Affinage

PPP2R1A

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

Round 2 corrected
Length
589 aa
Mass
65.3 kDa
Annotated
2026-04-28
85 papers in source corpus 30 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP2R1A encodes the Aα scaffold subunit of protein phosphatase 2A (PP2A), a 15-HEAT-repeat protein whose intrarepeat ridge provides the binding platform for the catalytic C subunit (via HEAT repeat 11) and variable regulatory B subunits (via HEAT repeats 5–7), thereby nucleating diverse PP2A holoenzymes that dephosphorylate substrates in the AKT/mTOR, WNT/Nodal, cGAS-STING, and endocannabinoid signaling pathways (PMID:9989501, PMID:16166293, PMID:28619992, PMID:40839403). Cancer-associated missense mutations concentrated at the B-subunit interface cause loss-of-function haploinsufficiency or dominant-negative effects through gained TIPRL1 interaction, hyperactivating AKT/GSK3β/mTOR signaling and promoting tumorigenesis, while the recurrent R183W mutant redirects phosphatase activity toward deoxycytidine kinase in a B56δ-dependent gain-of-function mode (PMID:16166293, PMID:27485451, PMID:38888850). Holoenzyme assembly is modulated by phosphorylation at S303/T268/S314, succinylation at K541 by HAT1, direct binding of sphingosine at Cys317, and transcriptional regulation by BRG1/ETS1/CREB/NF-κB (PMID:24465463, PMID:41132830, PMID:40588551, PMID:19750005). De novo PPP2R1A variants cause a neurodevelopmental syndrome whose severity correlates with differential disruption of B55α versus striatin subunit binding and phosphatase activity (PMID:33106617).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1999 High

    Determining the three-dimensional architecture of the PP2A scaffold resolved how a single protein could simultaneously recruit catalytic and regulatory subunits: 15 tandem HEAT repeats form a left-handed superhelix with a continuous intrarepeat ridge serving as the protein-interaction surface.

    Evidence X-ray crystallography at 2.3 Å resolution

    PMID:9989501

    Open questions at the time
    • No holoenzyme structure showing simultaneous C- and B-subunit engagement
    • Flexibility of HEAT repeats in solution not captured by crystal packing
  2. 2000 Medium

    Identification of PPP2R1A mutations in breast and lung carcinomas established the gene as somatically altered in cancer, raising the question of whether mutations cause loss or gain of PP2A function.

    Evidence Sequencing of tumor versus matched normal DNA in primary carcinomas

    PMID:10713707

    Open questions at the time
    • Functional consequence of individual mutations not tested
    • Small sample size limits frequency estimation
  3. 2000 Medium

    Mapping Lys416 within HEAT repeat 11 as the shared contact for both the catalytic subunit and HSF2 defined the first discrete residue-level determinant of C-subunit recruitment and revealed that non-PP2A partners compete for the same surface.

    Evidence Point mutagenesis and molecular competition binding assays

    PMID:10872807

    Open questions at the time
    • Competition with HSF2 not validated in vivo
    • Structural basis of competition not resolved
  4. 2005 High

    Demonstrating that cancer-associated Aα mutants are haploinsufficient — impairing subunit binding, reducing phosphatase activity, activating AKT, and enabling tumorigenesis — established the functional mechanism linking PPP2R1A mutation to oncogenesis.

    Evidence Binding assays, PP2A activity measurement, AKT pathway readouts, and tumor formation in immunodeficient mice

    PMID:16166293

    Open questions at the time
    • Contribution of individual holoenzyme subtypes to tumor suppression not dissected
    • Whether all cancer-associated mutations act through haploinsufficiency versus dominant-negative mechanisms remained unclear
  5. 2006 High

    Discovery that a PP2A holoenzyme containing PPP2R1A is recruited to centromeres via shugoshin to dephosphorylate cohesin expanded the gene's function beyond signal transduction to mitotic chromosome segregation fidelity.

    Evidence Co-IP, immunofluorescence co-localization, and in vitro cohesin dephosphorylation assay

    PMID:16541025

    Open questions at the time
    • Which regulatory B subunit mediates centromeric targeting not fully resolved
    • Meiotic versus mitotic contributions not separated
  6. 2007 High

    Identification of CIP2A as a direct PP2A inhibitor that stabilizes c-Myc by blocking PP2A-mediated Ser62 dephosphorylation linked the Aα-scaffolded holoenzyme to oncoprotein turnover control.

    Evidence Co-IP, in vitro PP2A activity assay, siRNA knockdown, and tumor formation assays

    PMID:17632056

    Open questions at the time
    • Which specific B subunit mediates c-Myc dephosphorylation through CIP2A-regulated holoenzyme not determined
  7. 2009 Medium

    Mapping the PPP2R1A promoter revealed multi-factor transcriptional regulation (CREB, ETS-1, AP-2α positive; SP-1 negative), explaining how Aα protein levels are dynamically controlled at the transcriptional level.

    Evidence EMSA, reporter gene assays, mutagenesis, and ChIP in mouse cells

    PMID:19750005

    Open questions at the time
    • Physiological stimuli that trigger transcription factor switching not identified
    • Human promoter regulation not confirmed
  8. 2011 Medium

    High-frequency PPP2R1A mutations in serous endometrial carcinoma (40.8%), mapped to HEAT repeats 5 and 7 at the B-subunit interface, established the gene as one of the most commonly mutated in this tumor type and pointed to selective disruption of regulatory subunit binding.

    Evidence Targeted sequencing of tumor cohorts with structural mapping to holoenzyme interfaces

    PMID:21381030 PMID:21435433

    Open questions at the time
    • Which B-subunit interactions are selectively lost by specific mutations not biochemically resolved at this point
  9. 2014 Medium

    Discovery that in vivo phosphorylation of PPP2R1A at S303, T268, and S314 inhibits catalytic subunit binding established a post-translational regulatory switch for holoenzyme assembly, with decreased phosphorylation in failing hearts explaining increased PP2A activity.

    Evidence Mass spectrometry phosphosite identification in cardiac tissue, phosphomimetic mutagenesis, and Co-IP

    PMID:24465463

    Open questions at the time
    • Kinase(s) responsible for these phosphorylation events not identified
    • In vivo cardiac phenotype not tested by phosphosite knock-in
  10. 2016 High

    Resolving the dominant-negative mechanism of recurrent endometrial cancer mutations showed that Aα mutants gain interaction with TIPRL1, forming substrate-trapping complexes that hyperphosphorylate AKT/GSK3β/mTOR substrates — a qualitatively different oncogenic mechanism from simple haploinsufficiency.

    Evidence Co-IP, phosphatase activity assays, anchorage-independent growth, tumor formation, and TIPRL1 siRNA rescue

    PMID:27485451

    Open questions at the time
    • Structural basis of TIPRL1 gain-of-interaction not determined
    • Whether all HEAT repeat 5/7 mutants use the same TIPRL1-dependent mechanism not established
  11. 2016 Medium

    Linking eEF-2 kinase to translational control of PPP2R1A protein levels, and thereby to c-Myc stability and aerobic glycolysis, revealed that Aα abundance is regulated not only transcriptionally but also at the translational level with direct metabolic consequences.

    Evidence siRNA knockdown of eEF-2K, protein synthesis measurement, and glycolytic flux assays

    PMID:27181208

    Open questions at the time
    • Mechanism by which eEF-2K restricts PPP2R1A mRNA translation not resolved
    • Generalizability beyond the tested cell lines not confirmed
  12. 2017 High

    Knockout of Ppp2r1a in mouse embryos demonstrated that the Aα scaffold is essential for gastrulation by enabling WNT and Nodal signal transduction in the epiblast, extending the gene's role to early developmental patterning.

    Evidence Mouse homologous recombination knockout, transcriptome analysis, marker gene analysis, and genetic rescue

    PMID:28619992

    Open questions at the time
    • Which PP2A holoenzyme subtype mediates WNT/Nodal signaling in epiblast not identified
    • Whether Aβ (PPP2R1B) provides any compensatory activity during gastrulation not tested
  13. 2019 High

    Crystal structure of the P179R cancer mutant and functional rescue by wild-type Aα expression provided atomic-level understanding of how a single substitution reshapes the HEAT-repeat conformation to impair C-subunit binding, holoenzyme formation, and tumor suppression.

    Evidence X-ray crystallography, enhanced sampling molecular dynamics, biochemical binding/activity assays, and in vivo tumor/metastasis rescue models

    PMID:31142515

    Open questions at the time
    • Whether conformational change also affects B-subunit selectivity not resolved structurally
  14. 2019 Medium

    Isogenic CRISPR knock-in of the P179R mutation showed that heterozygous PPP2R1A loss-of-function enhances centrosome clustering after whole-genome doubling, providing a cellular fitness mechanism for mutation selection in aneuploid tumors.

    Evidence CRISPR knock-in in RPE-1 cells, mitosis assays, centrosome clustering quantification

    PMID:31357169

    Open questions at the time
    • Mechanism linking PP2A loss to centrosome clustering not molecularly defined
    • Generalizability to other PPP2R1A mutants not tested
  15. 2020 Medium

    Genotype-phenotype correlations across 30 individuals with de novo PPP2R1A variants established a neurodevelopmental syndrome, with severity determined by differential disruption of B55α versus striatin subunit interactions, directly connecting holoenzyme composition to brain development.

    Evidence Clinical genetics across a multi-center cohort, biochemical characterization of phosphatase activity and subunit interactions

    PMID:33106617

    Open questions at the time
    • Neuronal cell-type-specific functions of affected holoenzymes not characterized
    • Animal models of specific neurodevelopmental variants not yet generated at the time
  16. 2020 Medium

    Demonstrating that BRG1/ETS1 activates PPP2R1A transcription in vascular endothelium, leading to eNOS dephosphorylation and reduced NO bioavailability, linked Aα-scaffolded PP2A to endothelial dysfunction and atherogenesis.

    Evidence ChIP, reporter assay, endothelial-specific BRG1 knockdown mouse, eNOS phosphorylation and NO biosynthesis measurement

    PMID:32903816

    Open questions at the time
    • Which PP2A holoenzyme directly dephosphorylates eNOS Ser1177 not identified
    • Relevance to human atherosclerosis not validated
  17. 2023 High

    Discovery that PPP2R1A associates with an alternative WAVE Shell Complex (containing NHSL1) at lamellipodia and is required for RAC1-dependent actin polymerization and migration persistence revealed a non-canonical scaffolding role outside the phosphatase holoenzyme.

    Evidence Differential AP-MS upon RAC1 activation, Co-IP, random and directed migration assays, cell-free actin polymerization, NHSL1 depletion rescue

    PMID:37322026

    Open questions at the time
    • Whether PP2A catalytic activity is required at the WAVE complex or the Aα subunit acts as a pure scaffold not resolved
    • Structural basis of PPP2R1A–NHSL1 interaction not determined
  18. 2024 Medium

    The R183W hotspot mutant was shown to redirect PP2A activity toward deoxycytidine kinase (dCK) in a B56δ-dependent gain-of-function, establishing a mutation-specific substrate rewiring mechanism that causes nucleoside analogue resistance in uterine serous carcinoma.

    Evidence Stable expression of R183W, pharmacological PP2A inhibition, B56δ knockdown, dCK phosphorylation measurement, clofarabine sensitivity assays

    PMID:38888850

    Open questions at the time
    • Direct physical interaction between mutant holoenzyme and dCK not demonstrated
    • Whether other hotspot mutations share B56δ-dependent rewiring not tested
  19. 2024 Medium

    BRG1 was found to repress (rather than activate) PPP2R1A in B-ALL, showing context-dependent transcriptional regulation: BRG1 occupancy at the PPP2R1A promoter suppresses expression and activates PI3K/AKT/c-Myc signaling, with BRG1 silencing restoring PPP2R1A and inhibiting leukemia in vivo.

    Evidence ChIP, siRNA/shRNA knockdown, cell proliferation/apoptosis assays, xenograft mouse model

    PMID:39187513

    Open questions at the time
    • Mechanism by which the same factor (BRG1) activates PPP2R1A in endothelium but represses it in B-ALL not resolved
    • Whether co-factor switching explains the context-dependent effect not tested
  20. 2025 High

    Isogenic CRISPR prime-edited R183W/R183P models demonstrated that PPP2R1A mutations cause ATR inhibitor sensitivity through S-phase stress and premature mitotic entry, identifying a therapeutic vulnerability in ARID1A-mutant ovarian clear cell carcinoma.

    Evidence CRISPR prime editing, CRISPR interference screens, S-phase stress and genomic instability assays, in vivo xenograft ATRi treatment

    PMID:39939726

    Open questions at the time
    • Whether ATRi sensitivity generalizes to other PPP2R1A-mutant cancer types not tested
    • Mechanism connecting PP2A loss to replication stress checkpoint deficiency not molecularly defined
  21. 2025 High

    Conditional PPP2R1A haploinsufficiency in forebrain excitatory neurons revealed that Aα-scaffolded PP2A stabilizes EZH2, limiting MAGL transcription and preserving 2-AG endocannabinoid levels for retrograde synaptic suppression; MAGL inhibition rescues synaptic and cognitive deficits, providing a therapeutic rationale for the neurodevelopmental disorder.

    Evidence Conditional knockout mouse (NEX-Cre), electrophysiology, 2-AG quantification, MAGL/EZH2 expression analysis, ChIP, pharmacological rescue with JZL184

    PMID:40839403

    Open questions at the time
    • Whether this EZH2-MAGL-2AG axis operates in inhibitory neurons or other brain regions not tested
    • Direct PP2A substrate linking EZH2 stabilization not identified
  22. 2025 Medium

    Direct binding of sphingosine to PPP2R1A (and structurally related karyopherins) triggers reversible unfolding and PP2A activation, establishing the Aα scaffold as a sensor of endogenous sphingolipid signaling distinct from ceramide-mediated PP2A regulation.

    Evidence Activity-based protein profiling, direct binding assays, PP2A activity assay, comparison with ceramide

    PMID:40588551

    Open questions at the time
    • Binding site on PPP2R1A for sphingosine not mapped at residue-level resolution
    • In vivo physiological relevance of sphingosine-induced unfolding not demonstrated
  23. 2025 Medium

    HAT1-mediated succinylation of PPP2R1A at K541 was identified as a new post-translational modification that blocks holoenzyme assembly and prevents PPP2R1A-dependent dephosphorylation of PCK1, linking PP2A scaffold regulation to gluconeogenesis suppression and lipogenesis in hepatocarcinogenesis.

    Evidence Multi-omics, HAT1 knockout mouse with DEN/CCl4 model, co-IP, succinylation site mapping, PCK1 dephosphorylation assay

    PMID:41132830

    Open questions at the time
    • Whether succinylation at K541 is reversible and what desuccinylase is responsible not identified
    • Quantitative stoichiometry of K541 succinylation in normal versus tumor liver not determined
  24. 2026 Medium

    Covalent modification of PPP2R1A at Cys317 by Pseudolarolide B stabilizes the Aα conformation and promotes holoenzyme assembly, providing proof-of-concept that small molecules can directly activate PP2A through the scaffold subunit.

    Evidence ABPP, covalent binding site identification, PP2A activity assay, molecular dynamics, co-IP of PP2A subunits

    PMID:41795341

    Open questions at the time
    • Selectivity of Pseudolarolide B across the proteome not comprehensively assessed
    • In vivo pharmacokinetics and therapeutic window not established
  25. 2026 Medium

    PPP2R1A deficiency in SLE monocytes amplifies cGAS-STING signaling and ISG expression, and FTY720-mediated PP2A activation reverses this hyperinflammation, establishing a role for Aα-scaffolded PP2A in innate immune homeostasis and autoimmunity.

    Evidence Patient monocyte isolation, PP2A activity assay, pharmacological gain/loss of function (LB-100, FTY720), cGAMP stimulation, ISG and cytokine measurement

    PMID:41582267

    Open questions at the time
    • Direct PP2A substrate in the cGAS-STING pathway in monocytes not identified
    • Whether PPP2R1A deficiency is causal or secondary in SLE pathogenesis not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the structural basis by which specific cancer mutations redirect B-subunit selectivity (e.g., B56δ gain by R183W) to rewire substrate specificity; (2) the identity and relative contributions of different holoenzyme subtypes in neuronal, immune, and developmental contexts; and (3) whether the non-phosphatase scaffolding function at the WAVE Shell Complex is catalytically independent.
  • No complete structural model of a mutant Aα holoenzyme with redirected B subunit
  • Neurodevelopmental variant-specific animal models lacking for most variants
  • Catalytic activity requirement at WAVE complex not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005694 chromosome 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-112316 Neuronal System 1
Partners
ABI1CIP2ANHSL1PPP2CAPPP2R5APPP2R5DSGOL1TIPRL
Complex memberships
PP2A holoenzymeShugoshin-PP2A complexWAVE Shell Complex (NHSL1-containing)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Crystal structure of the PP2A PR65/Aα subunit at 2.3 Å resolution revealed 15 tandemly repeated HEAT motifs forming an elongated molecule with a double layer of antiparallel alpha helices arranged in a novel left-hand superhelical conformation; intrarepeat turns are aligned to form a continuous protein interaction ridge that serves as the binding interface for catalytic and regulatory subunits. X-ray crystallography Cell High 9989501
2000 PPP2R1A mutations (nucleotide substitutions changing highly conserved amino acids and a frameshift) were identified in breast carcinoma and lung carcinoma samples, establishing PPP2R1A as a gene altered in human cancers and suggesting a tumor suppressive role for the PP2A holoenzyme. Sequencing of tumor vs. matched normal DNA Oncogene Medium 10713707
2000 The intra-repeat loop within HEAT repeat 11 of PR65/Aα (specifically lysine 416) is critical for interaction with heat shock transcription factor 2 (HSF2), and this same residue mediates binding to the PP2A catalytic subunit; HSF2 competes with the catalytic subunit for PR65 binding through this shared contact point. Point mutagenesis and binding assays (molecular competition assays) Biochemical and biophysical research communications Medium 10872807
2005 Cancer-associated PPP2R1A (Aα) mutants exhibit defects in binding to other PP2A subunits and impaired phosphatase activity; partial suppression of endogenous Aα expression activated the AKT pathway and permitted immortalized human cells to form tumors in immunodeficient mice, establishing that cancer-associated Aα mutations cause functional haploinsufficiency that disturbs PP2A holoenzyme composition. Functional transformation assays, binding studies, in vivo tumor formation, AKT pathway readouts Cancer research High 16166293
2006 A specific subtype of PP2A containing PPP2R1A co-localizes with shugoshin at centromeres; purified shugoshin complex can reverse phosphorylation of cohesin in vitro, revealing that PP2A (assembled on the Aα scaffold) is recruited to centromeres via shugoshin to dephosphorylate cohesin and protect it from dissociation during mitosis and meiosis. Co-immunoprecipitation, in vitro dephosphorylation assay, immunofluorescence co-localization Nature High 16541025
2007 CIP2A (Cancerous Inhibitor of PP2A) directly interacts with c-Myc and inhibits PP2A activity toward c-Myc serine 62, preventing proteolytic degradation of c-Myc; this establishes the PP2A holoenzyme (assembled on the Aα scaffold) as a direct regulator of c-Myc stability in cancer cells. Co-IP, in vitro PP2A activity assay, siRNA knockdown, tumor formation assays Cell High 17632056
2009 Transcription of PPP2R1A (PP2A-Aα) is positively regulated by CREB, ETS-1, and AP-2α, and negatively regulated by SP-1, acting through defined cis-elements in the proximal promoter, as demonstrated by gel shift, reporter gene, and ChIP assays in mouse cells. Gel mobility shift assay, in vitro mutagenesis, reporter gene activity assay, ChIP PloS one Medium 19750005
2011 Somatic missense mutations in PPP2R1A were identified at high frequency (40.8%) in high-grade serous endometrial tumors; mutated residues are located in HEAT repeats at the interface between the Aα subunit and regulatory B-subunits of the PP2A holoenzyme, disrupting those interactions. Targeted sequencing of tumor samples, structural mapping The Journal of pathology Medium 21381030 21435433
2013 The transcriptional activity of PPP2R1A is regulated by NF-κB through the functional genetic variant -241(-/G) (rs11453459) in the PPP2R1A promoter, and additionally by methylation status of CpG islands in the promoter region. Reporter gene assay, ChIP, methylation analysis PloS one Medium 23555712
2014 PPP2R1A (PR65A) is phosphorylated in vivo at S303, T268, and S314 in cardiac tissue; phosphomimetic substitutions at these sites inhibit the interaction of PR65A with the PP2A catalytic subunit and PP2A holoenzyme signaling, while failing hearts show decreased PR65A phosphorylation and increased PP2A activity. Mass spectrometry identification of in vivo phosphosites, HEK cell transfection with phosphomimetic/non-phosphorylated mutants, Co-IP, 2D-DIGE phosphoprotein profiling PloS one Medium 24465463
2016 The most recurrent PPP2R1A mutations in endometrial carcinoma (in HEAT repeats 5 and 7) act via a dominant-negative mechanism: beyond loss-of-function on subset of PP2A holoenzymes, Aα mutants gain interaction with the PP2A inhibitor TIPRL1, forming substrate-trapping complexes with impaired phosphatase activity that hyperphosphorylate oncogenic substrates in the GSK3β, Akt, and mTOR/p70S6K pathways; TIPRL1 silencing rescues GSK3β phosphorylation and the growth advantage. Co-IP, phosphatase activity assays, anchorage-independent growth, tumor formation, TIPRL1 siRNA rescue Cancer research High 27485451
2016 eEF-2 kinase restricts synthesis of PPP2R1A (PP2A-Aα protein), and knockdown of eEF-2K leads to increased PP2A-Aα protein synthesis which promotes ubiquitin-proteasomal degradation of c-Myc and downregulation of pyruvate kinase M2, thereby reducing glycolysis (Warburg effect) in cancer cells. siRNA knockdown, protein synthesis measurement, glucose uptake and lactate/ATP production assays, immunoblotting Oncogene Medium 27181208
2016 The PPP2R1A W257G patient-derived mutation enhances cancer cell migration through activation of the SRC-JNK-c-Jun signaling pathway; this mutant loses the ability to bind most B56 regulatory subunits (except B56δ), and overexpression of wild-type PPP2R1A increases binding to B56 subunits and total PP2A and PPP2R1A-associated PP2Ac phosphatase activity. Cell migration assay, PP2A activity assay, Co-IP, kinase pathway analysis, in vivo tumor growth Scientific reports Medium 27272709
2017 Genetic knockout of Ppp2r1a in mouse embryos causes major gastrulation defects with impaired WNT and Nodal signal transduction in the epiblast, preventing primitive streak and mesoderm formation, as confirmed by homologous recombination knockout and genetic rescue; this establishes Ppp2r1a as essential for embryonic patterning downstream of WNT and Nodal signaling. Mouse knockout by homologous recombination, transcriptome analysis, marker gene analysis, genetic rescue Biology open High 28619992
2019 The P179R missense mutation in PPP2R1A changes the protein's stable conformational profile (shown by enhanced sampling molecular dynamics simulations and crystal structure of the mutant), significantly impairs binding to the PP2A catalytic subunit disrupting holoenzyme formation and enzymatic activity; restoration of wild-type Aα in a patient-derived P179R-mutant cell line restores enzyme function and attenuates tumorigenesis and metastasis in vivo. Molecular dynamics simulation, X-ray crystallography, biochemical binding assays, enzymatic activity assays, in vivo tumor/metastasis models Cancer research High 31142515
2019 The cancer-associated heterozygous P179R mutation in PPP2R1A 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 by which PPP2R1A mutations increase cellular fitness after whole-genome doubling. CRISPR knock-in of heterozygous P179R in RPE-1 cells, mitosis assays, centrosome clustering quantification, PP2A assembly measurement iScience Medium 31357169
2020 De novo variants in PPP2R1A cause neurodevelopmental disorders with a spectrum of severity correlated with biochemical dysfunction: variants that impair both B55α-subunit binding and increase striatin binding are associated with profound intellectual disability, epilepsy, and corpus callosum hypoplasia, while variants without B55α binding deficit cause macrocephaly and milder presentations; biochemical characterization showed variants differentially affect phosphatase activity and interaction with B55α vs. striatin subunits. Clinical genetics, biochemical characterization of phosphatase activity, interaction assays with PP2A subunits Genetics in medicine Medium 33106617
2020 BRG1, acting with the transcription factor ETS1, is recruited to the PPP2R1A (PR65A) promoter and activates its transcription; BRG1-driven PPP2R1A expression in vascular endothelial cells promotes dephosphorylation of eNOS at serine 1177, reducing NO bioavailability and contributing to atherogenesis. ChIP, siRNA knockdown, reporter assay, endothelial-specific BRG1 knockdown mouse model with eNOS phosphorylation and NO biosynthesis measurement Frontiers in cell and developmental biology Medium 32903816
2023 PPP2R1A is identified by proteomics as differentially associated with the WAVE complex subunit ABI1 upon RAC1 activation; PPP2R1A associates at the lamellipodial edge with an alternative WAVE Shell Complex containing NHSL1, is required for migration persistence and RAC1-dependent actin polymerization, and this requirement is abolished by NHSL1 depletion; tumor-associated PPP2R1A mutations impair WAVE Shell Complex binding and migration regulation. Proteomics (differential AP-MS), co-immunoprecipitation, random and directed migration assays, cell-free actin polymerization, NHSL1 depletion rescue Nature communications High 37322026
2024 BRG1 occupies the transcriptional activation site of PPP2R1A in B-ALL cells, thereby inhibiting PPP2R1A expression and activating the PI3K/AKT signaling pathway to upregulate c-Myc and BCL-2; silencing BRG1 restores PPP2R1A expression and inhibits leukemia progression in xenograft models. ChIP, siRNA/shRNA knockdown, cell proliferation/apoptosis assays, xenograft mouse model Cell death & disease Medium 39187513
2024 The PPP2R1A hotspot mutant p.R183W promotes dephosphorylation and inactivation of deoxycytidine kinase (dCK) in uterine serous carcinoma cells by a gain-of-function mechanism dependent on B56δ subunit recruitment, resulting in increased resistance to the nucleoside analogue clofarabine; B56δ knockdown or PP2A inhibition rescued clofarabine sensitivity. Stable cell line expression, pharmacological PP2A inhibition, dsiRNA B56δ knockdown, apoptosis/cell cycle/DNA damage assays, dCK phosphorylation measurement Cellular oncology Medium 38888850
2024 African swine fever virus protein p17 recruits host PP2A scaffold subunit PR65A (PPP2R1A) to down-regulate phospho-IRF3 levels, while simultaneously targeting STING for apoptotic degradation, thereby inhibiting IFN-β induction through the cGAS-STING-IRF3 pathway. Co-IP, IRF3 phosphorylation assay, IFN-β reporter assay, STING degradation assay Frontiers in microbiology Medium 38957619
2025 PPP2R1A mutations (p.R183W and p.R183P) generated by CRISPR prime editing cause ATRi-induced S-phase stress, premature mitotic entry, genomic instability and ATR inhibitor sensitivity in ovarian clear cell carcinoma cells, both in vitro and in vivo; CRISPR-Cas9 screens confirmed that inactivation of PP2A subunits including PPP2R1A enhances ATRi sensitivity in ARID1A-mutant OCCC. CRISPR-Cas9/prime editing to generate isogenic models, CRISPR interference screens, S-phase stress assays, mitotic entry assays, genomic instability measurement, in vivo xenograft ATRi treatment Oncogene High 39939726
2025 PPP2R1A haploinsufficiency in forebrain excitatory neurons increases excitatory synaptic strength by reducing 2-arachidonoyl glycerol (2-AG) levels; this occurs via destabilization of EZH2, which increases MAGL transcription and accelerates 2-AG degradation, reducing endocannabinoid-mediated suppression of presynaptic release; MAGL inhibitor JZL184 restores both synaptic and learning deficits. Conditional knockout mouse (NEX-Cre), electrophysiology, 2-AG quantification, MAGL/EZH2 expression analysis, ChIP, pharmacological rescue with JZL184 The Journal of clinical investigation High 40839403
2025 Sphingosine and constrained analogs (FTY720, SH-BC-893) directly bind PPP2R1A as well as structurally related karyopherins (importin-β1, transportin-1, importin-5, importin-7), triggering reversible unfolding of these proteins, resulting in PP2A activation; ceramide does not engage these proteins, distinguishing the mechanisms of the two endogenous sphingolipids. Activity-based protein profiling, direct binding assays, PP2A activity assay, nuclear import assays, comparison with ceramide The EMBO journal Medium 40588551
2025 HAT1 succinylates PPP2R1A at lysine 541 (K541), blocking PP2A holoenzyme assembly and the interaction of PPP2R1A with phosphoenolpyruvate carboxykinase 1 (PCK1); loss of PPP2R1A-mediated dephosphorylation of PCK1 at serine 90 promotes gluconeogenesis suppression and lipogenesis activation via SREBP1, supporting liver tumor growth. Multi-omics, HAT1 knockout mice with DEN/CCl4 hepatocarcinogenesis model, co-IP, succinylation site mapping, PCK1 dephosphorylation assay, SREBP1 nuclear translocation assay Acta pharmaceutica Sinica. B Medium 41132830
2026 Pseudolarolide B (PB) covalently binds to Cys317 of PPP2R1A, enhancing the structural stability of the Aα subunit and promoting recruitment of both the catalytic (C) and regulatory (B) subunits, thereby facilitating assembly of the active PP2A holoenzyme and augmenting its phosphatase activity to dephosphorylate key proteins in inflammatory signaling pathways. Activity-based protein profiling (ABPP), covalent binding site identification, PP2A activity assay, molecular dynamics simulation, co-IP of PP2A subunits Bioorganic chemistry Medium 41795341
2026 PPP2R1A deficiency in SLE CD14+ monocytes reduces PP2A phosphatase activity (with increased inhibitory PP2Ac-Y307 phosphorylation), amplifying cGAS-STING-dependent ISG expression and cytokine hypersecretion; pharmacological PP2A inhibition in healthy monocytes mimics SLE hyperinflammation, while FTY720-mediated PP2A activation in SLE monocytes reverses it. Patient monocyte isolation, PP2A activity assay, pharmacological modulation (LB-100, FTY720), cGAS-STING pathway stimulation (cGAMP), ISG and cytokine measurement Clinical rheumatology Medium 41582267
2026 PCYT2 promotes phosphorylation of YAP1 (preventing its nuclear translocation and inhibiting YAP1 pathway activation) in a PPP2R1A-dependent manner in clear cell renal cell carcinoma, as demonstrated by the finding that the regulatory effect of PCYT2 on YAP1 phosphorylation was abolished upon PPP2R1A knockdown. Gene overexpression/silencing, Co-IP, YAP1 phosphorylation and nuclear translocation assay, siRNA knockdown of PPP2R1A, in vivo xenograft Toxicology and applied pharmacology Low 41802576

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2010 Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science (New York, N.Y.) 1022 20826764
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
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