retaining binding to B56/B' family subunits, forming substrate-trapping complexes with impaired phosphatase activity; this leads to hyperphosphorylation of GSK3β, Akt, and mTOR/p70S6K substrates and promotes tumor growth; TIPRL1 silencing restores GSK3β phosphorylation and rescues the growth advantage. Co-immunoprecipitation; phosphatase activity assays; overexpression of Aα mutants in endometrial cancer cells; anchorage-independent growth and tumor formation assays; TIPRL1 silencing rescue experiments; phospho-substrate analysis Cancer research High 27485451
2016 PPP2R1A mutation W257G enhances cancer cell migration through activation of the SRC-JNK-c-Jun pathway; W257G loses the ability to bind most B56 regulatory subunits except B56δ; wild-type PPP2R1A overexpression increases binding to B56 subunits and total PP2A activity. Cell migration assays; pathway inhibitor studies; Co-immunoprecipitation of PPP2R1A with B56 subunits; PP2A activity assay; in vitro and in vivo proliferation assays Scientific reports Medium 27272709
2017 Ppp2r1a (PP2A scaffolding subunit PR65α) is required for embryonic patterning, primitive streak formation, gastrulation, and mesoderm formation in mice; loss of Ppp2r1a impairs both WNT and Nodal signal transduction in the epiblast, causing patterning defects; identified by gene knockout, homologous recombination, and genetic rescue. Gene knockout by homologous recombination; genetic rescue; transcriptome analysis; marker gene analysis in mouse embryos Biology open High 28619992
2019 The P179R missense mutation in PPP2R1A changes the stable conformation of the Aα subunit (shown by enhanced sampling molecular dynamics and a mutant crystal structure), significantly impairs binding to the PP2A catalytic subunit, disrupts holoenzyme formation, and reduces enzymatic activity; restoration of wild-type Aα in a P179R patient-derived cell line restores PP2A function and attenuates tumorigenesis and metastasis in vivo. Molecular dynamics simulations; X-ray crystallography of mutant PP2A Aα; biochemical binding assays; PP2A activity assay; in vivo tumor/metastasis models with Aα restoration; small molecule PP2A reactivation Cancer research High 31142515
2019 The P179R heterozygous PPP2R1A mutation decreases PP2A holoenzyme assembly and intracellular targeting during mitosis and enhances centrosome clustering when centrosome number is increased (by cytokinesis failure or centrosome amplification), likely through PP2A Aα loss of function, providing a mechanism for increased cellular fitness after whole-genome doubling. CRISPR-Cas9 knock-in of P179R in human RPE-1 cells; centrosome clustering quantification; PP2A assembly assays; immunofluorescence for mitotic spindle analysis iScience Medium 31357169
2020 BRG1 activates PPP2R1A (PR65A) transcription by interacting with ETS1 and being recruited to the PR65A promoter; this BRG1-ETS1-PP2A-Aα cascade regulates eNOS phosphorylation (Ser1177) and NO bioavailability in vascular endothelial cells; BRG1 or ETS1 depletion represses PR65A expression and rescues eNOS phosphorylation and NO biosynthesis under oxLDL treatment. BRG1 knockdown in endothelial cells and in Apoe-/- mice; NO biosynthesis measurement; eNOS phosphorylation Western blot; ChIP assay for BRG1 and ETS1 at PR65A promoter; Co-immunoprecipitation of BRG1 and ETS1 Frontiers in cell and developmental biology Medium 32903816
2020 De novo PPP2R1A variants cause variable PP2A dysfunction: variants with combined impaired B55α binding and increased striatin binding are associated with more severe biochemical disruption; severity of B55α binding deficit correlates with phenotypic severity (profound ID, epilepsy, microcephaly), while variants without B55α binding deficit show macrocephaly and milder ID. Phosphatase activity assay; PP2A subunit interaction binding assays for B55α and striatin; clinical phenotyping of 30 individuals with 16 different PPP2R1A variants Genetics in medicine Medium 33106617
2023 PPP2R1A associates with an alternative WAVE complex (WAVE Shell Complex, WSC) containing NHSL1 instead of the canonical Arp2/3-activating WAVE subunit, at the lamellipodial edge; this association is RAC1-activation-dependent; PPP2R1A is required for migration persistence and RAC1-dependent actin polymerization in cell extracts; PPP2R1A tumor mutations impair WSC binding; NHSL1 depletion abolishes the requirement for PPP2R1A in migration. Proteomics (differential Co-IP of ABI1 with/without RAC1 activation); Co-immunoprecipitation; live-cell imaging; random and directed migration assays; actin polymerization in cell extracts; NHSL1 depletion rescue experiments; analysis of tumor-associated PPP2R1A mutations on WSC binding Nature communications High 37322026
2024 African swine fever virus p17 recruits the host scaffold protein PR65A (PPP2R1A), a PP2A subunit, along with interactions with STING and IRF3, to downregulate phospho-IRF3 levels, inhibiting IFN-β induction; p17 also targets STING for partial degradation via apoptosis induction, further inhibiting p-TBK1 and p-IRF3. Co-immunoprecipitation of p17 with PR65A, STING, and IRF3; IRF3 phosphorylation Western blot; IFN-β reporter assays; apoptosis assays Frontiers in microbiology Medium 38957619
2024 PPP2R1A p.R183W gain-of-function mutation promotes dephosphorylation and inactivation of deoxycytidine kinase (dCK) via B56δ-containing PP2A complexes, causing resistance to the nucleoside analogue clofarabine; B56δ knockdown or PP2A inhibition rescued clofarabine sensitivity, confirming a gain-of-function mechanism for R183W through altered substrate targeting. Stable expression of R183W in uterine serous carcinoma cells; clofarabine resistance assays; apoptosis assays; γH2AX, ATM, Chk1/2 activation; dCK phosphorylation analysis; B56δ siRNA knockdown rescue; pharmacologic PP2A inhibition Cellular oncology Medium 38888850
2024 BRG1 occupies the transcriptional activation site of PPP2R1A and inhibits its expression, thereby activating the PI3K/AKT signaling pathway and upregulating c-Myc and BCL-2; BRG1 knockdown de-represses PPP2R1A, suppressing AKT signaling and leukemia progression. ChIP assay; PPP2R1A knockdown/overexpression in B-ALL cell lines; cell cycle and apoptosis assays; PI3K/AKT pathway Western blot; xenograft mouse model Cell death & disease Medium 39187513
2025 Sphingosine and constrained analogs (FTY720, SH-BC-893) directly bind PPP2R1A and trigger reversible unfolding of the scaffold subunit, resulting in PP2A activation; these compounds also bind structurally related karyopherins (importin-β1, transportin-1, importin-5, importin-7), simultaneously inhibiting nuclear import; ceramide does not bind PPP2R1A and does not activate PP2A through this mechanism. Direct binding assays of sphingosine/analogs to PPP2R1A; protein unfolding assays; PP2A activity assays; nuclear import assays; comparative binding of ceramide (negative result) The EMBO journal Medium 40588551
2025 Ppp2r1a haploinsufficiency in forebrain excitatory neurons increases presynaptic release probability (via reduced 2-arachidonoyl glycerol/2-AG endocannabinoid), reduces inhibitory synapse numbers, and impairs spatial learning; the 2-AG reduction is caused by increased MAGL transcription driven by EZH2 destabilization; MAGL inhibitor JZL184 rescues synaptic and learning deficits. Conditional heterozygous Ppp2r1a knockout in forebrain neurons (NEX-het-cKO); electrophysiology (excitatory and inhibitory synaptic transmission); 2-AG level measurement; MAGL and EZH2 expression analysis; JZL184 pharmacologic rescue; spatial learning/memory behavioral assays The Journal of clinical investigation High 40839403
2025 HAT1 succinylates PPP2R1A at lysine 541 (K541), blocking PP2A holoenzyme assembly and PPP2R1A interaction with PCK1; this prevents dephosphorylation of PCK1 at serine 90, inhibiting gluconeogenic enzyme activity and activating SREBP1-induced lipogenesis gene expression to promote liver tumor growth. Multi-omics (proteomics/metabolomics); HAT1 knockout mouse model; succinylation mapping; Co-immunoprecipitation of PPP2R1A with PCK1; PCK1 S90 phosphorylation analysis; SREBP1 nuclear translocation assay; in vivo tumor growth Acta pharmaceutica Sinica. B Medium 41132830
2026 Pseudolarolide B (PB) covalently binds Cys317 of PPP2R1A, enhancing structural stability of the A subunit and promoting recruitment of both catalytic (C) and regulatory (B) subunits, thereby facilitating PP2A holoenzyme assembly, augmenting phosphatase activity, and dephosphorylating key inflammatory signaling proteins. Activity-based protein profiling (ABPP) to identify PPP2R1A as direct target; covalent binding site identification at Cys317; holoenzyme assembly assays; PP2A phosphatase activity assay; molecular dynamics simulations; inflammatory signaling phospho-substrate analysis Bioorganic chemistry Medium 41795341

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 356 9989501
2000 Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 188 10713707
2005 Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity. Cancer research 144 16166293
2016 Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth. Cancer research 107 27485451
2011 Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. The Journal of pathology 96 21381030
2011 Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. The American journal of pathology 79 21435433
2019 The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis. Cancer research 52 31142515
2020 The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genetics in medicine : official journal of the American College of Medical Genetics 44 33106617
2016 eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis. Oncogene 43 27181208
2011 PPP2R1A mutations are common in the serous type of endometrial cancer. Molecular carcinogenesis 42 21882256
2016 Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway. Scientific reports 32 27272709
2018 The presence of KRAS, PPP2R1A and ARID1A mutations in 101 Chinese samples with ovarian endometriosis. Mutation research 31 29547736
2020 BRG1 Activates PR65A Transcription to Regulate NO Bioavailability in Vascular Endothelial Cells. Frontiers in cell and developmental biology 24 32903816
2025 PPP2R1A mutations portend improved survival after cancer immunotherapy. Nature 22 40604275
2009 Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1. PloS one 22 19750005
2019 A Newborn with Severe Ventriculomegaly: Expanding the PPP2R1A Gene Mutation Phenotype. Journal of pediatric genetics 17 31687265
2013 High expression of PP2A-Aα is associated with diapause induction during the photoperiod-sensitive stage of the cotton bollworm, Helicoverpa armigera. Journal of insect physiology 17 23557680
2013 Role of a novel functional variant in the PPP2R1A promoter on the regulation of PP2A-Aalpha and the risk of hepatocellular carcinoma. PloS one 16 23555712
2019 Association of PPP2R1A with Alzheimer's disease and specific cognitive domains. Neurobiology of aging 15 31349112
2017 Patterning and gastrulation defects caused by the t lethal are due to loss of Ppp2r1a. Biology open 15 28619992
2023 PPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex. Nature communications 14 37322026
2011 Mutation of PPP2R1A: a new clue in unveiling the pathogenesis of uterine serous carcinoma. The Journal of pathology 13 21432855
2000 Molecular basis of competition between HSF2 and catalytic subunit for binding to the PR65/A subunit of PP2A. Biochemical and biophysical research communications 13 10872807
2013 PPP2R1A mutation is a rare event in ovarian carcinoma across histological subtypes. Anticancer research 12 23267135
2023 Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature. Genes 11 36672867
2022 PPP2R1A neurodevelopmental disorder is associated with congenital heart defects. American journal of medical genetics. Part A 10 36209351
2025 PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma. Oncogene 9 39939726
2019 A Cancer-Associated Missense Mutation in PP2A-Aα Increases Centrosome Clustering during Mitosis. iScience 9 31357169
2024 BRG1 promotes progression of B-cell acute lymphoblastic leukemia by disrupting PPP2R1A transcription. Cell death & disease 8 39187513
2021 Refractory Epilepsy in a Toddler With PPP2R1A Gene Mutation and Congenital Hydrocephalus. Cureus 8 34984142
2014 PR65A phosphorylation regulates PP2A complex signaling. PloS one 8 24465463
2001 Absence of PPP2R1A mutations in Wilms tumor. Oncogene 8 11360189
2024 African swine fever virus structural protein p17 inhibits IRF3 activation by recruiting host protein PR65A and inducing apoptotic degradation of STING. Frontiers in microbiology 7 38957619
2018 PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma. Oncotarget 7 29861864
2023 Novel Variants of PPP2R1A in Catalytic Subunit Binding Domain and Genotype-Phenotype Analysis in Neurodevelopmentally Delayed Patients. Genes 6 37761890
2013 Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer. Molecular medicine reports 6 23588898
2022 ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification: Profiling high-risk subtypes of histomorphologically low-risk and treatment-insensitive endometrioid endometrial cancer. PloS one 5 36454788
2025 Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling. The Journal of clinical investigation 4 40839403
2024 The PPP2R1A cancer hotspot mutant p.R183W increases clofarabine resistance in uterine serous carcinoma cells by a gain-of-function mechanism. Cellular oncology (Dordrecht, Netherlands) 4 38888850
2025 Effect of Propolis on PPP2R1A and Apoptosis in Cancer Cells. Biochemistry research international 3 39850502
2023 Quantum-based modeling implies that bidentate Arg89-substrate binding enhances serine/threonine protein phosphatase-2A(PPP2R5D/PPP2R1A/PPP2CA)-mediated dephosphorylation. Frontiers in cell and developmental biology 3 37377738
2023 Case Report: The first report of PPP2R1A mutations in mesonephric-like adenocarcinoma of endometrial carcinoma. Frontiers in oncology 3 38111534
2025 p53abn high-risk endometrial cancer with PPP2R1A mutation might not benefit from adjuvant chemotherapy. American journal of clinical pathology 2 40413719
2025 Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function. Acta pharmaceutica Sinica. B 2 41132830
2023 PPP2R1A-Related Neurodevelopmental Disorder: The First Korean Case with a Novel Variant of PPP2R1A and Literature Review. Annals of clinical and laboratory science 2 37945024
2018 [Phenotype and mechanism of inducible ppp2r1a knockout mouse model]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 2 29747346
2025 Silencing PPP2R1A inhibits the progression of gastric cancer cells. Journal of cancer research and clinical oncology 1 40251453
2025 Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A. The EMBO journal 1 40588551
2023 Advanced Optical Microscopy: Unveiling Functional Insights Regarding a Novel PPP2R1A Variant and Its Unreported Phenotype. International journal of molecular sciences 1 37762002
2018 Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis. Oncogene 1 29973686
2026 PP2A dysfunction mediated by PPP2R1A deficiency drives cGAS-STING-dependent hyperinflammation in SLE CD14+ monocytes. Clinical rheumatology 0 41582267
2026 Platycodin D alleviates idiopathic pulmonary fibrosis by targeting PPP2R1A and regulating the PP2A-mediated PI3K/Akt pathway to inhibit fibroblast transdifferentiation. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41759424
2026 Covalent targeting of PP2A scaffold subunit PPP2R1A by Pseudolarolide B enhances holoenzyme assembly to exert anti-inflammatory activity. Bioorganic chemistry 0 41795341
2026 Phosphoethanolamine cytidylyltransferase 2 exerts an anti-tumor role in clear cell renal cell carcinoma by modulating the hippo/YAP1 signaling pathway in a PPP2R1A-dependent manner. Toxicology and applied pharmacology 0 41802576
2025 Clinical and Molecular Spectrum of PPP2R1A-Related Neurodevelopmental Disorders: A Systematic Review. Genes 0 41465181

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