{"gene":"PPP2R2A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"B55α (PPP2R2A) directly interacts with Akt and targets the PP2A holoenzyme to Akt, selectively dephosphorylating Akt at Thr-308 but not Ser-473, thereby regulating cell proliferation and survival. Confirmed by co-immunoprecipitation of endogenous PP2A-AB55C holoenzymes with Akt, in vitro pulldown, in vitro dephosphorylation assays, overexpression, and siRNA knockdown experiments.","method":"Co-immunoprecipitation, in vitro pulldown, in vitro dephosphorylation assay, siRNA knockdown, overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution dephosphorylation assay plus multiple orthogonal cell-based methods (co-IP, pulldown, KD, OE), single lab but rigorous and comprehensive","pmids":["18042541"],"is_preprint":false},{"year":2010,"finding":"PP2A-B55α trimeric complex is a key regulator of mitotic exit in human cells, required for mitotic spindle breakdown and postmitotic reassembly of nuclear envelope, Golgi apparatus, and decondensed chromatin. PP2A-B55α functions downstream of Cdk1 inactivation. Mitotic PP2A-B55α has reduced phosphatase activity toward Cdk1 substrate histone H1 and is hyper-phosphorylated on all subunits. Mitotic PP2A complexes co-purify with importin-β1, and co-depletion of importin-β1 delays mitotic exit synergistically.","method":"RNAi live-cell imaging screen, chemically induced mitotic exit assay, phosphatase activity assay toward histone H1, co-purification/mass spectrometry, double RNAi knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide RNAi screen with live imaging, biochemical phosphatase assay, co-purification, epistasis by double KD; multiple orthogonal methods in one rigorous study","pmids":["20711181"],"is_preprint":false},{"year":2010,"finding":"Mitotic exit in Cdk1-inactivated cells depends on activity of PP2A complexes containing B55α or B55δ regulatory subunits, placing PP2A/B55α downstream of Cdk1 and the kinase Mastl (Greatwall) in the mitotic exit pathway. Demonstrated by genetic epistasis in mouse embryonic and adult cells.","method":"Genetically engineered mice, genetic epistasis (Cdc20 ablation + Cdk1/Mastl inactivation)","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis in engineered mouse models, clearly positions PP2A/B55α in the mitotic exit pathway","pmids":["21156286"],"is_preprint":false},{"year":2012,"finding":"PPP2R2A-containing PP2A complexes directly dephosphorylate ATM at S367, S1893, and S1981, regulating ATM retention at double-strand break (DSB) sites. Loss of PPP2R2A increases ATM phosphorylation and CHK2 activity, leading to G1/S arrest and downregulation of BRCA1 and RAD51, impairing homologous recombination repair.","method":"Loss-of-function screen, biochemical dephosphorylation assays, siRNA knockdown, cell-cycle analysis, HR repair assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct dephosphorylation assay on defined ATM phosphosites, epistasis via KD with defined molecular phenotype, single lab multiple orthogonal methods","pmids":["23087057"],"is_preprint":false},{"year":2013,"finding":"Upon glutamine deprivation, B55α is induced in a ROS-dependent manner and activates p53 through direct interaction with and dephosphorylation of EDD (a negative regulator of p53). α4 promotes assembly of an adaptive PP2A complex containing B55α under these conditions. The B55α-EDD-p53 pathway is essential for cancer cell survival under low glutamine conditions.","method":"Co-immunoprecipitation, biochemical interaction assays, RNAi knockdown, in vitro and in vivo tumor growth assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, defined substrate dephosphorylation, in vitro and in vivo functional assays, single lab multiple orthogonal methods","pmids":["23499005"],"is_preprint":false},{"year":2010,"finding":"B55α PP2A holoenzyme plays a major role in restricting phosphorylation of p107 (retinoblastoma-related protein) and inducing its activation in human cells. Targeted selectivity exists between pocket proteins and distinct PP2A holoenzymes.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, cell-cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional KD/OE with defined phosphorylation readout, single lab","pmids":["20663872"],"is_preprint":false},{"year":2011,"finding":"B55α (PPP2R2A) interacts with FoxM1 transcription factor and promotes its dephosphorylation and inactivation, antagonizing Cyclin A/Cdk-dependent activation of FoxM1 to restrict its activity to G2 phase. Overexpression of B55α decreases FoxM1 activity; depletion leads to premature FoxM1 activation dependent on Cyclin A/Cdk phosphorylation.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, FoxM1 activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP shows direct interaction, KD/OE with defined phosphorylation and activity readouts, single lab","pmids":["21813648"],"is_preprint":false},{"year":2012,"finding":"B55α-containing PP2A holoenzyme (identified by chemical cross-linking and mass spectrometry) dephosphorylates FOXO1 at Thr24 and Ser256 to promote FOXO1 nuclear translocation in pancreatic islet β-cells under oxidative stress. Knockdown of B55α inhibits FOXO1 nuclear translocation and attenuates oxidative stress-induced cell death.","method":"Chemical cross-linking, mass spectrometry, co-immunoprecipitation, siRNA knockdown, nuclear fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — cross-linking MS identifies holoenzyme complex, KD with defined phosphorylation and localization readouts, multiple orthogonal methods, single lab","pmids":["22417654"],"is_preprint":false},{"year":2013,"finding":"PP2A-B55α holoenzyme is responsible for FGF-induced p107 dephosphorylation and growth arrest in chondrocytes. B55α binds p107 with higher affinity in its dephosphorylated state; only B55α (not other B subunits) binds p107. FGF induces dephosphorylation of B55α itself on multiple serine residues, dramatically increasing its affinity for the PP2A A/C dimer and p107.","method":"Co-immunoprecipitation, siRNA knockdown, phosphorylation analysis, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with specificity controls, KD with defined phenotype, identification of B55α dephosphorylation as activation mechanism, independently confirmed by companion paper (PMID:23775125)","pmids":["23716589","23775125"],"is_preprint":false},{"year":2013,"finding":"Reciprocal solution-based mass spectrometry identified PP2A/B55α complex as a major component of p107 complexes in chondrocytes. FGF1 triggers rapid accumulation of p107-PP2A/B55α complexes coinciding with p107 dephosphorylation and nuclear accumulation, leading to cell cycle exit. B55α knockdown delays FGF1-induced dephosphorylation of p107.","method":"Reciprocal mass spectrometry, co-immunoprecipitation, siRNA knockdown, nuclear fractionation, chromatin immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based complex identification, reciprocal co-IP, KD with functional readout, multiple orthogonal methods in one study","pmids":["23775125"],"is_preprint":false},{"year":2013,"finding":"Adenovirus E4orf4 binds across the putative substrate binding groove of B55α such that the substrate p107 can no longer interact with PP2A-B55α, thus inhibiting PP2A activity by preventing substrate access. E4orf4 binding was mapped to the α1,α2 helices of B55α using mutagenesis and structural prediction; loss of binding reduces E4orf4-induced cell death.","method":"Structure-guided mutagenesis, immunoprecipitation, GST pulldown, cell death assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis-guided binding site mapping with functional consequence, single lab","pmids":["24244166"],"is_preprint":false},{"year":2013,"finding":"E4orf4 binding site in PP2A-B55α maps to α1 and α2 helices (blade 1/2 region) of the seven-bladed β-propeller. This site lies above the substrate binding groove and does not overlap it. Loss of E4orf4 binding at this site reduces E4orf4-induced cell death.","method":"Bioinformatics, mutagenesis, immunoprecipitation, GST pulldown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis with functional validation, single lab, complementary to PMID:24244166","pmids":["23530045"],"is_preprint":false},{"year":2014,"finding":"PR55α-PP2A specifically dephosphorylates c-Jun at T239, promoting c-Jun binding to chromatin at genes regulating tumor cell migration and invasion, without affecting phosphorylation at S63. PR55α-PP2A thus enhances AP-1 transcriptional activity and tumor cell migration/invasion.","method":"Co-immunoprecipitation, phosphorylation-specific antibodies, chromatin immunoprecipitation, migration/invasion assays, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, site-specific dephosphorylation, functional migration assays, single lab","pmids":["24632621"],"is_preprint":false},{"year":2014,"finding":"F-box protein FBXL16 binds PP2A containing B55α specificity subunit (PP2A-B55α) and negatively regulates its activity. FBXL16 negatively regulates phosphorylation of the established PP2A-B55α substrate vimentin as shown by phosphoproteomics.","method":"Shotgun mass spectrometry, phosphoproteomics, siRNA screen","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex identification and phosphoproteomic substrate validation, single lab","pmids":["24390425"],"is_preprint":false},{"year":2015,"finding":"B55α mediates PP2A/Plk1 association and dephosphorylation of Plk1 at Thr-210 in response to DNA damage in Xenopus egg extracts. PP2A-B55α association with Plk1 increases after DNA damage in an ATM/ATR and checkpoint kinase-dependent manner.","method":"Xenopus egg extract biochemistry, co-immunoprecipitation, phosphatase activity assays, DNA damage induction","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical extract system with co-IP and defined phosphatase activity, single lab","pmids":["25483054"],"is_preprint":false},{"year":2017,"finding":"β-Adrenoceptor stimulation induces B55α-PP2A-mediated dephosphorylation of HDAC5 at Ser259/Ser498, leading to HDAC5 nuclear accumulation in cardiomyocytes. B55α specifically interacts with HDAC5 (and the PP2A catalytic and scaffolding subunits), and this interaction increases >3-fold with isoproterenol. Knockdown of B55α attenuates isoproterenol-induced HDAC5 dephosphorylation.","method":"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, 3D confocal microscopy localization assay","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying specific interaction, KD with defined dephosphorylation/localization readout, single lab multiple orthogonal methods","pmids":["28343149"],"is_preprint":false},{"year":2017,"finding":"PHD2 promotes degradation of B55α by hydroxylating it at proline 319. Conversely, B55α-associated PP2A promotes partial deactivation of PHD2. In glucose-starved conditions, PHD2 reduces B55α protein levels, correlating with breast cancer cell death; PHD2 silencing rescues B55α and prevents apoptosis.","method":"Hydroxylation assay, siRNA knockdown, overexpression, xenograft tumor model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identifies PTM (hydroxylation at P319) with functional consequence, in vivo confirmation, single lab","pmids":["28329677"],"is_preprint":false},{"year":2018,"finding":"SAMHD1 dephosphorylation at T592 is mediated by PP2A-B55α holoenzymes during mitotic exit (M/G1 transition), rendering SAMHD1 antivirally active against HIV-1. Identified using complementary proteomics and biochemical approaches. PP2A-B55α also controls SAMHD1 pT592 levels in non-cycling monocyte-derived macrophages.","method":"Proteomics, biochemical co-immunoprecipitation, cell cycle synchronization, HIV-1 infection assays, siRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary proteomics and biochemical approaches, functional HIV restriction assay, primary cell validation, single lab with robust methodology","pmids":["29884836"],"is_preprint":false},{"year":2019,"finding":"PR55α inhibits the MOB1-triggered autoactivation of LATS1/2 kinases (core Hippo pathway members) and directly interacts with YAP, leading to YAP activation and promotion of anchorage-independent growth in pancreatic cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown, kinase activity assays, gene transcription assays, anchorage-independent growth assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifies direct interaction with YAP and LATS regulatory cascade, KD with defined functional readout, single lab","pmids":["31659153"],"is_preprint":false},{"year":2020,"finding":"PPP2R2A negatively regulates translation of c-Myc protein, and PPP2R2A deficiency elevates replication stress by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Identified in a genome-wide loss-of-function screen.","method":"Genome-wide shRNA pooled screen, c-Myc protein level analysis, replication dynamics assays, in vitro and in vivo drug sensitivity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen followed by mechanistic validation of c-Myc regulation, single lab","pmids":["32522823"],"is_preprint":false},{"year":2020,"finding":"AMOTL2 is a novel binding partner of PPP2R2A in NSCLC cells. AMOTL2 binds PPP2R2A in the cytoplasm and reduces its nuclear localization, thereby inhibiting PPP2R2A-mediated dephosphorylation of JUN at T239 and increasing JUN T239 phosphorylation. This AMOTL2-PPP2R2A-JUN axis regulates cell proliferation.","method":"Mass spectrometry, co-immunoprecipitation, GST pulldown, immunofluorescence, CRISPR/Cas9 screen","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by multiple orthogonal methods (co-IP, GST pulldown, IF), functional localization consequence demonstrated, single lab","pmids":["32950569"],"is_preprint":false},{"year":2020,"finding":"PP2A-B55α complex restrains PHD2 activity in endothelial cells, promoting EC survival in a HIF-dependent manner, and dephosphorylates p38, protecting ECs against cell stress. B55α inhibition leads to EC apoptosis and vessel pruning.","method":"Genetic EC-specific B55α deficiency (knockout mouse model), biochemical phosphatase assays, HIF pathway analysis, p38 phosphorylation analysis, in vivo vascular imaging","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo EC-specific KO with defined pathway mechanism (PHD2, HIF, p38 dephosphorylation), single lab","pmids":["32527198"],"is_preprint":false},{"year":2021,"finding":"PP2A/B55α substrate recruitment is mediated by a conserved short linear motif (SLiM) 'HxRVxxV619-625' in substrate p107 (region R1, residues 615-626) that is necessary for B55α binding and dephosphorylation of proximal pSer-615 in vitro and in cells. A related SLiM '[RK]-V-x-x-[VI]-R' is present in numerous B55α substrates including TAU; mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α. A computational model details the interaction of residues from the SLiM, the B55α groove, and phosphosite presentation.","method":"Molecular biology, mutagenesis, in vitro dephosphorylation assays, cellular phosphorylation assays, data-guided computational modeling","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted dephosphorylation assays with mutagenesis of defined SLiM motif validated both in vitro and in cells, computational structural model, single lab with multiple orthogonal methods","pmids":["34661528"],"is_preprint":false},{"year":2021,"finding":"PPP2R2A binds to, dephosphorylates, and activates GEF-H1 at Ser885, increasing RhoA-GTP levels and ROCK activity in T cells, thereby enhancing Th1 and Th17 differentiation. T cell-specific PPP2R2A knockout mice showed reduced Th1/Th17 differentiation and less autoimmunity.","method":"Co-immunoprecipitation, phosphorylation assays, T cell-specific conditional knockout mice, RhoA activity assay, T cell differentiation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, defined dephosphorylation at specific site (Ser885), conditional KO mouse model with functional immune readout, multiple orthogonal methods","pmids":["33762326"],"is_preprint":false},{"year":2021,"finding":"p53 negatively regulates PR55α protein stability via FBXL20 (a p53-target gene encoding an SCF E3 ubiquitin ligase component). Loss of p53 function leads to reduced FBXL20 expression, decreased PR55α ubiquitination, and increased PR55α protein stability; increased PR55α dephosphorylates c-Myc at T58 (a known PR55α substrate), increasing c-Myc stability.","method":"siRNA knockdown, gene deletion, HPV-E6-mediated degradation, mutant p53 expression, ubiquitination assays, co-immunoprecipitation","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple approaches to p53 inactivation all converge on FBXL20/PR55α axis, ubiquitination assay, substrate dephosphorylation confirmed, single lab","pmids":["34731788"],"is_preprint":false},{"year":2020,"finding":"Ppp2r2a homozygous knockout mice are embryonic lethal and display neural tube defects, syndactyly, and severe epidermal defects including impaired epidermal barrier acquisition, thin/poorly differentiated stratified epithelium, reduced integrin and basement membrane protein expression, and aberrant junction proteins—establishing PP2A-B55α as an essential regulator of ectodermal/epidermal development.","method":"CRISPR/Cas9 knockout mouse generation, embryonic staging, immunohistochemistry, immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR/Cas9 in vivo KO with detailed developmental phenotype analysis at multiple stages and multiple molecular markers, single lab but comprehensive in vivo study","pmids":["32582689"],"is_preprint":false},{"year":2017,"finding":"PP2A-B55α is required for meiosis in mouse oocytes. Knockdown of PP2A-B55α leads to abnormal asymmetric division, disordered spindle dynamics, chromosome congression defects, increased aneuploidy, and DNA damage response induction. In fertilized zygotes, knockdown impairs development to blastocyst stage by inducing sustained DNA damage, apoptosis, and inhibiting proliferation.","method":"siRNA knockdown in mouse oocytes, immunofluorescence for spindle/chromosome analysis, aneuploidy scoring, blastocyst development assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotypes including spindle/chromosome readouts and DNA damage, single lab","pmids":["28439046"],"is_preprint":false},{"year":2023,"finding":"PP2A-B55α holoenzyme is the major serine/threonine phosphatase regulating the phosphorylation status of desmoplakin (DP) C-terminus in keratinocytes. PP2A-B55α interacts with DP at intercellular membranes (shown by 2D/3D epidermal models and human skin samples) and is required for maintaining strong desmosome-mediated intercellular adhesion.","method":"Chemical and genetic inhibition, co-immunoprecipitation, immunofluorescence in 2D/3D epidermal models and human skin, adhesion strength assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifies specific interaction, genetic KD with defined adhesion phenotype, validated in human skin, single lab","pmids":["37543698"],"is_preprint":false},{"year":2024,"finding":"FAM122A functions as a competitive inhibitor of B55α/PP2A. FAM122A binds B55α through a conserved SLiM '[RK]-V-x-x-[VI]-R' motif that blocks substrate docking; FAM122A competitively inhibits CDK substrate binding and dephosphorylation by B55α/PP2A in cell lysates. FAM122A deficiency reduces cell proliferation, cell cycle progression, and hinders G1/S and intra-S phase checkpoints; FAM122A-KO attenuates CHK1 and CHK2 activation in response to replication stress.","method":"Computational structure prediction, mutagenesis, in vitro competition assay with cell lysates, CRISPR/Cas9 KO, cell cycle analysis, DNA damage response assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — competitive inhibition assay with defined SLiM, structural prediction validated by mutagenesis and functional assays, CRISPR KO with defined phenotype, single lab with multiple orthogonal methods","pmids":["38982062"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of PP2A-B55α with IER5 N-terminal region (IER5-N50) reveals that IER5-N50 occludes the substrate recruitment surface on B55α. IER5-N50 inhibits PP2A/B55α-catalyzed dephosphorylation of pTau in biochemical assays. Mutations disrupting the IER5-B55α interface abolish co-immunoprecipitation of PP2A-B55α. IER5 antagonism of B55α in keratinocytes is required for KRT1 expression.","method":"Cryo-EM structure determination, in vitro dephosphorylation assay, mutagenesis, co-immunoprecipitation, IER5 knockout cell rescue experiments","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with defined binding interface, in vitro biochemical inhibition assay, mutagenesis validation, functional cellular rescue; multiple orthogonal methods in one study","pmids":["40209703"],"is_preprint":false},{"year":2024,"finding":"Eya3 directly interacts with the N-terminal domain of Myc and recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability. Eya3 increases Ser/Thr phosphatase activity of PP2A-B55α (but not PP2A-B56α). The Eya3 NTD (~250 aa, fully disordered) uses a 38-residue segment to interact with B55α. Knockdown/phosphoproteomics shows Eya3 and B55α share highly similar phosphosite motifs (preference for Ser/Thr-Pro). The cancer hotspot mutation MycP59A enhances Eya3-PP2A-B55α dephosphorylation of pT58.","method":"Biochemical co-IP, pulldown, in vitro phosphatase activity assay, NMR (disordered domain characterization), phosphoproteomics, mutagenesis, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphatase activity assay, phosphoproteomics, mutagenesis, biochemical interaction mapping; multiple orthogonal methods single lab","pmids":["38796066"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of PP2A-B55α bound to Eya3 show that Eya3 binds B55α through an extended peptide in the Eya3 NTD that occupies a similar area on B55α as substrates and peptide inhibitors. An inhibitory peptide B55i also occludes this surface. B55i inhibits the B55α-Eya3 interaction in vitro and increases Myc pT58, decreasing Myc levels in TNBC cells.","method":"Cryo-EM structure determination, in vitro interaction assay, cellular Myc phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional validation in vitro and in cells, single lab","pmids":["40414499"],"is_preprint":false},{"year":2013,"finding":"Ppp2r2a is required for Connexin-43 dephosphorylation at Serine 368 during epidermal barrier acquisition. Knockdown of Ppp2r2a prevented plasma membrane co-localization and interaction between Connexin 43 and Zo-1, and increased Cx43 phosphorylation at Ser368, implicating PP2A-B55α in regulating tight junction formation through Cx43 dephosphorylation.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence, epidermal barrier assay","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phosphorylation and localization phenotype at specific site, single lab","pmids":["24433183"],"is_preprint":false},{"year":2018,"finding":"PPP2R2A interacts with GFPT1/2 (glutamine:fructose-6-phosphate amidotransferase 1/2) and dephosphorylates GFPT2 specifically (but not GFPT1); knockdown of PPP2R2A enhanced GFPT2 phosphorylation and promoted total cellular O-GlcNAcylation in breast cancer cells. Interaction confirmed by GST pulldown, co-IP, and immunofluorescence.","method":"Tandem affinity purification, mass spectrometry, GST pulldown, co-immunoprecipitation, immunofluorescence, O-GlcNAcylation assay, shRNA knockdown","journal":"Sheng wu gong cheng xue bao (Chinese journal of biotechnology)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (TAP-MS, GST pulldown, co-IP, IF) with functional phosphorylation readout, single lab","pmids":["29943541"],"is_preprint":false},{"year":2023,"finding":"VPA (a histone deacetylase inhibitor) promotes PPP2R2A-mediated dephosphorylation of Chk1 at Ser317 and Ser345, accelerating G2/M progression. The effect of VPA on PPP2R2A operates at the post-transcriptional level through HDAC1/2. PPP2R2A residues D197 and N181 are essential for PPP2R2A-Chk1 signaling.","method":"Phosphorylation assays, mutagenesis, co-immunoprecipitation, cell cycle analysis, in vivo experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifies functional residues, KD/OE with defined phosphorylation readout, single lab","pmids":["36781846"],"is_preprint":false},{"year":2025,"finding":"PP2A-B55α/PPP2R2A is identified as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α regulates early mitophagy by releasing ULK1 from its inhibitory regulation, and later (2-4 hours) promotes nuclear translocation of TFEB to support mitophagy. PP2A-B55α also controls mitochondrial biogenesis by stabilizing PARIS (a PGC-1α inhibitor and Parkin substrate). PP2A-B55α targeting rescues neurodegenerative phenotypes in a Drosophila Parkinson's disease model.","method":"Unbiased LC-MS/MS and transcriptomics, phosphoproteomics, genetic manipulation, nuclear fractionation, in vivo Drosophila model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — unbiased multi-omics discovery, genetic validation, in vivo Drosophila model, multiple orthogonal methods; single lab but comprehensive","pmids":["41042873"],"is_preprint":false},{"year":2025,"finding":"PP2A-B55α directly dephosphorylates c-Myc at Thr58 and regulates two distinct c-Myc degradation pathways in a biphasic manner: B55α suppression increases Thr58 phosphorylation and enhances FBXW7-dependent degradation, while B55α overexpression promotes Thr58-independent UBR5-mediated degradation. PP2A-B55α complex also binds and dephosphorylates UBR5. B55δ shows weaker UBR5 binding affinity and fails to induce c-Myc degradation.","method":"Biochemical dephosphorylation assays, co-immunoprecipitation, mutagenesis, ubiquitination assays, overexpression/knockdown","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro biochemical dephosphorylation, co-IP identifying UBR5 as novel substrate, isoform specificity comparison (B55α vs B55δ), multiple orthogonal methods, single lab","pmids":["41818150"],"is_preprint":false},{"year":2025,"finding":"PPP2R2A deficiency causes cytosolic DNA accumulation leading to cGAS-STING-type I IFN pathway activation. PPP2R2A deficiency elevates PD-L1 expression via GSK-3β-dependent and STING-dependent mechanisms, modulating the tumor immune microenvironment.","method":"siRNA knockdown, PPP2R2A heterozygous cell lines, cGAS-STING pathway assays, PD-L1 expression analysis, GSK-3β inhibition, mouse lung cancer model, immune cell profiling","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement with GSK-3β and STING epistasis, in vivo mouse model, single lab","pmids":["41411055"],"is_preprint":false},{"year":2024,"finding":"PPP2R2A deficiency in NSCLC promotes epithelial-mesenchymal transition (EMT) and metastatic behavior. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 (Slug) expression via the GSK3β-β-catenin pathway. PPP2R2A deficiency also increases the cancer stem cell population and enhances drug resistance.","method":"shRNA knockdown, CRISPR/Cas9 homozygous/hemizygous depletion, bulk RNA-sequencing, GSEA, EMT marker analysis, invasion/migration assays, tail vein metastasis assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with GSEA defines pathway (GSK3β-β-catenin-Slug), KD/KO with functional invasion and in vivo metastasis readout, single lab","pmids":["38986733"],"is_preprint":false},{"year":2024,"finding":"PPP2R2A controls NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. PPP2R2A deficiency promotes NAD+ biosynthesis; elevated NR inhibits Th17 and promotes Treg differentiation by PARylating histone H1.2, altering Foxp3 and Il17a locus occupancy.","method":"T cell-specific PPP2R2A knockout (lupus-prone mice), metabolomics, chromatin immunoprecipitation, cytokine assays, NR supplementation experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with mechanistic metabolic readout and chromatin biology, single lab","pmids":["38889006"],"is_preprint":false},{"year":2024,"finding":"PR55α is a potent inhibitor of p16 transcription; ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced cellular senescence. This function is p53-independent and specifically affects p16 (not p14/ARF).","method":"Ectopic expression, shRNA knockdown, RT-PCR for p16 expression, RB phosphorylation analysis, senescence assays (SA-β-gal, BrdU incorporation)","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined transcriptional and functional readout, p53-independence established, single lab","pmids":["38441530"],"is_preprint":false}],"current_model":"PPP2R2A (B55α/PR55α) encodes the regulatory B subunit of the PP2A heterotrimer that determines substrate specificity and subcellular targeting; established substrates and mechanisms include: selective dephosphorylation of Akt-Thr308 (suppressing PI3K signaling), dephosphorylation of Cdk1 substrates (histone H1, p107, pRB-family, FoxM1) to drive mitotic exit and G1/S cell-cycle regulation, dephosphorylation of SAMHD1-T592 to activate HIV restriction, dephosphorylation of c-Myc-T58 and UBR5 to regulate c-Myc stability in a biphasic manner, dephosphorylation of GEF-H1-Ser885 to activate RhoA/ROCK signaling in T cells, dephosphorylation of ATM to regulate DSB repair, dephosphorylation of EDD to activate p53 under glutamine deprivation, dephosphorylation of HDAC5 to promote its nuclear accumulation in cardiomyocytes, and regulation of mitophagy/biogenesis via ULK1 and TFEB; substrate recruitment is mediated by a conserved SLiM ([RK]-V-x-x-[VI]-R) that docks into a groove on B55α whose structure has been solved by cryo-EM; additional regulatory mechanisms include PHD2-mediated hydroxylation of B55α-P319 (promoting its degradation), p53/FBXL20-mediated ubiquitination (controlling B55α protein stability), and competitive inhibition by FAM122A and IER5 that occlude the substrate-binding groove."},"narrative":{"mechanistic_narrative":"PPP2R2A (B55α/PR55α) is the regulatory B subunit that targets the PP2A holoenzyme to specific substrates, defining a serine/threonine phosphatase activity central to cell-cycle control, signaling, and development [PMID:20711181, PMID:34661528]. Its best-defined role is in mitotic exit: PP2A-B55α acts downstream of Cdk1 and the Mastl(Greatwall) kinase to dephosphorylate Cdk1 substrates and drive spindle breakdown and reassembly of the nuclear envelope, Golgi, and chromatin [PMID:20711181, PMID:21156286]. B55α-PP2A confers substrate selectivity across a broad set of phosphoproteins—selectively dephosphorylating Akt-Thr308 but not Ser473 [PMID:18042541], the pocket protein p107 and FoxM1 to enforce G1/S and G2 control [PMID:20663872, PMID:21813648, PMID:23716589, PMID:23775125], ATM at DSB sites to govern homologous-recombination repair [PMID:23087057], SAMHD1-Thr592 to activate HIV-1 restriction during M/G1 [PMID:29884836], and c-Myc-Thr58 (with concomitant dephosphorylation of the ligase UBR5) to control Myc stability biphasically [PMID:41818150]. Substrate recruitment is governed by a conserved short linear motif ([RK]-V-x-x-[VI]-R) that docks into a groove on the B55α β-propeller, a mechanism validated for p107 and TAU [PMID:34661528] and visualized by cryo-EM of B55α bound to inhibitory partners [PMID:40209703, PMID:40414499]. This same surface is targeted by competitive regulators FAM122A and IER5, which occlude substrate docking [PMID:38982062, PMID:40209703], while the cofactor Eya3 binds the groove region to recruit and stimulate B55α-mediated dephosphorylation of Myc-Thr58 [PMID:38796066, PMID:40414499]. B55α abundance is itself controlled by PHD2-mediated hydroxylation at Pro319 driving degradation [PMID:28329677] and by p53/FBXL20-dependent ubiquitination [PMID:34731788]. Beyond proliferation, PP2A-B55α controls T-cell differentiation via GEF-H1/RhoA/ROCK signaling [PMID:33762326], cardiomyocyte HDAC5 trafficking [PMID:28343149], mitophagy and mitochondrial biogenesis through ULK1, TFEB, and PARIS [PMID:41042873], and epidermal/ectodermal development, where Ppp2r2a knockout mice are embryonic lethal with neural tube and epidermal barrier defects [PMID:32582689].","teleology":[{"year":2007,"claim":"Established that B55α confers PP2A substrate selectivity at the level of individual phosphosites by showing it directs the holoenzyme to dephosphorylate Akt specifically at Thr308.","evidence":"Co-IP of endogenous holoenzymes with Akt, in vitro dephosphorylation, siRNA/overexpression in cells","pmids":["18042541"],"confidence":"High","gaps":["Did not define the docking determinant on B55α","Physiological contexts of selective Thr308 control not mapped"]},{"year":2010,"claim":"Placed PP2A-B55α as the executor of mitotic exit downstream of Cdk1 inactivation, answering how dephosphorylation of Cdk1 substrates is coordinated to reverse mitotic phosphorylation.","evidence":"Genome-wide RNAi live-cell imaging screen, histone H1 phosphatase assay, importin-β1 co-purification, and genetic epistasis (Cdc20/Cdk1/Mastl) in mouse cells","pmids":["20711181","21156286"],"confidence":"High","gaps":["Full substrate set during mitotic exit not enumerated","Mechanism of B55α activation timing relative to Mastl not resolved structurally"]},{"year":2010,"claim":"Defined B55α-specific regulation of pocket proteins, showing it restrains p107 and FoxM1 phosphorylation to control G1/S and G2 transitions.","evidence":"Co-IP, siRNA/overexpression with cell-cycle and FoxM1 activity readouts","pmids":["20663872","21813648"],"confidence":"Medium","gaps":["Direct in vitro dephosphorylation of these substrates not shown in these studies","Selectivity among pocket proteins partially addressed"]},{"year":2012,"claim":"Extended B55α function to the DNA damage response by showing it dephosphorylates ATM at defined sites to regulate retention at DSBs and HR repair.","evidence":"Loss-of-function screen, biochemical dephosphorylation of defined ATM phosphosites, siRNA, HR repair assays","pmids":["23087057"],"confidence":"High","gaps":["Recruitment mechanism to DSB sites not defined","Interplay with CHK2 feedback only partially mapped"]},{"year":2013,"claim":"Demonstrated that B55α itself is regulated by dephosphorylation as an activation switch, and linked it to stress and metabolic signaling (p107/FGF, EDD/p53, FOXO1).","evidence":"Reciprocal co-IP/MS, phosphorylation analysis of B55α, KD with phosphorylation/localization readouts in chondrocytes, β-cells, and cancer cells","pmids":["23716589","23775125","23499005","22417654"],"confidence":"High","gaps":["Kinases driving B55α phosphorylation not fully identified","Quantitative affinity changes with phospho-state not structurally explained"]},{"year":2013,"claim":"Mapped a viral inhibitor (E4orf4) binding site on the B55α β-propeller above the substrate groove, distinguishing an allosteric/occlusion site from the substrate-docking surface.","evidence":"Structure-guided mutagenesis, IP, GST pulldown, cell death assays","pmids":["24244166","23530045"],"confidence":"Medium","gaps":["No high-resolution structure of the E4orf4-B55α complex in these studies","Relationship to endogenous regulators unclear at the time"]},{"year":2018,"claim":"Connected mitotic-exit dephosphorylation to antiviral immunity by showing B55α dephosphorylates SAMHD1-Thr592 at M/G1 to activate HIV-1 restriction.","evidence":"Proteomics, co-IP, cell-cycle synchronization, HIV-1 infection assays, validation in macrophages","pmids":["29884836"],"confidence":"High","gaps":["Regulation in fully non-cycling cells incompletely defined","Direct SLiM in SAMHD1 not mapped here"]},{"year":2021,"claim":"Resolved the molecular grammar of substrate recruitment by defining a conserved SLiM ([RK]-V-x-x-[VI]-R) that docks into the B55α groove and dictates dephosphorylation of proximal phosphosites.","evidence":"Mutagenesis of the SLiM in p107 and TAU, in vitro and cellular dephosphorylation, data-guided computational modeling","pmids":["34661528"],"confidence":"High","gaps":["Computational model not yet an experimental structure","How phosphosite presentation distance is tuned remains partial"]},{"year":2021,"claim":"Defined immune and developmental roles in vivo: B55α activates GEF-H1/RhoA/ROCK to drive Th1/Th17 differentiation, and is essential for ectodermal/epidermal development.","evidence":"T-cell conditional KO with RhoA activity and differentiation assays; CRISPR KO mice with developmental phenotyping","pmids":["33762326","32582689"],"confidence":"High","gaps":["Tissue-specific substrate repertoires not exhaustively defined","Embryonic lethality limits adult tissue analysis"]},{"year":2024,"claim":"Established competitive inhibition as a core regulatory logic: FAM122A occludes the substrate groove to block CDK-substrate dephosphorylation, controlling cell-cycle checkpoints.","evidence":"Structure prediction, mutagenesis, in vitro competition assays, CRISPR KO with checkpoint and DDR readouts","pmids":["38982062"],"confidence":"High","gaps":["Competition kinetics versus diverse substrates not fully quantified","Regulation of FAM122A availability not addressed"]},{"year":2025,"claim":"Provided experimental structures of the B55α regulatory interface, showing IER5 and Eya3 engage the substrate-recruitment surface as inhibitor and recruiter respectively, with translation to peptide-based modulation of Myc.","evidence":"Cryo-EM of B55α-IER5-N50 and B55α-Eya3, in vitro pTau/pMyc dephosphorylation, mutagenesis, inhibitory peptide B55i in TNBC cells","pmids":["40209703","40414499","38796066"],"confidence":"High","gaps":["Full catalytic-cycle structure with bound substrate not captured","Selectivity of Eya3 stimulation across substrates beyond Myc not defined"]},{"year":2025,"claim":"Expanded B55α into mitochondrial quality control and tumor immunity, regulating mitophagy/biogenesis via ULK1/TFEB/PARIS and the cGAS-STING/PD-L1 axis.","evidence":"Multi-omics, phosphoproteomics, nuclear fractionation, Drosophila PD model; KD/heterozygous cells with cGAS-STING and PD-L1 assays in lung cancer models","pmids":["41042873","41411055"],"confidence":"Medium","gaps":["Direct substrates within mitophagy and STING pathways not all defined","Mechanism of cytosolic DNA accumulation upon deficiency unresolved"]},{"year":null,"claim":"How the single B55α groove discriminates among its many SLiM-bearing substrates and competitive regulators in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimental structure of B55α with a bound physiological substrate phosphosite","Combinatorial rules governing substrate prioritization in vivo unknown","Quantitative competition between FAM122A, IER5, Eya3, and substrates not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,17,22,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6,36]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,22,30]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20,7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,5,6,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,14,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,18,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,32,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,23,37,39]}],"complexes":["PP2A holoenzyme (A-B55α-C trimer)"],"partners":["AKT1","ATM","FOXM1","SAMHD1","UBR5","FAM122A","IER5","EYA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P63151","full_name":"Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform","aliases":["PP2A subunit B isoform B55-alpha","B55","PP2A subunit B isoform PR55-alpha","PP2A subunit B isoform R2-alpha","PP2A subunit B isoform alpha"],"length_aa":447,"mass_kda":51.7,"function":"Substrate-recognition subunit of protein phosphatase 2A (PP2A) that plays a key role in cell cycle by controlling mitosis entry and exit (PubMed:1849734, PubMed:33108758). Involved in chromosome clustering during late mitosis by mediating dephosphorylation of MKI67 (By similarity). Essential for serine/threonine-protein phosphatase 2A-mediated dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P63151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP2R2A","classification":"Not Classified","n_dependent_lines":269,"n_total_lines":1208,"dependency_fraction":0.222682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPP2CA","stoichiometry":4.0},{"gene":"KIAA1143","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP2R2A","total_profiled":1310},"omim":[{"mim_id":"617249","title":"FAMILY WITH SEQUENCE SIMILARITY 122, MEMBER A; FAM122A","url":"https://www.omim.org/entry/617249"},{"mim_id":"616062","title":"ANKYRIN REPEAT- AND LEM DOMAIN-CONTAINING PROTEIN 2; ANKLE2","url":"https://www.omim.org/entry/616062"},{"mim_id":"613992","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, DELTA; PPP2R2D","url":"https://www.omim.org/entry/613992"},{"mim_id":"610286","title":"LEUCINE CARBOXYL METHYLTRANSFERASE 1; LCMT1","url":"https://www.omim.org/entry/610286"},{"mim_id":"605997","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, GAMMA ISOFORM; PPP2R2C","url":"https://www.omim.org/entry/605997"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP2R2A"},"hgnc":{"alias_symbol":["PR52A","PR55A","B55A","PR55alpha","B55alpha"],"prev_symbol":[]},"alphafold":{"accession":"P63151","domains":[{"cath_id":"2.40.128","chopping":"32-124_165-173","consensus_level":"medium","plddt":92.5997,"start":32,"end":173}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P63151","model_url":"https://alphafold.ebi.ac.uk/files/AF-P63151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P63151-F1-predicted_aligned_error_v6.png","plddt_mean":92.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP2R2A","jax_strain_url":"https://www.jax.org/strain/search?query=PPP2R2A"},"sequence":{"accession":"P63151","fasta_url":"https://rest.uniprot.org/uniprotkb/P63151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P63151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P63151"}},"corpus_meta":[{"pmid":"18042541","id":"PMC_18042541","title":"Regulation 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Confirmed by co-immunoprecipitation of endogenous PP2A-AB55C holoenzymes with Akt, in vitro pulldown, in vitro dephosphorylation assays, overexpression, and siRNA knockdown experiments.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pulldown, in vitro dephosphorylation assay, siRNA knockdown, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution dephosphorylation assay plus multiple orthogonal cell-based methods (co-IP, pulldown, KD, OE), single lab but rigorous and comprehensive\",\n      \"pmids\": [\"18042541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PP2A-B55α trimeric complex is a key regulator of mitotic exit in human cells, required for mitotic spindle breakdown and postmitotic reassembly of nuclear envelope, Golgi apparatus, and decondensed chromatin. PP2A-B55α functions downstream of Cdk1 inactivation. Mitotic PP2A-B55α has reduced phosphatase activity toward Cdk1 substrate histone H1 and is hyper-phosphorylated on all subunits. Mitotic PP2A complexes co-purify with importin-β1, and co-depletion of importin-β1 delays mitotic exit synergistically.\",\n      \"method\": \"RNAi live-cell imaging screen, chemically induced mitotic exit assay, phosphatase activity assay toward histone H1, co-purification/mass spectrometry, double RNAi knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide RNAi screen with live imaging, biochemical phosphatase assay, co-purification, epistasis by double KD; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20711181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mitotic exit in Cdk1-inactivated cells depends on activity of PP2A complexes containing B55α or B55δ regulatory subunits, placing PP2A/B55α downstream of Cdk1 and the kinase Mastl (Greatwall) in the mitotic exit pathway. Demonstrated by genetic epistasis in mouse embryonic and adult cells.\",\n      \"method\": \"Genetically engineered mice, genetic epistasis (Cdc20 ablation + Cdk1/Mastl inactivation)\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis in engineered mouse models, clearly positions PP2A/B55α in the mitotic exit pathway\",\n      \"pmids\": [\"21156286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PPP2R2A-containing PP2A complexes directly dephosphorylate ATM at S367, S1893, and S1981, regulating ATM retention at double-strand break (DSB) sites. Loss of PPP2R2A increases ATM phosphorylation and CHK2 activity, leading to G1/S arrest and downregulation of BRCA1 and RAD51, impairing homologous recombination repair.\",\n      \"method\": \"Loss-of-function screen, biochemical dephosphorylation assays, siRNA knockdown, cell-cycle analysis, HR repair assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct dephosphorylation assay on defined ATM phosphosites, epistasis via KD with defined molecular phenotype, single lab multiple orthogonal methods\",\n      \"pmids\": [\"23087057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Upon glutamine deprivation, B55α is induced in a ROS-dependent manner and activates p53 through direct interaction with and dephosphorylation of EDD (a negative regulator of p53). α4 promotes assembly of an adaptive PP2A complex containing B55α under these conditions. The B55α-EDD-p53 pathway is essential for cancer cell survival under low glutamine conditions.\",\n      \"method\": \"Co-immunoprecipitation, biochemical interaction assays, RNAi knockdown, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, defined substrate dephosphorylation, in vitro and in vivo functional assays, single lab multiple orthogonal methods\",\n      \"pmids\": [\"23499005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B55α PP2A holoenzyme plays a major role in restricting phosphorylation of p107 (retinoblastoma-related protein) and inducing its activation in human cells. Targeted selectivity exists between pocket proteins and distinct PP2A holoenzymes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, cell-cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional KD/OE with defined phosphorylation readout, single lab\",\n      \"pmids\": [\"20663872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"B55α (PPP2R2A) interacts with FoxM1 transcription factor and promotes its dephosphorylation and inactivation, antagonizing Cyclin A/Cdk-dependent activation of FoxM1 to restrict its activity to G2 phase. Overexpression of B55α decreases FoxM1 activity; depletion leads to premature FoxM1 activation dependent on Cyclin A/Cdk phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, FoxM1 activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP shows direct interaction, KD/OE with defined phosphorylation and activity readouts, single lab\",\n      \"pmids\": [\"21813648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"B55α-containing PP2A holoenzyme (identified by chemical cross-linking and mass spectrometry) dephosphorylates FOXO1 at Thr24 and Ser256 to promote FOXO1 nuclear translocation in pancreatic islet β-cells under oxidative stress. Knockdown of B55α inhibits FOXO1 nuclear translocation and attenuates oxidative stress-induced cell death.\",\n      \"method\": \"Chemical cross-linking, mass spectrometry, co-immunoprecipitation, siRNA knockdown, nuclear fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — cross-linking MS identifies holoenzyme complex, KD with defined phosphorylation and localization readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22417654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PP2A-B55α holoenzyme is responsible for FGF-induced p107 dephosphorylation and growth arrest in chondrocytes. B55α binds p107 with higher affinity in its dephosphorylated state; only B55α (not other B subunits) binds p107. FGF induces dephosphorylation of B55α itself on multiple serine residues, dramatically increasing its affinity for the PP2A A/C dimer and p107.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phosphorylation analysis, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with specificity controls, KD with defined phenotype, identification of B55α dephosphorylation as activation mechanism, independently confirmed by companion paper (PMID:23775125)\",\n      \"pmids\": [\"23716589\", \"23775125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Reciprocal solution-based mass spectrometry identified PP2A/B55α complex as a major component of p107 complexes in chondrocytes. FGF1 triggers rapid accumulation of p107-PP2A/B55α complexes coinciding with p107 dephosphorylation and nuclear accumulation, leading to cell cycle exit. B55α knockdown delays FGF1-induced dephosphorylation of p107.\",\n      \"method\": \"Reciprocal mass spectrometry, co-immunoprecipitation, siRNA knockdown, nuclear fractionation, chromatin immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based complex identification, reciprocal co-IP, KD with functional readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23775125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Adenovirus E4orf4 binds across the putative substrate binding groove of B55α such that the substrate p107 can no longer interact with PP2A-B55α, thus inhibiting PP2A activity by preventing substrate access. E4orf4 binding was mapped to the α1,α2 helices of B55α using mutagenesis and structural prediction; loss of binding reduces E4orf4-induced cell death.\",\n      \"method\": \"Structure-guided mutagenesis, immunoprecipitation, GST pulldown, cell death assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-guided binding site mapping with functional consequence, single lab\",\n      \"pmids\": [\"24244166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E4orf4 binding site in PP2A-B55α maps to α1 and α2 helices (blade 1/2 region) of the seven-bladed β-propeller. This site lies above the substrate binding groove and does not overlap it. Loss of E4orf4 binding at this site reduces E4orf4-induced cell death.\",\n      \"method\": \"Bioinformatics, mutagenesis, immunoprecipitation, GST pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis with functional validation, single lab, complementary to PMID:24244166\",\n      \"pmids\": [\"23530045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PR55α-PP2A specifically dephosphorylates c-Jun at T239, promoting c-Jun binding to chromatin at genes regulating tumor cell migration and invasion, without affecting phosphorylation at S63. PR55α-PP2A thus enhances AP-1 transcriptional activity and tumor cell migration/invasion.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-specific antibodies, chromatin immunoprecipitation, migration/invasion assays, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, site-specific dephosphorylation, functional migration assays, single lab\",\n      \"pmids\": [\"24632621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"F-box protein FBXL16 binds PP2A containing B55α specificity subunit (PP2A-B55α) and negatively regulates its activity. FBXL16 negatively regulates phosphorylation of the established PP2A-B55α substrate vimentin as shown by phosphoproteomics.\",\n      \"method\": \"Shotgun mass spectrometry, phosphoproteomics, siRNA screen\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex identification and phosphoproteomic substrate validation, single lab\",\n      \"pmids\": [\"24390425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B55α mediates PP2A/Plk1 association and dephosphorylation of Plk1 at Thr-210 in response to DNA damage in Xenopus egg extracts. PP2A-B55α association with Plk1 increases after DNA damage in an ATM/ATR and checkpoint kinase-dependent manner.\",\n      \"method\": \"Xenopus egg extract biochemistry, co-immunoprecipitation, phosphatase activity assays, DNA damage induction\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical extract system with co-IP and defined phosphatase activity, single lab\",\n      \"pmids\": [\"25483054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"β-Adrenoceptor stimulation induces B55α-PP2A-mediated dephosphorylation of HDAC5 at Ser259/Ser498, leading to HDAC5 nuclear accumulation in cardiomyocytes. B55α specifically interacts with HDAC5 (and the PP2A catalytic and scaffolding subunits), and this interaction increases >3-fold with isoproterenol. Knockdown of B55α attenuates isoproterenol-induced HDAC5 dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, 3D confocal microscopy localization assay\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying specific interaction, KD with defined dephosphorylation/localization readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"28343149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHD2 promotes degradation of B55α by hydroxylating it at proline 319. Conversely, B55α-associated PP2A promotes partial deactivation of PHD2. In glucose-starved conditions, PHD2 reduces B55α protein levels, correlating with breast cancer cell death; PHD2 silencing rescues B55α and prevents apoptosis.\",\n      \"method\": \"Hydroxylation assay, siRNA knockdown, overexpression, xenograft tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identifies PTM (hydroxylation at P319) with functional consequence, in vivo confirmation, single lab\",\n      \"pmids\": [\"28329677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAMHD1 dephosphorylation at T592 is mediated by PP2A-B55α holoenzymes during mitotic exit (M/G1 transition), rendering SAMHD1 antivirally active against HIV-1. Identified using complementary proteomics and biochemical approaches. PP2A-B55α also controls SAMHD1 pT592 levels in non-cycling monocyte-derived macrophages.\",\n      \"method\": \"Proteomics, biochemical co-immunoprecipitation, cell cycle synchronization, HIV-1 infection assays, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary proteomics and biochemical approaches, functional HIV restriction assay, primary cell validation, single lab with robust methodology\",\n      \"pmids\": [\"29884836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PR55α inhibits the MOB1-triggered autoactivation of LATS1/2 kinases (core Hippo pathway members) and directly interacts with YAP, leading to YAP activation and promotion of anchorage-independent growth in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, kinase activity assays, gene transcription assays, anchorage-independent growth assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifies direct interaction with YAP and LATS regulatory cascade, KD with defined functional readout, single lab\",\n      \"pmids\": [\"31659153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PPP2R2A negatively regulates translation of c-Myc protein, and PPP2R2A deficiency elevates replication stress by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Identified in a genome-wide loss-of-function screen.\",\n      \"method\": \"Genome-wide shRNA pooled screen, c-Myc protein level analysis, replication dynamics assays, in vitro and in vivo drug sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen followed by mechanistic validation of c-Myc regulation, single lab\",\n      \"pmids\": [\"32522823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AMOTL2 is a novel binding partner of PPP2R2A in NSCLC cells. AMOTL2 binds PPP2R2A in the cytoplasm and reduces its nuclear localization, thereby inhibiting PPP2R2A-mediated dephosphorylation of JUN at T239 and increasing JUN T239 phosphorylation. This AMOTL2-PPP2R2A-JUN axis regulates cell proliferation.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, GST pulldown, immunofluorescence, CRISPR/Cas9 screen\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by multiple orthogonal methods (co-IP, GST pulldown, IF), functional localization consequence demonstrated, single lab\",\n      \"pmids\": [\"32950569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PP2A-B55α complex restrains PHD2 activity in endothelial cells, promoting EC survival in a HIF-dependent manner, and dephosphorylates p38, protecting ECs against cell stress. B55α inhibition leads to EC apoptosis and vessel pruning.\",\n      \"method\": \"Genetic EC-specific B55α deficiency (knockout mouse model), biochemical phosphatase assays, HIF pathway analysis, p38 phosphorylation analysis, in vivo vascular imaging\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo EC-specific KO with defined pathway mechanism (PHD2, HIF, p38 dephosphorylation), single lab\",\n      \"pmids\": [\"32527198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PP2A/B55α substrate recruitment is mediated by a conserved short linear motif (SLiM) 'HxRVxxV619-625' in substrate p107 (region R1, residues 615-626) that is necessary for B55α binding and dephosphorylation of proximal pSer-615 in vitro and in cells. A related SLiM '[RK]-V-x-x-[VI]-R' is present in numerous B55α substrates including TAU; mutation of conserved SLiM residues in TAU dramatically inhibits dephosphorylation by PP2A/B55α. A computational model details the interaction of residues from the SLiM, the B55α groove, and phosphosite presentation.\",\n      \"method\": \"Molecular biology, mutagenesis, in vitro dephosphorylation assays, cellular phosphorylation assays, data-guided computational modeling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted dephosphorylation assays with mutagenesis of defined SLiM motif validated both in vitro and in cells, computational structural model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34661528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPP2R2A binds to, dephosphorylates, and activates GEF-H1 at Ser885, increasing RhoA-GTP levels and ROCK activity in T cells, thereby enhancing Th1 and Th17 differentiation. T cell-specific PPP2R2A knockout mice showed reduced Th1/Th17 differentiation and less autoimmunity.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, T cell-specific conditional knockout mice, RhoA activity assay, T cell differentiation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, defined dephosphorylation at specific site (Ser885), conditional KO mouse model with functional immune readout, multiple orthogonal methods\",\n      \"pmids\": [\"33762326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"p53 negatively regulates PR55α protein stability via FBXL20 (a p53-target gene encoding an SCF E3 ubiquitin ligase component). Loss of p53 function leads to reduced FBXL20 expression, decreased PR55α ubiquitination, and increased PR55α protein stability; increased PR55α dephosphorylates c-Myc at T58 (a known PR55α substrate), increasing c-Myc stability.\",\n      \"method\": \"siRNA knockdown, gene deletion, HPV-E6-mediated degradation, mutant p53 expression, ubiquitination assays, co-immunoprecipitation\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple approaches to p53 inactivation all converge on FBXL20/PR55α axis, ubiquitination assay, substrate dephosphorylation confirmed, single lab\",\n      \"pmids\": [\"34731788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ppp2r2a homozygous knockout mice are embryonic lethal and display neural tube defects, syndactyly, and severe epidermal defects including impaired epidermal barrier acquisition, thin/poorly differentiated stratified epithelium, reduced integrin and basement membrane protein expression, and aberrant junction proteins—establishing PP2A-B55α as an essential regulator of ectodermal/epidermal development.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation, embryonic staging, immunohistochemistry, immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR/Cas9 in vivo KO with detailed developmental phenotype analysis at multiple stages and multiple molecular markers, single lab but comprehensive in vivo study\",\n      \"pmids\": [\"32582689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PP2A-B55α is required for meiosis in mouse oocytes. Knockdown of PP2A-B55α leads to abnormal asymmetric division, disordered spindle dynamics, chromosome congression defects, increased aneuploidy, and DNA damage response induction. In fertilized zygotes, knockdown impairs development to blastocyst stage by inducing sustained DNA damage, apoptosis, and inhibiting proliferation.\",\n      \"method\": \"siRNA knockdown in mouse oocytes, immunofluorescence for spindle/chromosome analysis, aneuploidy scoring, blastocyst development assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotypes including spindle/chromosome readouts and DNA damage, single lab\",\n      \"pmids\": [\"28439046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PP2A-B55α holoenzyme is the major serine/threonine phosphatase regulating the phosphorylation status of desmoplakin (DP) C-terminus in keratinocytes. PP2A-B55α interacts with DP at intercellular membranes (shown by 2D/3D epidermal models and human skin samples) and is required for maintaining strong desmosome-mediated intercellular adhesion.\",\n      \"method\": \"Chemical and genetic inhibition, co-immunoprecipitation, immunofluorescence in 2D/3D epidermal models and human skin, adhesion strength assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifies specific interaction, genetic KD with defined adhesion phenotype, validated in human skin, single lab\",\n      \"pmids\": [\"37543698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM122A functions as a competitive inhibitor of B55α/PP2A. FAM122A binds B55α through a conserved SLiM '[RK]-V-x-x-[VI]-R' motif that blocks substrate docking; FAM122A competitively inhibits CDK substrate binding and dephosphorylation by B55α/PP2A in cell lysates. FAM122A deficiency reduces cell proliferation, cell cycle progression, and hinders G1/S and intra-S phase checkpoints; FAM122A-KO attenuates CHK1 and CHK2 activation in response to replication stress.\",\n      \"method\": \"Computational structure prediction, mutagenesis, in vitro competition assay with cell lysates, CRISPR/Cas9 KO, cell cycle analysis, DNA damage response assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — competitive inhibition assay with defined SLiM, structural prediction validated by mutagenesis and functional assays, CRISPR KO with defined phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38982062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of PP2A-B55α with IER5 N-terminal region (IER5-N50) reveals that IER5-N50 occludes the substrate recruitment surface on B55α. IER5-N50 inhibits PP2A/B55α-catalyzed dephosphorylation of pTau in biochemical assays. Mutations disrupting the IER5-B55α interface abolish co-immunoprecipitation of PP2A-B55α. IER5 antagonism of B55α in keratinocytes is required for KRT1 expression.\",\n      \"method\": \"Cryo-EM structure determination, in vitro dephosphorylation assay, mutagenesis, co-immunoprecipitation, IER5 knockout cell rescue experiments\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with defined binding interface, in vitro biochemical inhibition assay, mutagenesis validation, functional cellular rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"40209703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Eya3 directly interacts with the N-terminal domain of Myc and recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability. Eya3 increases Ser/Thr phosphatase activity of PP2A-B55α (but not PP2A-B56α). The Eya3 NTD (~250 aa, fully disordered) uses a 38-residue segment to interact with B55α. Knockdown/phosphoproteomics shows Eya3 and B55α share highly similar phosphosite motifs (preference for Ser/Thr-Pro). The cancer hotspot mutation MycP59A enhances Eya3-PP2A-B55α dephosphorylation of pT58.\",\n      \"method\": \"Biochemical co-IP, pulldown, in vitro phosphatase activity assay, NMR (disordered domain characterization), phosphoproteomics, mutagenesis, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphatase activity assay, phosphoproteomics, mutagenesis, biochemical interaction mapping; multiple orthogonal methods single lab\",\n      \"pmids\": [\"38796066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of PP2A-B55α bound to Eya3 show that Eya3 binds B55α through an extended peptide in the Eya3 NTD that occupies a similar area on B55α as substrates and peptide inhibitors. An inhibitory peptide B55i also occludes this surface. B55i inhibits the B55α-Eya3 interaction in vitro and increases Myc pT58, decreasing Myc levels in TNBC cells.\",\n      \"method\": \"Cryo-EM structure determination, in vitro interaction assay, cellular Myc phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional validation in vitro and in cells, single lab\",\n      \"pmids\": [\"40414499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ppp2r2a is required for Connexin-43 dephosphorylation at Serine 368 during epidermal barrier acquisition. Knockdown of Ppp2r2a prevented plasma membrane co-localization and interaction between Connexin 43 and Zo-1, and increased Cx43 phosphorylation at Ser368, implicating PP2A-B55α in regulating tight junction formation through Cx43 dephosphorylation.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence, epidermal barrier assay\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phosphorylation and localization phenotype at specific site, single lab\",\n      \"pmids\": [\"24433183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPP2R2A interacts with GFPT1/2 (glutamine:fructose-6-phosphate amidotransferase 1/2) and dephosphorylates GFPT2 specifically (but not GFPT1); knockdown of PPP2R2A enhanced GFPT2 phosphorylation and promoted total cellular O-GlcNAcylation in breast cancer cells. Interaction confirmed by GST pulldown, co-IP, and immunofluorescence.\",\n      \"method\": \"Tandem affinity purification, mass spectrometry, GST pulldown, co-immunoprecipitation, immunofluorescence, O-GlcNAcylation assay, shRNA knockdown\",\n      \"journal\": \"Sheng wu gong cheng xue bao (Chinese journal of biotechnology)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (TAP-MS, GST pulldown, co-IP, IF) with functional phosphorylation readout, single lab\",\n      \"pmids\": [\"29943541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPA (a histone deacetylase inhibitor) promotes PPP2R2A-mediated dephosphorylation of Chk1 at Ser317 and Ser345, accelerating G2/M progression. The effect of VPA on PPP2R2A operates at the post-transcriptional level through HDAC1/2. PPP2R2A residues D197 and N181 are essential for PPP2R2A-Chk1 signaling.\",\n      \"method\": \"Phosphorylation assays, mutagenesis, co-immunoprecipitation, cell cycle analysis, in vivo experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifies functional residues, KD/OE with defined phosphorylation readout, single lab\",\n      \"pmids\": [\"36781846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP2A-B55α/PPP2R2A is identified as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α regulates early mitophagy by releasing ULK1 from its inhibitory regulation, and later (2-4 hours) promotes nuclear translocation of TFEB to support mitophagy. PP2A-B55α also controls mitochondrial biogenesis by stabilizing PARIS (a PGC-1α inhibitor and Parkin substrate). PP2A-B55α targeting rescues neurodegenerative phenotypes in a Drosophila Parkinson's disease model.\",\n      \"method\": \"Unbiased LC-MS/MS and transcriptomics, phosphoproteomics, genetic manipulation, nuclear fractionation, in vivo Drosophila model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased multi-omics discovery, genetic validation, in vivo Drosophila model, multiple orthogonal methods; single lab but comprehensive\",\n      \"pmids\": [\"41042873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP2A-B55α directly dephosphorylates c-Myc at Thr58 and regulates two distinct c-Myc degradation pathways in a biphasic manner: B55α suppression increases Thr58 phosphorylation and enhances FBXW7-dependent degradation, while B55α overexpression promotes Thr58-independent UBR5-mediated degradation. PP2A-B55α complex also binds and dephosphorylates UBR5. B55δ shows weaker UBR5 binding affinity and fails to induce c-Myc degradation.\",\n      \"method\": \"Biochemical dephosphorylation assays, co-immunoprecipitation, mutagenesis, ubiquitination assays, overexpression/knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro biochemical dephosphorylation, co-IP identifying UBR5 as novel substrate, isoform specificity comparison (B55α vs B55δ), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41818150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPP2R2A deficiency causes cytosolic DNA accumulation leading to cGAS-STING-type I IFN pathway activation. PPP2R2A deficiency elevates PD-L1 expression via GSK-3β-dependent and STING-dependent mechanisms, modulating the tumor immune microenvironment.\",\n      \"method\": \"siRNA knockdown, PPP2R2A heterozygous cell lines, cGAS-STING pathway assays, PD-L1 expression analysis, GSK-3β inhibition, mouse lung cancer model, immune cell profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement with GSK-3β and STING epistasis, in vivo mouse model, single lab\",\n      \"pmids\": [\"41411055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPP2R2A deficiency in NSCLC promotes epithelial-mesenchymal transition (EMT) and metastatic behavior. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 (Slug) expression via the GSK3β-β-catenin pathway. PPP2R2A deficiency also increases the cancer stem cell population and enhances drug resistance.\",\n      \"method\": \"shRNA knockdown, CRISPR/Cas9 homozygous/hemizygous depletion, bulk RNA-sequencing, GSEA, EMT marker analysis, invasion/migration assays, tail vein metastasis assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with GSEA defines pathway (GSK3β-β-catenin-Slug), KD/KO with functional invasion and in vivo metastasis readout, single lab\",\n      \"pmids\": [\"38986733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPP2R2A controls NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. PPP2R2A deficiency promotes NAD+ biosynthesis; elevated NR inhibits Th17 and promotes Treg differentiation by PARylating histone H1.2, altering Foxp3 and Il17a locus occupancy.\",\n      \"method\": \"T cell-specific PPP2R2A knockout (lupus-prone mice), metabolomics, chromatin immunoprecipitation, cytokine assays, NR supplementation experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with mechanistic metabolic readout and chromatin biology, single lab\",\n      \"pmids\": [\"38889006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PR55α is a potent inhibitor of p16 transcription; ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced cellular senescence. This function is p53-independent and specifically affects p16 (not p14/ARF).\",\n      \"method\": \"Ectopic expression, shRNA knockdown, RT-PCR for p16 expression, RB phosphorylation analysis, senescence assays (SA-β-gal, BrdU incorporation)\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined transcriptional and functional readout, p53-independence established, single lab\",\n      \"pmids\": [\"38441530\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP2R2A (B55α/PR55α) encodes the regulatory B subunit of the PP2A heterotrimer that determines substrate specificity and subcellular targeting; established substrates and mechanisms include: selective dephosphorylation of Akt-Thr308 (suppressing PI3K signaling), dephosphorylation of Cdk1 substrates (histone H1, p107, pRB-family, FoxM1) to drive mitotic exit and G1/S cell-cycle regulation, dephosphorylation of SAMHD1-T592 to activate HIV restriction, dephosphorylation of c-Myc-T58 and UBR5 to regulate c-Myc stability in a biphasic manner, dephosphorylation of GEF-H1-Ser885 to activate RhoA/ROCK signaling in T cells, dephosphorylation of ATM to regulate DSB repair, dephosphorylation of EDD to activate p53 under glutamine deprivation, dephosphorylation of HDAC5 to promote its nuclear accumulation in cardiomyocytes, and regulation of mitophagy/biogenesis via ULK1 and TFEB; substrate recruitment is mediated by a conserved SLiM ([RK]-V-x-x-[VI]-R) that docks into a groove on B55α whose structure has been solved by cryo-EM; additional regulatory mechanisms include PHD2-mediated hydroxylation of B55α-P319 (promoting its degradation), p53/FBXL20-mediated ubiquitination (controlling B55α protein stability), and competitive inhibition by FAM122A and IER5 that occlude the substrate-binding groove.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP2R2A (B55α/PR55α) is the regulatory B subunit that targets the PP2A holoenzyme to specific substrates, defining a serine/threonine phosphatase activity central to cell-cycle control, signaling, and development [#1, #22]. Its best-defined role is in mitotic exit: PP2A-B55α acts downstream of Cdk1 and the Mastl(Greatwall) kinase to dephosphorylate Cdk1 substrates and drive spindle breakdown and reassembly of the nuclear envelope, Golgi, and chromatin [#1, #2]. B55α-PP2A confers substrate selectivity across a broad set of phosphoproteins—selectively dephosphorylating Akt-Thr308 but not Ser473 [#0], the pocket protein p107 and FoxM1 to enforce G1/S and G2 control [#5, #6, #8], ATM at DSB sites to govern homologous-recombination repair [#3], SAMHD1-Thr592 to activate HIV-1 restriction during M/G1 [#17], and c-Myc-Thr58 (with concomitant dephosphorylation of the ligase UBR5) to control Myc stability biphasically [#36]. Substrate recruitment is governed by a conserved short linear motif ([RK]-V-x-x-[VI]-R) that docks into a groove on the B55α β-propeller, a mechanism validated for p107 and TAU [#22] and visualized by cryo-EM of B55α bound to inhibitory partners [#29, #31]. This same surface is targeted by competitive regulators FAM122A and IER5, which occlude substrate docking [#28, #29], while the cofactor Eya3 binds the groove region to recruit and stimulate B55α-mediated dephosphorylation of Myc-Thr58 [#30, #31]. B55α abundance is itself controlled by PHD2-mediated hydroxylation at Pro319 driving degradation [#16] and by p53/FBXL20-dependent ubiquitination [#24]. Beyond proliferation, PP2A-B55α controls T-cell differentiation via GEF-H1/RhoA/ROCK signaling [#23], cardiomyocyte HDAC5 trafficking [#15], mitophagy and mitochondrial biogenesis through ULK1, TFEB, and PARIS [#35], and epidermal/ectodermal development, where Ppp2r2a knockout mice are embryonic lethal with neural tube and epidermal barrier defects [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that B55α confers PP2A substrate selectivity at the level of individual phosphosites by showing it directs the holoenzyme to dephosphorylate Akt specifically at Thr308.\",\n      \"evidence\": \"Co-IP of endogenous holoenzymes with Akt, in vitro dephosphorylation, siRNA/overexpression in cells\",\n      \"pmids\": [\"18042541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the docking determinant on B55α\", \"Physiological contexts of selective Thr308 control not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed PP2A-B55α as the executor of mitotic exit downstream of Cdk1 inactivation, answering how dephosphorylation of Cdk1 substrates is coordinated to reverse mitotic phosphorylation.\",\n      \"evidence\": \"Genome-wide RNAi live-cell imaging screen, histone H1 phosphatase assay, importin-β1 co-purification, and genetic epistasis (Cdc20/Cdk1/Mastl) in mouse cells\",\n      \"pmids\": [\"20711181\", \"21156286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate set during mitotic exit not enumerated\", \"Mechanism of B55α activation timing relative to Mastl not resolved structurally\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined B55α-specific regulation of pocket proteins, showing it restrains p107 and FoxM1 phosphorylation to control G1/S and G2 transitions.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression with cell-cycle and FoxM1 activity readouts\",\n      \"pmids\": [\"20663872\", \"21813648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro dephosphorylation of these substrates not shown in these studies\", \"Selectivity among pocket proteins partially addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended B55α function to the DNA damage response by showing it dephosphorylates ATM at defined sites to regulate retention at DSBs and HR repair.\",\n      \"evidence\": \"Loss-of-function screen, biochemical dephosphorylation of defined ATM phosphosites, siRNA, HR repair assays\",\n      \"pmids\": [\"23087057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment mechanism to DSB sites not defined\", \"Interplay with CHK2 feedback only partially mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that B55α itself is regulated by dephosphorylation as an activation switch, and linked it to stress and metabolic signaling (p107/FGF, EDD/p53, FOXO1).\",\n      \"evidence\": \"Reciprocal co-IP/MS, phosphorylation analysis of B55α, KD with phosphorylation/localization readouts in chondrocytes, β-cells, and cancer cells\",\n      \"pmids\": [\"23716589\", \"23775125\", \"23499005\", \"22417654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases driving B55α phosphorylation not fully identified\", \"Quantitative affinity changes with phospho-state not structurally explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped a viral inhibitor (E4orf4) binding site on the B55α β-propeller above the substrate groove, distinguishing an allosteric/occlusion site from the substrate-docking surface.\",\n      \"evidence\": \"Structure-guided mutagenesis, IP, GST pulldown, cell death assays\",\n      \"pmids\": [\"24244166\", \"23530045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the E4orf4-B55α complex in these studies\", \"Relationship to endogenous regulators unclear at the time\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected mitotic-exit dephosphorylation to antiviral immunity by showing B55α dephosphorylates SAMHD1-Thr592 at M/G1 to activate HIV-1 restriction.\",\n      \"evidence\": \"Proteomics, co-IP, cell-cycle synchronization, HIV-1 infection assays, validation in macrophages\",\n      \"pmids\": [\"29884836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation in fully non-cycling cells incompletely defined\", \"Direct SLiM in SAMHD1 not mapped here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the molecular grammar of substrate recruitment by defining a conserved SLiM ([RK]-V-x-x-[VI]-R) that docks into the B55α groove and dictates dephosphorylation of proximal phosphosites.\",\n      \"evidence\": \"Mutagenesis of the SLiM in p107 and TAU, in vitro and cellular dephosphorylation, data-guided computational modeling\",\n      \"pmids\": [\"34661528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Computational model not yet an experimental structure\", \"How phosphosite presentation distance is tuned remains partial\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined immune and developmental roles in vivo: B55α activates GEF-H1/RhoA/ROCK to drive Th1/Th17 differentiation, and is essential for ectodermal/epidermal development.\",\n      \"evidence\": \"T-cell conditional KO with RhoA activity and differentiation assays; CRISPR KO mice with developmental phenotyping\",\n      \"pmids\": [\"33762326\", \"32582689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific substrate repertoires not exhaustively defined\", \"Embryonic lethality limits adult tissue analysis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established competitive inhibition as a core regulatory logic: FAM122A occludes the substrate groove to block CDK-substrate dephosphorylation, controlling cell-cycle checkpoints.\",\n      \"evidence\": \"Structure prediction, mutagenesis, in vitro competition assays, CRISPR KO with checkpoint and DDR readouts\",\n      \"pmids\": [\"38982062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Competition kinetics versus diverse substrates not fully quantified\", \"Regulation of FAM122A availability not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided experimental structures of the B55α regulatory interface, showing IER5 and Eya3 engage the substrate-recruitment surface as inhibitor and recruiter respectively, with translation to peptide-based modulation of Myc.\",\n      \"evidence\": \"Cryo-EM of B55α-IER5-N50 and B55α-Eya3, in vitro pTau/pMyc dephosphorylation, mutagenesis, inhibitory peptide B55i in TNBC cells\",\n      \"pmids\": [\"40209703\", \"40414499\", \"38796066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full catalytic-cycle structure with bound substrate not captured\", \"Selectivity of Eya3 stimulation across substrates beyond Myc not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded B55α into mitochondrial quality control and tumor immunity, regulating mitophagy/biogenesis via ULK1/TFEB/PARIS and the cGAS-STING/PD-L1 axis.\",\n      \"evidence\": \"Multi-omics, phosphoproteomics, nuclear fractionation, Drosophila PD model; KD/heterozygous cells with cGAS-STING and PD-L1 assays in lung cancer models\",\n      \"pmids\": [\"41042873\", \"41411055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates within mitophagy and STING pathways not all defined\", \"Mechanism of cytosolic DNA accumulation upon deficiency unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single B55α groove discriminates among its many SLiM-bearing substrates and competitive regulators in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of B55α with a bound physiological substrate phosphosite\", \"Combinatorial rules governing substrate prioritization in vivo unknown\", \"Quantitative competition between FAM122A, IER5, Eya3, and substrates not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 17, 22, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6, 36]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 22, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 14, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 32, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 23, 37, 39]}\n    ],\n    \"complexes\": [\"PP2A holoenzyme (A-B55α-C trimer)\"],\n    \"partners\": [\"AKT1\", \"ATM\", \"FoxM1\", \"SAMHD1\", \"UBR5\", \"FAM122A\", \"IER5\", \"EYA3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}