{"gene":"PPP1CA","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"PP1α (PPP1CA) dephosphorylates phospho-Thr186 in the Cdk9 T-loop, thereby releasing P-TEFb from the inactive 7SK snRNP complex. This occurs downstream of Ca2+/PP2B signaling: PP2B first induces a conformational change in 7SK snRNP that enables PP1α access, and PP1α then dephosphorylates Cdk9 Thr186. The released, dephosphorylated P-TEFb is subsequently recruited by Brd4 to the preinitiation complex.","method":"Co-immunoprecipitation, in vitro phosphatase assays, siRNA knockdown, UV/HMBA stimulation of P-TEFb release","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro dephosphorylation assay identifying specific substrate site (Cdk9 T186), reciprocal co-IP, siRNA knockdown with defined phenotypic readout, multiple orthogonal methods in a single rigorous study","pmids":["18483222"],"is_preprint":false},{"year":1999,"finding":"PP1α (PPP1CA) is phosphorylated at Thr-320 by Cdk2 (but not Cdk4) during M-phase and again at the G1/S transition in a pRB-dependent manner. PP1α phosphorylated at Thr-320 co-precipitates with pRB during G1/S but is found in pRB-immunodepleted extracts in M-phase, indicating distinct subpopulations of PP1α regulate different cell cycle transitions. Expression of a T320A phosphorylation-resistant PP1α mutant in pRB-expressing cells causes G1 arrest.","method":"In vitro kinase assay with Cdk2/Cdk4, phospho-specific antibodies, co-immunoprecipitation with pRB, inhibitor treatments (Cdk2 inhibitor), cell cycle synchronization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay identifying specific substrate/kinase (Cdk2→PP1α Thr320), co-IP with pRB, mutagenesis (T320A), multiple orthogonal methods in one rigorous study","pmids":["10506210"],"is_preprint":false},{"year":2006,"finding":"PP1α (PPP1CA) associates with caspase-9 in vitro and in vivo in IL-2-proliferating cells. IL-2 deprivation induces PP1α dephosphorylation and activation, leading to dephosphorylation of phospho-Thr125 on caspase-9, thereby activating caspase-9 and subsequent caspase-3 cleavage. PP1α is indispensable for triggering caspase-9 in cell-free systems. Two novel PP1α-binding sites on caspase-9 distinct from the canonical RVxF motif were identified.","method":"Co-immunoprecipitation in vivo and in vitro, cell-free caspase activation assays, siRNA knockdown of PP1α, IL-2 deprivation model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro co-IP, cell-free reconstitution of caspase activation, siRNA loss-of-function with specific phenotypic readout, identification of novel binding sites","pmids":["16888006"],"is_preprint":false},{"year":2010,"finding":"PINCH1 directly binds PP1α and inhibits its phosphatase activity, resulting in increased Akt1 phosphorylation and enhanced cell survival/radioresistance. PP1α acts as an Akt1-dephosphorylating phosphatase that is negatively regulated by PINCH1 at integrin adhesion sites.","method":"Direct binding assay (PINCH1-PP1α interaction), PP1α activity assays, Akt1 phosphorylation measurements, siRNA knockdown, in vitro and in vivo irradiation survival assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding established, PP1α enzymatic activity inhibition assay, siRNA knockdown with defined phenotype, in vivo validation","pmids":["20530873"],"is_preprint":false},{"year":2014,"finding":"PP1A (PPP1CA) dephosphorylates TAZ during canonical Wnt3a signaling. Wnt3a-induced dephosphorylation of TAZ by PP1A prevents TAZ from binding 14-3-3 proteins, stabilizes TAZ, and induces its nuclear localization, thereby promoting osteoblastic differentiation. Depletion of PP1A blocks Wnt3a-induced TAZ stabilization.","method":"siRNA knockdown of PP1A, western blotting for TAZ phosphorylation, co-immunoprecipitation with 14-3-3, nuclear fractionation, osteogenic differentiation assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA loss-of-function with specific substrate (TAZ Ser89 dephosphorylation), subcellular localization experiments, functional differentiation readout, multiple orthogonal methods","pmids":["24510127"],"is_preprint":false},{"year":2011,"finding":"PP1A (PPP1CA) interacts with and dephosphorylates YAP2 at Serine-127 in vitro and in vivo. PP1A-mediated YAP2 dephosphorylation induces nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadaic acid increases YAP2 phospho-Ser127 and promotes its cytoplasmic retention.","method":"Co-immunoprecipitation, in vitro dephosphorylation assay, subcellular fractionation, okadaic acid treatment, YAP2 transcriptional reporter assays, siRNA knockdown","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro dephosphorylation assay, co-IP, subcellular fractionation, pharmacologic inhibition, multiple orthogonal methods identifying specific substrate site","pmids":["21909427"],"is_preprint":false},{"year":2008,"finding":"PPP1CA (PP1α) contributes to oncogenic Ras-induced senescence. Loss of PPP1CA function (via antisense RNA or shRNA) bypasses ras/p53-induced growth arrest and senescence. PPP1CA is required for p53-dependent induction of p21 after DNA damage and subsequent pRb dephosphorylation. Oncogenic Ras increases intracellular ceramide levels and PPP1CA protein levels; ceramide-induced senescence is blocked by PPP1CA downregulation.","method":"Retroviral genetic screen, shRNA knockdown of PPP1CA, western blotting for p21 and pRb phosphorylation, ceramide addition experiments, tumor growth assays","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen plus shRNA validation, specific substrate identification (pRb dephosphorylation), ceramide pathway placement, multiple orthogonal methods","pmids":["18204081"],"is_preprint":false},{"year":2018,"finding":"PP1α (PPP1CA) acts as a B-Raf activating phosphatase in an S6K/PP1α/B-Raf signaling pathway that leads to MAPK activation. PML sequesters PP1α into PML nuclear bodies, repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding, and cytoplasmic accumulation. PPP1CA gene is genomically amplified in metastatic prostate cancer.","method":"Co-immunoprecipitation, subcellular fractionation, in vitro phosphatase assays, genomic amplification analysis, PML knockdown/overexpression, B-Raf activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphatase assay establishing PP1α→B-Raf dephosphorylation, co-IP for complex members, subcellular localization with functional consequences, pathway epistasis via PML","pmids":["29335436"],"is_preprint":false},{"year":2019,"finding":"USP11 stabilizes PPP1CA by deubiquitinating it, protecting PPP1CA from proteasome-mediated degradation. The USP11/PPP1CA complex activates the ERK/MAPK signaling pathway to promote colorectal cancer progression.","method":"LC-MS/MS interactome, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, siRNA/overexpression experiments, in vitro and in vivo tumor assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP validation of USP11-PPP1CA interaction, ubiquitination/deubiquitination assays, single lab with two orthogonal methods","pmids":["31521612"],"is_preprint":false},{"year":2019,"finding":"Cavin-3, upon UV-induced release from caveolae, interacts with and inhibits PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, defining a pro-apoptotic signaling pathway from surface caveolae to the nucleus.","method":"Biotin affinity proteomics, mass spectrometry, cell-free protein binding assays, co-immunoprecipitation, UV stress experiments, H2AX phosphorylation measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cell-free reconstitution binding assay, validated by co-IP, functional consequence (H2AX phosphorylation, apoptosis), multiple orthogonal methods","pmids":["31332168"],"is_preprint":false},{"year":2021,"finding":"PP1A (PPP1CA) dephosphorylates SRSF1, and reduced PP1α activity enhances SRSF1 phosphorylation and nucleus translocation, causing a switch in MKNK2 alternative splicing from MKNK2a to MKNK2b in colon adenocarcinoma. PP1α and SRPK1/2 exert opposing functions balancing SRSF1 phosphorylation and localization.","method":"Western blotting, immunohistochemistry, PP1α activity assays, siRNA knockdown, alternative splicing analysis by PCR, xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PP1α activity assays, siRNA knockdown with defined splicing phenotype, pathway epistasis with SRPK1/2, single lab","pmids":["33602301"],"is_preprint":false},{"year":2021,"finding":"The Smad4-MYO18A-PP1A complex dephosphorylates PAK1 at Thr-423. MYO18A functions as the PP1-interacting protein (regulatory subunit) for PP1A substrate recognition in cholangiocarcinoma, binding PP1A via its RVFFR motif and Smad4 via its CC domain. PP1A-mediated PAK1-T423 dephosphorylation inhibits β-catenin-S675 phosphorylation and its nuclear translocation.","method":"LC-MS/MS, co-immunoprecipitation, biochemical complex reconstitution, site-directed mutagenesis (RVFFR motif), phosphorylation assays for PAK1 and β-catenin, in vitro and in vivo functional assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — LC-MS/MS plus biochemical validation of ternary complex, mutagenesis of PP1-binding motif, specific substrate site (PAK1-T423) identified, multiple orthogonal methods","pmids":["34799729"],"is_preprint":false},{"year":2023,"finding":"CARM1 methylates PPP1CA at Arg-23 (R23). This arginine methylation affects PPP1CA-mediated dephosphorylation of AKT-T450 and AMPK-T172, and increases activities of phosphofructokinase-1 and PFKFB3, upregulating glycolytic flux. This mechanism promotes osteogenic differentiation and inhibits osteoclastic differentiation.","method":"In vitro methylation assays (identifying R23 as methylation site), CRISPR/Cas9 knockout, lentiviral overexpression, transcriptomic and metabolomic assays, western blotting for AKT and AMPK phosphorylation","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro methylation assay identifying specific site (R23), CRISPR KO and OE functional validation, single lab","pmids":["37649137"],"is_preprint":false},{"year":2023,"finding":"SUV39H2 methyltransferase monomethylates PPP1CA at Lys-141 (K141). K141 methylation disrupts PPP1CA's interaction with TFEB and blocks TFEB dephosphorylation and nuclear translocation, leading to autophagy deficiency and nucleus pulposus cell senescence. PPP1R9B (spinophilin) facilitates PPP1CA-TFEB targeting, and K141 methylation also impairs PPP1R9B binding to PPP1CA.","method":"Proteomic analysis (identifying SUV39H2 as writer), in vitro methylation assays, co-immunoprecipitation, western blotting for TFEB phosphorylation and localization, CRISPR/KO and overexpression, autophagy assays, animal models of IDD","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro methylation assay, specific modification site (K141), co-IP disruption, TFEB dephosphorylation assay, multiple orthogonal methods, in vivo validation","pmids":["37605006"],"is_preprint":false},{"year":2023,"finding":"PP1A (PPP1CA/Ppp1Ca) directly binds to and dephosphorylates the NaCl cotransporter (NCC) in the kidney in a potassium-regulated manner, reducing blood pressure. Dietary potassium upregulates Ppp1Ca expression and suppresses its negative regulator Ppp1r1a (I1), shifting the balance toward PP1A-mediated NCC dephosphorylation. Confirmed using genetically engineered mice with constitutively active SPAK kinase.","method":"Transcriptomics screen, direct binding assay (PP1A-NCC), in vivo dephosphorylation experiments in SPAK-constitutively active transgenic mice, high-potassium dietary intervention, blood pressure measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay, in vivo dephosphorylation of specific substrate (NCC) using genetically engineered mice, identification of regulatory mechanism, replicated across multiple experimental conditions","pmids":["37676724"],"is_preprint":false},{"year":2008,"finding":"Drosophila URI binds PP1alpha with much higher affinity than PP1beta, and this isoform-discriminating ability is conserved in humans. URI loss-of-function in Drosophila causes transcriptional defects, reduced cell viability, germline differentiation defects, and nuclear DNA damage accumulation.","method":"Binding affinity measurements (Drosophila and human URI vs PP1alpha/PP1beta), generation of uri loss-of-function allele, viability assays, transcriptional analysis, DNA damage markers","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding measurements discriminating PP1alpha vs PP1beta, genetic loss-of-function with defined phenotypes, ortholog study with confirmed conservation in humans","pmids":["18412953"],"is_preprint":false},{"year":2017,"finding":"PP1α activity is regulated by oxidative stress via formation of transient intramolecular disulfide bonds (involving Cys39 and Cys127), which protect the enzyme from irreversible over-oxidation. Glutathione (GSH) mediates this protection mechanism, reducing PP1α activity under redox stress. The dimerization of PP1α via these cysteines protects the active surface.","method":"Mass spectrometry with cross-over-read search for disulfide-linked species, in vitro PP1α activity assays under oxidative conditions, site-specific cysteine analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — MS identification of disulfide species, in vitro activity assays, single lab, mechanistic characterization of redox regulation","pmids":["30531830"],"is_preprint":false},{"year":2013,"finding":"PP1α (PPP1CA), PP1β, and Wip1 phosphatases regulate histone H4 Ser47 phosphorylation (H4S47ph) levels and H3.3 deposition. Depletion of each phosphatase increases H4S47ph. PP1α and PP1β bind H3-H4 in vitro and in vivo and also interact with the Pak2 kinase in vivo, suggesting regulation at the level of both the substrate H4S47 and the kinase Pak2. Depletion of these phosphatases increases H3.3 occupancy and chaperone (HIRA/Daxx) association.","method":"siRNA knockdown of PP1α, PP1β, and Wip1; co-immunoprecipitation for H3-H4 and Pak2 binding; ChIP for H3.3 occupancy; western blotting for H4S47ph levels","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for substrate (H3-H4) and kinase (Pak2) interactions, siRNA depletion with H4S47ph readout, single lab with multiple orthogonal methods","pmids":["23828041"],"is_preprint":false},{"year":2017,"finding":"The GADD34/PP1α complex dephosphorylates both eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47) in response to arsenite-induced oxidative stress. A GADD34 mutant unable to bind PP1α fails to restore eIF2α or SIRT1 dephosphorylation in GADD34-/- MEFs. SIRT1 dephosphorylation by the GADD34/PP1α complex increases SIRT1 deacetylase activity, affecting cell fate after oxidative stress.","method":"Mass spectrometry of GADD34 acetylation, co-immunoprecipitation of GADD34/PP1α/eIF2α/SIRT1 complex, rescue experiments in GADD34-/- MEFs with WT vs PP1α-binding-deficient GADD34 mutant, in vitro and in-cell SIRT1 deacetylase activity assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — rescue experiments with PP1α-binding-deficient mutant, in vitro activity assays, specific substrate sites (eIF2α pSer51, SIRT1 pSer47), multiple orthogonal methods in rigorous study","pmids":["28984870"],"is_preprint":false},{"year":2005,"finding":"PP1 inhibitor-3 (Inh3) co-localizes with PP1alpha at centrosomes (and with PP1gamma1 at nucleoli) in interphase HEK 293 cells. Inh3 co-immunoprecipitates with PP1alpha and PP1gamma1 but not PP1beta in vitro, demonstrating isoform-specific interactions. The nuclear localization signal and nucleolar targeting signals of Inh3 were mapped by site-directed mutagenesis.","method":"Immunofluorescence co-localization, co-immunoprecipitation, site-directed mutagenesis of nuclear/nucleolar localization signals, laser scanning cytometry","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating isoform-specific binding, direct co-localization imaging, mutagenesis of targeting signals, single lab","pmids":["16256067"],"is_preprint":false},{"year":2014,"finding":"14-3-3ζ binds PP1α within residues 159–279 in a phosphorylation-independent manner. 14-3-3ζ does not affect PP1α catalytic activity in vitro, but causes cytoplasmic retention of PP1α: cells expressing both PP1α and 14-3-3ζ have a significantly higher cytoplasmic/nuclear PP1α ratio. Expression of dominant-negative 14-3-3ζ (K49E) causes nuclear accumulation of PP1α.","method":"Co-immunoprecipitation from HEK-293 lysates, GST pulldown, PP1α deletion mutant mapping, in vitro phosphatase activity assay, subcellular fractionation, dominant-negative 14-3-3ζ expression","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and GST pulldown for binding region, subcellular fractionation for localization, dominant-negative validation, single lab with multiple orthogonal methods","pmids":["24956593"],"is_preprint":false},{"year":2015,"finding":"HSV-1 γ34.5 protein targets PP1α to reverse translational arrest (dephosphorylation of eIF2α) during viral infection. HSV-1 carrying a PP1α-binding mutation in γ34.5 shows complete absence of disseminated disease in neonatal mice and increased survival in brain infection models. PP1α targeting by HSV-1 is required for later stages of disseminated infection but not for early replication in visceral organs.","method":"Murine neonatal infection model, HSV-1 PP1α-binding mutant virus, type I IFN-deficient mouse rescue experiments, brain slice culture pharmacologic inhibition of eIF2α dephosphorylation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — viral genetic mutant (PP1α-binding mutation in γ34.5) with in vivo disease phenotype, pharmacologic inhibition confirmation, mechanistic epistasis with IFN pathway","pmids":["26621722"],"is_preprint":false},{"year":2019,"finding":"PP1A (PPP1CA) directly dephosphorylates NACA (nascent polypeptide-associated complex and co-regulator α) at Thr-89, Ser-151, and Thr-174. NACA interacts with the PPP1CA catalytic subunit and regulatory subunits PPP1R9B, PPP1R12A, and PPP1R18. NACA dephosphorylation promotes nuclear localization of NACA, recruitment of BTF3/BTF3L4, and cooperatively potentiates cJUN/AP-1 transcriptional activity and osteoblast differentiation.","method":"Affinity purification-MS (identifying PP1A holoenzyme components), co-immunoprecipitation in HEK293T and MC3T3-E1 cells, phosphosite MS analysis, phosphomimetic and alanine substitution mutants, AP-1 reporter assays, osteogenic differentiation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — AP-MS plus co-IP for complex identification, MS mapping of dephosphorylation sites, phosphomimetic mutagenesis abolishing transcriptional activity, functional osteogenic readout, multiple orthogonal methods","pmids":["30948508"],"is_preprint":false},{"year":2011,"finding":"Taperin (C9orf75) preferentially docks the alpha isoform of PP1 over PP1beta via a classic RVxF motif, suppresses the general phosphatase activity of PP1α, and is found complexed to PP1α in both nuclear and cytoplasmic compartments. Taperin shuttles between nucleus and cytoplasm and is recruited to sites of DNA damage, interacting with Ku70, Ku80, PARP and topoisomerases.","method":"Biochemical binding assays, co-immunoprecipitation, SILAC MS for interactors, PP1 isoform specificity assays, subcellular fractionation, DNA damage recruitment assays","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay distinguishing PP1alpha from PP1beta, PP1 activity suppression assay, SILAC MS, single lab with multiple orthogonal methods","pmids":["23213405"],"is_preprint":false},{"year":2016,"finding":"PP1α is a negative regulator of TRPV1 (transient receptor potential vanilloid 1) channel activity. HSV-based coexpression of PP1α rescued viral replication suppressed by TRPV1 in a cell-based screen. In vivo, HSV vectors expressing PP1α reduced thermal sensitivity in rat footpads, demonstrating functional specificity for thermal but not chemical pain modalities.","method":"HSV-based cDNA library screen for TRPV1 negative regulators, viral rescue of replication, in vivo rat thermal sensitivity assays","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with in vitro and in vivo validation, single lab, mechanism of TRPV1 regulation not fully defined at biochemical level","pmids":["27382601"],"is_preprint":false},{"year":2021,"finding":"LACTB directly binds PP1A and attenuates the interaction between PP1A and YAP, reducing YAP dephosphorylation and increasing phospho-YAP (Ser127), which prevents YAP nuclear translocation in a LATS1-independent manner. This constitutes an SOX10/LACTB/PP1A signaling cascade controlling melanoma progression.","method":"Co-immunoprecipitation (LACTB-PP1A and PP1A-YAP interactions), western blotting for YAP phosphorylation, subcellular fractionation, siRNA/overexpression, in vivo xenograft experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing LACTB-PP1A binding and competitive displacement of YAP from PP1A, YAP phosphorylation readout, single lab with multiple orthogonal methods","pmids":["33675985"],"is_preprint":false},{"year":2021,"finding":"SNORD12B interacts with PP1α, disrupts the interaction between 14-3-3ζ and PP1α, and causes PP1α to relocalize from the cytosol to the nucleus. Nuclear sequestration of PP1α leads to enhanced cytosolic AKT phosphorylation and activation of AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation (SNORD12B-PP1α and 14-3-3ζ-PP1α interactions), subcellular fractionation, western blotting for AKT phosphorylation, RNA interference and overexpression, in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for RNA-protein and protein-protein interactions, subcellular localization with functional AKT phosphorylation consequence, single lab","pmids":["33941854"],"is_preprint":false},{"year":2024,"finding":"The peptide PDHK1-241aa (encoded by circPDHK1) interacts with PPP1CA and causes its relocation to the nucleus. This nuclear relocation of PPP1CA inhibits AKT dephosphorylation and activates the AKT-mTOR signaling pathway to promote clear cell renal cell carcinoma progression.","method":"Immunoprecipitation-mass spectrometry (identifying PPP1CA as PDHK1-241aa interactor), co-immunoprecipitation, immunofluorescence, subcellular fractionation, AKT phosphorylation western blot, functional assays in ccRCC cells and nude mice","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus co-IP validation, subcellular localization change with functional AKT phosphorylation consequence, single lab with multiple methods; note: circRNA study but mechanism is through encoded peptide interaction with PPP1CA protein","pmids":["38360682"],"is_preprint":false},{"year":2019,"finding":"MIIP interacts with PP1α via its C-terminal domain but does not affect PP1α protein level. MIIP interaction with PP1α enhances PP1α-mediated AKT dephosphorylation. Silencing PP1α reverses MIIP's inhibitory effect on AKT phosphorylation and cell growth; MIIPC lacking the PP1α-interacting C-terminus loses MIIP's tumor-suppressive function.","method":"Co-immunoprecipitation, immunofluorescence co-localization, western blotting for AKT phosphorylation, siRNA knockdown of PP1α, MIIP deletion mutants (MIIP∆C), xenograft assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, deletion mutant mapping of interaction domain, epistasis rescue experiment (PP1α knockdown reverses MIIP effect), single lab","pmids":["31092266"],"is_preprint":false},{"year":1997,"finding":"PP1α is phosphorylated by PKC at Ser-325 (in its C-terminal region) in response to B-cell receptor (IgM) stimulation. PP1 activity transiently decreases after B-cell stimulation. PP1alpha undergoes isoform-specific modification (altered isoelectric point pattern on 2D gels) upon BCR stimulation or PMA treatment, while PP1delta does not. The C-terminal peptide of PP1alpha is a better PKC substrate than PP1gamma1/2.","method":"2D electrophoresis + western blot, in vitro phosphorylation of C-terminal peptides by PKC with [gamma-32P]ATP, PP1 activity assays, B-cell stimulation model","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro PKC phosphorylation assay identifying specific site (Ser-325), B-cell stimulation model with PP1 activity readout, isoform specificity demonstrated, single lab","pmids":["9399575"],"is_preprint":false},{"year":2024,"finding":"In Zika virus infection, NS2B acts as a scaffold protein mediating interaction between PP1α and eIF2α. This NS2B-PP1α complex promotes eIF2α dephosphorylation by PP1α, inhibiting stress granule formation and promoting viral replication. The NS2B-PP1α complex is stabilized against ubiquitin-induced degradation. The NS2BV35A mutant interacts only with eIF2α and fails to inhibit stress granule formation.","method":"Co-immunoprecipitation of NS2B-PP1α-eIF2α complex, eIF2α dephosphorylation assays, stress granule formation assays, NS2BV35A mutagenesis, ubiquitination resistance assay, viral replication assays, brain organoid experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — complex reconstitution/co-IP, mutagenesis (NS2BV35A) abolishing complex function, dephosphorylation assay, specific functional readout (SG formation and viral replication), multiple orthogonal methods","pmids":["38935808"],"is_preprint":false},{"year":2025,"finding":"NY-ESO-1 acts as a scaffold protein recruiting the deubiquitinase OTUB1 to PP1α, forming a ternary NY-ESO-1/OTUB1/PP1α complex. OTUB1 deubiquitinase activity (not its E2-suppressing function) prevents PP1α polyubiquitination and promotes its stability. Accumulated PP1α then activates ERK1/2 signaling to promote anoikis resistance and tumor metastasis.","method":"Co-immunoprecipitation of ternary complex, ubiquitination assays, OTUB1 deubiquitinase activity assay, PP1α knockdown rescue experiments, ERK1/2 activity measurements, in vivo metastasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of ternary complex, deubiquitination assay, knockdown epistasis experiments, single lab with multiple orthogonal methods","pmids":["41053024"],"is_preprint":false},{"year":2025,"finding":"PP1A dephosphorylates Keap1 at site Ser104 (site 104), disrupting the Keap1-Nrf2 interaction, enhancing transcription of ferroptosis-related markers and immune checkpoint PD-L1, thereby inhibiting Lenvatinib-induced ferroptosis in hepatocellular carcinoma.","method":"Transcriptomic analysis, ferroptosis metabolite profiling (ROS, Fe2+, lipid-ROS, GSH), PP1A knockdown, western blotting for Keap1-Nrf2 interaction, PD-L1 expression, single-cell sequencing, co-culture T-cell exhaustion assays, in vivo tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific substrate site (Keap1 Ser104) identified with functional pathway consequence, PP1A KD experiments, multiple assays in single lab","pmids":["40344394"],"is_preprint":false},{"year":2025,"finding":"PP1α selectively removes activation-loop phosphorylation from AMPK (dephosphorylating the activation-loop sites) while autophosphorylation sites remain protected, establishing asymmetric phosphatase control of AMPK regulatory states.","method":"Phosphatase competition assay (PP1A treatment of phosphorylated AMPK), integrated bottom-up and top-down mass spectrometry for site-specific kinetics, proteoform characterization","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase competition assay with site-specific MS readout, rigorous biochemical characterization, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.10.681638"],"is_preprint":true}],"current_model":"PPP1CA (PP1α) is a broadly active serine/threonine phosphatase whose substrate specificity, localization, and activity are tightly controlled by regulatory/targeting subunits and post-translational modifications: it dephosphorylates a diverse array of substrates including Cdk9-Thr186 (releasing P-TEFb from 7SK snRNP), pRb, Akt, eIF2α, caspase-9-Thr125, YAP/TAZ-Ser127, SRSF1, NCC, NACA, PAK1-Thr423, Keap1, and H4S47; its activity is inhibited by Cdk2-mediated phosphorylation at Thr320 (cell cycle), PKC phosphorylation at Ser325 (B-cell signaling), GSH-dependent disulfide formation (redox stress), CARM1-mediated arginine methylation at R23, and SUV39H2-mediated lysine methylation at K141; its subcellular distribution between cytoplasm and nucleus is regulated by 14-3-3ζ (cytoplasmic retention), PML (nuclear sequestration), and various viral/oncogenic proteins; and it is stabilized by deubiquitinases USP11 and OTUB1."},"narrative":{"mechanistic_narrative":"PPP1CA (PP1α) is a broadly acting serine/threonine phosphatase whose substrate selection, subcellular localization, and activity are dictated by interchangeable regulatory/targeting subunits and a layered code of post-translational modifications, allowing one catalytic core to control transcription, cell-cycle progression, survival signaling, the translational stress response, and ion transport [PMID:18483222, PMID:37676724, PMID:28984870]. Its substrate repertoire is dictated by partner-directed targeting: it dephosphorylates Cdk9-Thr186 to release active P-TEFb from the 7SK snRNP downstream of Ca2+/PP2B signaling [PMID:18483222], caspase-9-Thr125 to license apoptosis upon IL-2 withdrawal [PMID:16888006], YAP-Ser127 and TAZ to drive Hippo-effector nuclear accumulation [PMID:21909427, PMID:24510127], PAK1-Thr423 within a Smad4–MYO18A–PP1A holoenzyme [PMID:34799729], the NaCl cotransporter NCC in a potassium-regulated manner to modulate blood pressure [PMID:37676724], NACA to potentiate AP-1 transcription [PMID:30948508], and eIF2α (via the GADD34/PP1α complex) to restore translation after oxidative stress [PMID:28984870]. Activity and access to substrates are gated by inhibitory phosphorylation at Thr320 by Cdk2 across cell-cycle transitions [PMID:10506210] and at Ser325 by PKC during B-cell receptor signaling [PMID:9399575], by redox-driven intramolecular disulfide formation protected by glutathione [PMID:30531830], and by CARM1-mediated arginine-23 methylation and SUV39H2-mediated lysine-141 methylation, the latter disrupting PP1α–TFEB and PP1α–spinophilin engagement to impair autophagy [PMID:37649137, PMID:37605006]. Nucleocytoplasmic partitioning is set by competing interactors—14-3-3ζ enforces cytoplasmic retention while diverse RNAs, peptides, and viral/oncogenic proteins (SNORD12B, PDHK1-241aa, PML) relocalize the enzyme [PMID:24956593, PMID:33941854, PMID:38360682, PMID:29335436]—and its abundance is stabilized by the deubiquitinases USP11 and OTUB1, which feed ERK/MAPK-driven tumor progression [PMID:31521612, PMID:41053024]. PP1α functions as a regulatory node in oncogenic Ras-induced senescence, requiring PPP1CA for p53/p21-dependent pRb dephosphorylation [PMID:18204081], and is hijacked by HSV-1 (γ34.5) and Zika virus (NS2B) to dephosphorylate eIF2α and overcome translational arrest during infection [PMID:26621722, PMID:38935808].","teleology":[{"year":1997,"claim":"Established that PP1α activity is regulated by signal-dependent C-terminal phosphorylation, identifying PKC-Ser325 as an isoform-specific modification linking BCR signaling to transient phosphatase suppression.","evidence":"In vitro PKC phosphorylation of C-terminal peptides, 2D electrophoresis, PP1 activity assays in a B-cell stimulation model","pmids":["9399575"],"confidence":"Medium","gaps":["Downstream substrate consequences of Ser325 phosphorylation not defined","Physiological PP1α targets in BCR signaling not mapped"]},{"year":1999,"claim":"Defined Cdk2-mediated Thr320 phosphorylation as a cell-cycle switch creating distinct PP1α subpopulations governing G1/S versus M-phase transitions.","evidence":"In vitro kinase assay with Cdk2/Cdk4, phospho-specific antibodies, co-IP with pRB, T320A mutagenesis, cell-cycle synchronization","pmids":["10506210"],"confidence":"High","gaps":["Direct cell-cycle substrates dephosphorylated by the Thr320-controlled pool not enumerated","Phosphatase that reverses Thr320 not identified"]},{"year":2005,"claim":"Demonstrated isoform-selective targeting of PP1α by inhibitor-3 to centrosomes, an early example of regulatory-subunit-driven spatial control distinguishing PP1α from PP1β/γ.","evidence":"Immunofluorescence co-localization, co-IP, mutagenesis of nuclear/nucleolar targeting signals in HEK293 cells","pmids":["16256067"],"confidence":"Medium","gaps":["Functional consequence of centrosomal PP1α localization unresolved","Centrosomal substrates not identified"]},{"year":2006,"claim":"Linked PP1α to apoptotic commitment by showing it directly dephosphorylates caspase-9-Thr125 upon survival-signal withdrawal, with novel non-RVxF binding sites on the substrate.","evidence":"In vivo/in vitro co-IP, cell-free caspase activation reconstitution, siRNA knockdown in an IL-2 deprivation model","pmids":["16888006"],"confidence":"High","gaps":["Regulatory subunit directing PP1α to caspase-9 not identified","Upstream signal activating PP1α after IL-2 withdrawal not fully resolved"]},{"year":2008,"claim":"Placed PP1α as the effector phosphatase that releases active P-TEFb from the 7SK snRNP, connecting Ca2+/PP2B signaling to transcriptional elongation via Cdk9-Thr186 dephosphorylation.","evidence":"Co-IP, in vitro phosphatase assays on Cdk9 T186, siRNA knockdown, UV/HMBA stimulation","pmids":["18483222"],"confidence":"High","gaps":["Targeting subunit recruiting PP1α to 7SK snRNP not defined","How PP2B-induced conformational change grants PP1α access at structural level unresolved"]},{"year":2008,"claim":"Established PP1α as a positive effector of oncogene-induced senescence, required for p53/p21-driven pRb dephosphorylation and ceramide-mediated growth arrest.","evidence":"Retroviral genetic screen, shRNA knockdown, p21/pRb phospho-blotting, ceramide addition, tumor growth assays","pmids":["18204081"],"confidence":"High","gaps":["Direct vs indirect role of PP1α in pRb dephosphorylation not separated","Mechanism linking ceramide to PP1α activation unclear"]},{"year":2008,"claim":"Demonstrated conserved isoform-discriminating binding of URI for PP1α over PP1β, reinforcing that PP1α partner selectivity has functional consequences for transcription and genome stability.","evidence":"Binding affinity measurements (Drosophila and human URI), uri loss-of-function allele, viability/transcription/DNA-damage assays","pmids":["18412953"],"confidence":"Medium","gaps":["Human URI–PP1α functional consequences not directly tested","Substrates of the URI–PP1α complex not defined"]},{"year":2011,"claim":"Identified PP1α as a Hippo-pathway phosphatase dephosphorylating YAP-Ser127 to drive nuclear accumulation and transcriptional activation, opposing cytoplasmic sequestration.","evidence":"Co-IP, in vitro dephosphorylation, subcellular fractionation, okadaic acid treatment, reporter assays, siRNA knockdown","pmids":["21909427"],"confidence":"High","gaps":["Regulatory subunit targeting PP1α to YAP not identified","Relationship to LATS kinase signaling not delineated here"]},{"year":2010,"claim":"Defined PP1α as an Akt1-dephosphorylating phosphatase at integrin adhesions whose activity is restrained by direct binding of PINCH1, coupling adhesion signaling to survival/radioresistance.","evidence":"Direct binding assay, PP1α activity assays, Akt1 phospho-measurement, siRNA knockdown, in vivo irradiation survival","pmids":["20530873"],"confidence":"High","gaps":["Akt residue dephosphorylated by PP1α not specified","Generalizability beyond adhesion-site context untested"]},{"year":2013,"claim":"Implicated PP1α in chromatin regulation by showing it binds H3-H4 and the Pak2 kinase and controls histone H4S47 phosphorylation and H3.3 deposition.","evidence":"siRNA knockdown, co-IP for H3-H4 and Pak2, ChIP for H3.3 occupancy, H4S47ph blotting","pmids":["23828041"],"confidence":"Medium","gaps":["Direct dephosphorylation of H4S47 by PP1α not isolated from Pak2 regulation","Targeting subunit for chromatin localization unknown"]},{"year":2014,"claim":"Extended PP1α's Hippo-effector role to TAZ during Wnt3a signaling, showing dephosphorylation blocks 14-3-3 binding, stabilizes TAZ, and drives osteoblastic differentiation.","evidence":"siRNA knockdown, TAZ phospho-blotting, 14-3-3 co-IP, nuclear fractionation, osteogenic differentiation assays","pmids":["24510127"],"confidence":"High","gaps":["Targeting subunit recruiting PP1α to TAZ not identified","Crosstalk with the YAP arm not resolved"]},{"year":2014,"claim":"Established 14-3-3ζ as a phosphorylation-independent cytoplasmic retention factor for PP1α, defining a key node in PP1α nucleocytoplasmic partitioning without affecting catalytic activity.","evidence":"Co-IP, GST pulldown, deletion mapping (residues 159-279), in vitro activity assay, subcellular fractionation, dominant-negative 14-3-3ζ (K49E)","pmids":["24956593"],"confidence":"Medium","gaps":["Signals that release PP1α from 14-3-3ζ not defined here","Substrate consequences of localization shift not measured"]},{"year":2017,"claim":"Revealed redox control of PP1α via reversible intramolecular disulfide formation (Cys39/Cys127) that, under glutathione, protects the enzyme from irreversible over-oxidation while lowering activity.","evidence":"Disulfide-targeted mass spectrometry, in vitro activity assays under oxidative conditions, site-specific cysteine analysis","pmids":["30531830"],"confidence":"Medium","gaps":["Physiological redox conditions triggering this in cells not established","Substrate-level consequences not tested"]},{"year":2017,"claim":"Showed the GADD34/PP1α complex acts on dual stress substrates—eIF2α-pSer51 and SIRT1-pSer47—coupling translational recovery to SIRT1 deacetylase activation after oxidative stress.","evidence":"GADD34 acetylation MS, co-IP of GADD34/PP1α/eIF2α/SIRT1, rescue in GADD34-/- MEFs with PP1α-binding-deficient mutant, deacetylase activity assays","pmids":["28984870"],"confidence":"High","gaps":["Whether SIRT1 is a direct PP1α substrate vs GADD34-bridged not fully separated","Selectivity over CReP-targeted PP1α not addressed"]},{"year":2015,"claim":"Demonstrated that HSV-1 γ34.5 hijacks PP1α to dephosphorylate eIF2α and reverse translational arrest, with PP1α-binding required for disseminated neonatal disease in vivo.","evidence":"Neonatal murine infection, PP1α-binding mutant virus, type I IFN-deficient rescue, brain-slice pharmacologic inhibition","pmids":["26621722"],"confidence":"High","gaps":["Structural basis of γ34.5–PP1α recruitment not detailed","Host eIF2α kinase counteracted not specified in this work"]},{"year":2016,"claim":"Identified PP1α as a negative regulator of TRPV1 thermal channel activity, expanding its role to sensory signaling.","evidence":"HSV-based cDNA screen, viral replication rescue, in vivo rat thermal sensitivity assays","pmids":["27382601"],"confidence":"Medium","gaps":["Biochemical mechanism of TRPV1 regulation (direct dephosphorylation?) not defined","TRPV1 phosphosite not identified"]},{"year":2019,"claim":"Mapped a multi-site PP1α–NACA dephosphorylation event (Thr89, Ser151, Thr174) through a defined holoenzyme (PPP1R9B/R12A/R18) that drives NACA nuclear localization and AP-1 transcriptional potentiation.","evidence":"AP-MS of holoenzyme, co-IP, phosphosite MS, phosphomimetic/alanine mutants, AP-1 reporter and osteogenic assays","pmids":["30948508"],"confidence":"High","gaps":["Which specific regulatory subunit targets NACA in vivo not isolated","Kinase counteracted on NACA not defined"]},{"year":2019,"claim":"Defined deubiquitinase-mediated stabilization of PP1α by USP11, linking PP1α abundance to ERK/MAPK-driven colorectal cancer progression.","evidence":"LC-MS/MS interactome, co-IP, ubiquitination assays, proteasome inhibition, in vitro/in vivo tumor assays","pmids":["31521612"],"confidence":"Medium","gaps":["Ubiquitin ligase targeting PP1α not identified","How ERK activation links to PP1α catalytic substrates unresolved"]},{"year":2019,"claim":"Showed Cavin-3, released from caveolae upon UV stress, binds and inhibits PP1α to promote H2AX phosphorylation and apoptosis, defining a surface-to-nucleus pro-apoptotic relay.","evidence":"Biotin affinity proteomics, MS, cell-free binding, co-IP, UV stress, H2AX phospho-measurement","pmids":["31332168"],"confidence":"High","gaps":["Whether H2AX is a direct PP1α substrate not established","Quantitative contribution of PP1α inhibition to apoptosis not isolated"]},{"year":2019,"claim":"Established MIIP as a positive regulator that enhances PP1α-mediated Akt dephosphorylation, with its tumor-suppressive function dependent on the PP1α-interacting C-terminus.","evidence":"Co-IP, co-localization, Akt phospho-blotting, PP1α siRNA epistasis, MIIPΔC mutants, xenografts","pmids":["31092266"],"confidence":"Medium","gaps":["Akt residue targeted not specified","Direct vs scaffolding role of MIIP not resolved"]},{"year":2021,"claim":"Identified PP1α as a regulator of SRSF1 phosphorylation/localization opposing SRPK1/2, controlling MKNK2 alternative splicing in colon cancer.","evidence":"PP1α activity assays, siRNA knockdown, splicing PCR, IHC, xenografts","pmids":["33602301"],"confidence":"Medium","gaps":["Direct SRSF1 dephosphorylation site by PP1α not mapped","Targeting subunit for SRSF1 not identified"]},{"year":2021,"claim":"Reconstituted a Smad4–MYO18A–PP1A holoenzyme in which MYO18A serves as the RVFFR-motif regulatory subunit directing PP1A to dephosphorylate PAK1-Thr423 and suppress β-catenin nuclear translocation.","evidence":"LC-MS/MS, co-IP, complex reconstitution, RVFFR mutagenesis, PAK1/β-catenin phospho-assays, in vivo functional assays","pmids":["34799729"],"confidence":"High","gaps":["Generalizability of the ternary complex beyond cholangiocarcinoma untested","Structural detail of substrate presentation absent"]},{"year":2021,"claim":"Showed competing interactors reposition PP1α: LACTB displaces PP1A from YAP to increase phospho-YAP, while the noncoding RNA SNORD12B disrupts the 14-3-3ζ–PP1α interaction to drive nuclear relocalization and cytosolic AKT-mTOR activation.","evidence":"Co-IP, subcellular fractionation, YAP/AKT phospho-blotting, RNAi/overexpression, xenografts","pmids":["33675985","33941854"],"confidence":"Medium","gaps":["Quantitative kinetics of competitive displacement not measured","Direct vs indirect AKT regulation upon relocalization not separated"]},{"year":2023,"claim":"Demonstrated arginine methylation of PP1α at R23 by CARM1 reprograms substrate output toward AKT-T450/AMPK-T172 dephosphorylation and glycolytic flux, controlling bone-cell differentiation.","evidence":"In vitro methylation assays, CRISPR KO, lentiviral OE, transcriptomic/metabolomic profiling, AKT/AMPK phospho-blotting","pmids":["37649137"],"confidence":"Medium","gaps":["Mechanism by which R23 methylation alters substrate selectivity unresolved","Whether methylation alters partner binding not tested"]},{"year":2023,"claim":"Established lysine methylation of PP1α at K141 by SUV39H2 as an inhibitory mark that disrupts PP1α–TFEB and PP1α–spinophilin (PPP1R9B) engagement, blocking TFEB dephosphorylation, autophagy, and accelerating senescence.","evidence":"Proteomics, in vitro methylation, co-IP disruption, TFEB phospho/localization assays, CRISPR KO/OE, autophagy assays, IDD animal models","pmids":["37605006"],"confidence":"High","gaps":["Demethylase reversing K141 not identified","Structural basis for K141-dependent partner discrimination unresolved"]},{"year":2023,"claim":"Defined PP1A as the potassium-regulated NCC phosphatase in kidney, directly dephosphorylating NCC with its negative regulator I1 (PPP1R1A) suppressed by dietary potassium, modulating blood pressure.","evidence":"Transcriptomics, direct binding assay, in vivo dephosphorylation in SPAK-constitutively-active mice, high-K diet, blood pressure measurement","pmids":["37676724"],"confidence":"High","gaps":["Targeting subunit directing PP1A to NCC not fully defined","Relative contribution vs PP3/calcineurin not isolated"]},{"year":2024,"claim":"Showed the circPDHK1-encoded peptide PDHK1-241aa relocalizes PPP1CA to the nucleus to relieve cytoplasmic AKT dephosphorylation and activate AKT-mTOR in renal cell carcinoma, a second relocalization-based hijack mechanism.","evidence":"IP-MS, co-IP, immunofluorescence, fractionation, AKT phospho-blotting, ccRCC cell and nude-mouse assays","pmids":["38360682"],"confidence":"Medium","gaps":["AKT residue and direct substrate status not specified","Competition with 14-3-3ζ for PP1α not examined"]},{"year":2024,"claim":"Demonstrated Zika NS2B scaffolds PP1α onto eIF2α to promote dephosphorylation, suppress stress granules, and stabilize PP1α against degradation, mirroring viral subversion of the translational stress response.","evidence":"Co-IP of NS2B-PP1α-eIF2α complex, eIF2α dephosphorylation and stress-granule assays, NS2BV35A mutagenesis, ubiquitination-resistance and viral replication assays, brain organoids","pmids":["38935808"],"confidence":"High","gaps":["Whether NS2B alters PP1α catalytic activity vs only localization unresolved","Host factors competing for PP1α during infection not mapped"]},{"year":2025,"claim":"Identified OTUB1 (recruited by NY-ESO-1) as a second PP1α-stabilizing deubiquitinase whose catalytic, not E2-suppressing, activity prevents PP1α polyubiquitination and drives ERK1/2-dependent metastasis.","evidence":"Ternary-complex co-IP, ubiquitination/deubiquitination assays, PP1α knockdown rescue, ERK1/2 activity, in vivo metastasis assays","pmids":["41053024"],"confidence":"Medium","gaps":["Ubiquitin ligase opposing OTUB1 on PP1α not identified","Link between PP1α accumulation and ERK substrates not mechanistically detailed"]},{"year":2025,"claim":"Showed PP1A dephosphorylates Keap1-Ser104 to disrupt Keap1-Nrf2, upregulating ferroptosis markers and PD-L1 and limiting Lenvatinib-induced ferroptosis in hepatocellular carcinoma.","evidence":"Transcriptomics, ferroptosis metabolite profiling, PP1A knockdown, Keap1-Nrf2 co-IP, PD-L1 blotting, single-cell sequencing, T-cell exhaustion co-culture, in vivo models","pmids":["40344394"],"confidence":"Medium","gaps":["Targeting subunit recruiting PP1A to Keap1 not defined","Direct dephosphorylation of Keap1 vs indirect effect not fully isolated"]},{"year":2025,"claim":"Provided site-resolved kinetics showing PP1α asymmetrically removes AMPK activation-loop phosphorylation while sparing autophosphorylation sites, refining how PP1α shapes AMPK regulatory states.","evidence":"In vitro phosphatase competition assay with integrated bottom-up/top-down MS proteoform analysis (preprint)","pmids":["bio_10.1101_2025.10.10.681638"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Cellular relevance of site selectivity not validated","Regulatory subunit directing AMPK dephosphorylation unknown"]},{"year":null,"claim":"How the combinatorial PTM code (Thr320/Ser325 phosphorylation, R23/K141 methylation, Cys oxidation) is integrated with the >100 possible regulatory subunits to specify substrate choice and localization in any given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking PP1α PTM state to subunit selectivity","Quantitative subunit occupancy in vivo not measured","Reciprocal regulation between localization controllers (14-3-3ζ, PML, RNAs) not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,5,11,14,18,22,32,33]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,5,14,18,22]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,26,27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20,26,27,23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,7,11,28]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[16,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,31,18]}],"complexes":["GADD34/PP1α complex","Smad4-MYO18A-PP1A complex","7SK snRNP","NY-ESO-1/OTUB1/PP1α complex"],"partners":["GADD34","MYO18A","PINCH1","14-3-3Ζ","USP11","OTUB1","PPP1R9B","NACA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62136","full_name":"Serine/threonine-protein phosphatase PP1-alpha catalytic subunit","aliases":[],"length_aa":330,"mass_kda":37.5,"function":"Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets (PubMed:28216226, PubMed:30158517, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670, PubMed:39603239, PubMed:39603240). Protein phosphatase 1 (PP1) is essential for cell division, transcription elongation, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis (PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670, PubMed:39603239, PubMed:39603240). Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Catalytic component of the PNUTS-PP1 protein phosphatase complex, a protein phosphatase 1 (PP1) complex that promotes RNA polymerase II transcription pause-release, allowing transcription elongation: the PNUTS-PP1 complex mediates the release of RNA polymerase II from promoter-proximal region of genes by catalyzing dephosphorylation of proteins involved in transcription, such as AFF4, CDK9, MEPCE, INTS12, NCBP1, POLR2M/GDOWN1 and SUPT6H (PubMed:39603239, PubMed:39603240). The PNUTS-PP1 complex also regulates transcription termination by mediating dephosphorylation of SUPT5H in termination zones downstream of poly(A) sites, thereby promoting deceleration of RNA polymerase II transcription (PubMed:31677974). PNUTS-PP1 complex is also involved in the response to replication stress by mediating dephosphorylation of POLR2A at 'Ser-5' of the CTD, promoting RNA polymerase II degradation (PubMed:33264625). PNUTS-PP1 also plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase (PubMed:20516061). Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage (PubMed:17283141). Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development (By similarity). In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation (PubMed:21712997). May dephosphorylate CSNK1D and CSNK1E (PubMed:21712997). Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Dephosphorylates CENPA (PubMed:25556658). Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy (PubMed:26083323). Together with PPP1CC (PP1-gamma subunit), dephosphorylates IFIH1/MDA5 and RIG-I leading to their activation and a functional innate immune response (PubMed:23499489). Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates the MAPK pathway activation (PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex specifically dephosphorylates the inhibitory phosphorylation at 'Ser-259' of RAF1 kinase, 'Ser-365' of BRAF kinase and 'Ser-214' of ARAF kinase, stimulating their kinase activities (PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c (PubMed:35768504, PubMed:36175670) (Microbial infection) Necessary for alphaviruses replication","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P62136/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP1CA","classification":"Common Essential","n_dependent_lines":857,"n_total_lines":1208,"dependency_fraction":0.7094370860927153},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPP1CA","total_profiled":1310},"omim":[{"mim_id":"620373","title":"ADIPOSE-SECRETED SIGNALING PROTEIN; ADISSP","url":"https://www.omim.org/entry/620373"},{"mim_id":"619541","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 3G; PPP1R3G","url":"https://www.omim.org/entry/619541"},{"mim_id":"619540","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 3E; PPP1R3E","url":"https://www.omim.org/entry/619540"},{"mim_id":"618785","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 2; CDCA2","url":"https://www.omim.org/entry/618785"},{"mim_id":"618159","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 21; PPP1R21","url":"https://www.omim.org/entry/618159"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP1CA"},"hgnc":{"alias_symbol":["PP1A","PP-1A","PP1alpha"],"prev_symbol":["PPP1A"]},"alphafold":{"accession":"P62136","domains":[{"cath_id":"3.60.21.10","chopping":"30-169_249-298","consensus_level":"high","plddt":97.6745,"start":30,"end":298}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62136","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62136-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62136-F1-predicted_aligned_error_v6.png","plddt_mean":91.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP1CA","jax_strain_url":"https://www.jax.org/strain/search?query=PPP1CA"},"sequence":{"accession":"P62136","fasta_url":"https://rest.uniprot.org/uniprotkb/P62136.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62136/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62136"}},"corpus_meta":[{"pmid":"18483222","id":"PMC_18483222","title":"PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18483222","citation_count":154,"is_preprint":false},{"pmid":"31521612","id":"PMC_31521612","title":"USP11 promotes growth and metastasis of colorectal cancer via PPP1CA-mediated activation of ERK/MAPK signaling pathway.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31521612","citation_count":110,"is_preprint":false},{"pmid":"24510127","id":"PMC_24510127","title":"Canonical Wnt signalling activates TAZ through PP1A during osteogenic differentiation.","date":"2014","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24510127","citation_count":96,"is_preprint":false},{"pmid":"32083638","id":"PMC_32083638","title":"Processing of the SARS-CoV pp1a/ab nsp7-10 region.","date":"2020","source":"The Biochemical 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This occurs downstream of Ca2+/PP2B signaling: PP2B first induces a conformational change in 7SK snRNP that enables PP1α access, and PP1α then dephosphorylates Cdk9 Thr186. The released, dephosphorylated P-TEFb is subsequently recruited by Brd4 to the preinitiation complex.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assays, siRNA knockdown, UV/HMBA stimulation of P-TEFb release\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro dephosphorylation assay identifying specific substrate site (Cdk9 T186), reciprocal co-IP, siRNA knockdown with defined phenotypic readout, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18483222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PP1α (PPP1CA) is phosphorylated at Thr-320 by Cdk2 (but not Cdk4) during M-phase and again at the G1/S transition in a pRB-dependent manner. PP1α phosphorylated at Thr-320 co-precipitates with pRB during G1/S but is found in pRB-immunodepleted extracts in M-phase, indicating distinct subpopulations of PP1α regulate different cell cycle transitions. Expression of a T320A phosphorylation-resistant PP1α mutant in pRB-expressing cells causes G1 arrest.\",\n      \"method\": \"In vitro kinase assay with Cdk2/Cdk4, phospho-specific antibodies, co-immunoprecipitation with pRB, inhibitor treatments (Cdk2 inhibitor), cell cycle synchronization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay identifying specific substrate/kinase (Cdk2→PP1α Thr320), co-IP with pRB, mutagenesis (T320A), multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"10506210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PP1α (PPP1CA) associates with caspase-9 in vitro and in vivo in IL-2-proliferating cells. IL-2 deprivation induces PP1α dephosphorylation and activation, leading to dephosphorylation of phospho-Thr125 on caspase-9, thereby activating caspase-9 and subsequent caspase-3 cleavage. PP1α is indispensable for triggering caspase-9 in cell-free systems. Two novel PP1α-binding sites on caspase-9 distinct from the canonical RVxF motif were identified.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro, cell-free caspase activation assays, siRNA knockdown of PP1α, IL-2 deprivation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro co-IP, cell-free reconstitution of caspase activation, siRNA loss-of-function with specific phenotypic readout, identification of novel binding sites\",\n      \"pmids\": [\"16888006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PINCH1 directly binds PP1α and inhibits its phosphatase activity, resulting in increased Akt1 phosphorylation and enhanced cell survival/radioresistance. PP1α acts as an Akt1-dephosphorylating phosphatase that is negatively regulated by PINCH1 at integrin adhesion sites.\",\n      \"method\": \"Direct binding assay (PINCH1-PP1α interaction), PP1α activity assays, Akt1 phosphorylation measurements, siRNA knockdown, in vitro and in vivo irradiation survival assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding established, PP1α enzymatic activity inhibition assay, siRNA knockdown with defined phenotype, in vivo validation\",\n      \"pmids\": [\"20530873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PP1A (PPP1CA) dephosphorylates TAZ during canonical Wnt3a signaling. Wnt3a-induced dephosphorylation of TAZ by PP1A prevents TAZ from binding 14-3-3 proteins, stabilizes TAZ, and induces its nuclear localization, thereby promoting osteoblastic differentiation. Depletion of PP1A blocks Wnt3a-induced TAZ stabilization.\",\n      \"method\": \"siRNA knockdown of PP1A, western blotting for TAZ phosphorylation, co-immunoprecipitation with 14-3-3, nuclear fractionation, osteogenic differentiation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA loss-of-function with specific substrate (TAZ Ser89 dephosphorylation), subcellular localization experiments, functional differentiation readout, multiple orthogonal methods\",\n      \"pmids\": [\"24510127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PP1A (PPP1CA) interacts with and dephosphorylates YAP2 at Serine-127 in vitro and in vivo. PP1A-mediated YAP2 dephosphorylation induces nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadaic acid increases YAP2 phospho-Ser127 and promotes its cytoplasmic retention.\",\n      \"method\": \"Co-immunoprecipitation, in vitro dephosphorylation assay, subcellular fractionation, okadaic acid treatment, YAP2 transcriptional reporter assays, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro dephosphorylation assay, co-IP, subcellular fractionation, pharmacologic inhibition, multiple orthogonal methods identifying specific substrate site\",\n      \"pmids\": [\"21909427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PPP1CA (PP1α) contributes to oncogenic Ras-induced senescence. Loss of PPP1CA function (via antisense RNA or shRNA) bypasses ras/p53-induced growth arrest and senescence. PPP1CA is required for p53-dependent induction of p21 after DNA damage and subsequent pRb dephosphorylation. Oncogenic Ras increases intracellular ceramide levels and PPP1CA protein levels; ceramide-induced senescence is blocked by PPP1CA downregulation.\",\n      \"method\": \"Retroviral genetic screen, shRNA knockdown of PPP1CA, western blotting for p21 and pRb phosphorylation, ceramide addition experiments, tumor growth assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen plus shRNA validation, specific substrate identification (pRb dephosphorylation), ceramide pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"18204081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PP1α (PPP1CA) acts as a B-Raf activating phosphatase in an S6K/PP1α/B-Raf signaling pathway that leads to MAPK activation. PML sequesters PP1α into PML nuclear bodies, repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding, and cytoplasmic accumulation. PPP1CA gene is genomically amplified in metastatic prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, in vitro phosphatase assays, genomic amplification analysis, PML knockdown/overexpression, B-Raf activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphatase assay establishing PP1α→B-Raf dephosphorylation, co-IP for complex members, subcellular localization with functional consequences, pathway epistasis via PML\",\n      \"pmids\": [\"29335436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP11 stabilizes PPP1CA by deubiquitinating it, protecting PPP1CA from proteasome-mediated degradation. The USP11/PPP1CA complex activates the ERK/MAPK signaling pathway to promote colorectal cancer progression.\",\n      \"method\": \"LC-MS/MS interactome, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, siRNA/overexpression experiments, in vitro and in vivo tumor assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP validation of USP11-PPP1CA interaction, ubiquitination/deubiquitination assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"31521612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cavin-3, upon UV-induced release from caveolae, interacts with and inhibits PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, defining a pro-apoptotic signaling pathway from surface caveolae to the nucleus.\",\n      \"method\": \"Biotin affinity proteomics, mass spectrometry, cell-free protein binding assays, co-immunoprecipitation, UV stress experiments, H2AX phosphorylation measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cell-free reconstitution binding assay, validated by co-IP, functional consequence (H2AX phosphorylation, apoptosis), multiple orthogonal methods\",\n      \"pmids\": [\"31332168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PP1A (PPP1CA) dephosphorylates SRSF1, and reduced PP1α activity enhances SRSF1 phosphorylation and nucleus translocation, causing a switch in MKNK2 alternative splicing from MKNK2a to MKNK2b in colon adenocarcinoma. PP1α and SRPK1/2 exert opposing functions balancing SRSF1 phosphorylation and localization.\",\n      \"method\": \"Western blotting, immunohistochemistry, PP1α activity assays, siRNA knockdown, alternative splicing analysis by PCR, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PP1α activity assays, siRNA knockdown with defined splicing phenotype, pathway epistasis with SRPK1/2, single lab\",\n      \"pmids\": [\"33602301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Smad4-MYO18A-PP1A complex dephosphorylates PAK1 at Thr-423. MYO18A functions as the PP1-interacting protein (regulatory subunit) for PP1A substrate recognition in cholangiocarcinoma, binding PP1A via its RVFFR motif and Smad4 via its CC domain. PP1A-mediated PAK1-T423 dephosphorylation inhibits β-catenin-S675 phosphorylation and its nuclear translocation.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, biochemical complex reconstitution, site-directed mutagenesis (RVFFR motif), phosphorylation assays for PAK1 and β-catenin, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — LC-MS/MS plus biochemical validation of ternary complex, mutagenesis of PP1-binding motif, specific substrate site (PAK1-T423) identified, multiple orthogonal methods\",\n      \"pmids\": [\"34799729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CARM1 methylates PPP1CA at Arg-23 (R23). This arginine methylation affects PPP1CA-mediated dephosphorylation of AKT-T450 and AMPK-T172, and increases activities of phosphofructokinase-1 and PFKFB3, upregulating glycolytic flux. This mechanism promotes osteogenic differentiation and inhibits osteoclastic differentiation.\",\n      \"method\": \"In vitro methylation assays (identifying R23 as methylation site), CRISPR/Cas9 knockout, lentiviral overexpression, transcriptomic and metabolomic assays, western blotting for AKT and AMPK phosphorylation\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation assay identifying specific site (R23), CRISPR KO and OE functional validation, single lab\",\n      \"pmids\": [\"37649137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUV39H2 methyltransferase monomethylates PPP1CA at Lys-141 (K141). K141 methylation disrupts PPP1CA's interaction with TFEB and blocks TFEB dephosphorylation and nuclear translocation, leading to autophagy deficiency and nucleus pulposus cell senescence. PPP1R9B (spinophilin) facilitates PPP1CA-TFEB targeting, and K141 methylation also impairs PPP1R9B binding to PPP1CA.\",\n      \"method\": \"Proteomic analysis (identifying SUV39H2 as writer), in vitro methylation assays, co-immunoprecipitation, western blotting for TFEB phosphorylation and localization, CRISPR/KO and overexpression, autophagy assays, animal models of IDD\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro methylation assay, specific modification site (K141), co-IP disruption, TFEB dephosphorylation assay, multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"37605006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PP1A (PPP1CA/Ppp1Ca) directly binds to and dephosphorylates the NaCl cotransporter (NCC) in the kidney in a potassium-regulated manner, reducing blood pressure. Dietary potassium upregulates Ppp1Ca expression and suppresses its negative regulator Ppp1r1a (I1), shifting the balance toward PP1A-mediated NCC dephosphorylation. Confirmed using genetically engineered mice with constitutively active SPAK kinase.\",\n      \"method\": \"Transcriptomics screen, direct binding assay (PP1A-NCC), in vivo dephosphorylation experiments in SPAK-constitutively active transgenic mice, high-potassium dietary intervention, blood pressure measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay, in vivo dephosphorylation of specific substrate (NCC) using genetically engineered mice, identification of regulatory mechanism, replicated across multiple experimental conditions\",\n      \"pmids\": [\"37676724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila URI binds PP1alpha with much higher affinity than PP1beta, and this isoform-discriminating ability is conserved in humans. URI loss-of-function in Drosophila causes transcriptional defects, reduced cell viability, germline differentiation defects, and nuclear DNA damage accumulation.\",\n      \"method\": \"Binding affinity measurements (Drosophila and human URI vs PP1alpha/PP1beta), generation of uri loss-of-function allele, viability assays, transcriptional analysis, DNA damage markers\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding measurements discriminating PP1alpha vs PP1beta, genetic loss-of-function with defined phenotypes, ortholog study with confirmed conservation in humans\",\n      \"pmids\": [\"18412953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PP1α activity is regulated by oxidative stress via formation of transient intramolecular disulfide bonds (involving Cys39 and Cys127), which protect the enzyme from irreversible over-oxidation. Glutathione (GSH) mediates this protection mechanism, reducing PP1α activity under redox stress. The dimerization of PP1α via these cysteines protects the active surface.\",\n      \"method\": \"Mass spectrometry with cross-over-read search for disulfide-linked species, in vitro PP1α activity assays under oxidative conditions, site-specific cysteine analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS identification of disulfide species, in vitro activity assays, single lab, mechanistic characterization of redox regulation\",\n      \"pmids\": [\"30531830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PP1α (PPP1CA), PP1β, and Wip1 phosphatases regulate histone H4 Ser47 phosphorylation (H4S47ph) levels and H3.3 deposition. Depletion of each phosphatase increases H4S47ph. PP1α and PP1β bind H3-H4 in vitro and in vivo and also interact with the Pak2 kinase in vivo, suggesting regulation at the level of both the substrate H4S47 and the kinase Pak2. Depletion of these phosphatases increases H3.3 occupancy and chaperone (HIRA/Daxx) association.\",\n      \"method\": \"siRNA knockdown of PP1α, PP1β, and Wip1; co-immunoprecipitation for H3-H4 and Pak2 binding; ChIP for H3.3 occupancy; western blotting for H4S47ph levels\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for substrate (H3-H4) and kinase (Pak2) interactions, siRNA depletion with H4S47ph readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23828041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The GADD34/PP1α complex dephosphorylates both eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47) in response to arsenite-induced oxidative stress. A GADD34 mutant unable to bind PP1α fails to restore eIF2α or SIRT1 dephosphorylation in GADD34-/- MEFs. SIRT1 dephosphorylation by the GADD34/PP1α complex increases SIRT1 deacetylase activity, affecting cell fate after oxidative stress.\",\n      \"method\": \"Mass spectrometry of GADD34 acetylation, co-immunoprecipitation of GADD34/PP1α/eIF2α/SIRT1 complex, rescue experiments in GADD34-/- MEFs with WT vs PP1α-binding-deficient GADD34 mutant, in vitro and in-cell SIRT1 deacetylase activity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — rescue experiments with PP1α-binding-deficient mutant, in vitro activity assays, specific substrate sites (eIF2α pSer51, SIRT1 pSer47), multiple orthogonal methods in rigorous study\",\n      \"pmids\": [\"28984870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PP1 inhibitor-3 (Inh3) co-localizes with PP1alpha at centrosomes (and with PP1gamma1 at nucleoli) in interphase HEK 293 cells. Inh3 co-immunoprecipitates with PP1alpha and PP1gamma1 but not PP1beta in vitro, demonstrating isoform-specific interactions. The nuclear localization signal and nucleolar targeting signals of Inh3 were mapped by site-directed mutagenesis.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, site-directed mutagenesis of nuclear/nucleolar localization signals, laser scanning cytometry\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating isoform-specific binding, direct co-localization imaging, mutagenesis of targeting signals, single lab\",\n      \"pmids\": [\"16256067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"14-3-3ζ binds PP1α within residues 159–279 in a phosphorylation-independent manner. 14-3-3ζ does not affect PP1α catalytic activity in vitro, but causes cytoplasmic retention of PP1α: cells expressing both PP1α and 14-3-3ζ have a significantly higher cytoplasmic/nuclear PP1α ratio. Expression of dominant-negative 14-3-3ζ (K49E) causes nuclear accumulation of PP1α.\",\n      \"method\": \"Co-immunoprecipitation from HEK-293 lysates, GST pulldown, PP1α deletion mutant mapping, in vitro phosphatase activity assay, subcellular fractionation, dominant-negative 14-3-3ζ expression\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and GST pulldown for binding region, subcellular fractionation for localization, dominant-negative validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24956593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HSV-1 γ34.5 protein targets PP1α to reverse translational arrest (dephosphorylation of eIF2α) during viral infection. HSV-1 carrying a PP1α-binding mutation in γ34.5 shows complete absence of disseminated disease in neonatal mice and increased survival in brain infection models. PP1α targeting by HSV-1 is required for later stages of disseminated infection but not for early replication in visceral organs.\",\n      \"method\": \"Murine neonatal infection model, HSV-1 PP1α-binding mutant virus, type I IFN-deficient mouse rescue experiments, brain slice culture pharmacologic inhibition of eIF2α dephosphorylation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — viral genetic mutant (PP1α-binding mutation in γ34.5) with in vivo disease phenotype, pharmacologic inhibition confirmation, mechanistic epistasis with IFN pathway\",\n      \"pmids\": [\"26621722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PP1A (PPP1CA) directly dephosphorylates NACA (nascent polypeptide-associated complex and co-regulator α) at Thr-89, Ser-151, and Thr-174. NACA interacts with the PPP1CA catalytic subunit and regulatory subunits PPP1R9B, PPP1R12A, and PPP1R18. NACA dephosphorylation promotes nuclear localization of NACA, recruitment of BTF3/BTF3L4, and cooperatively potentiates cJUN/AP-1 transcriptional activity and osteoblast differentiation.\",\n      \"method\": \"Affinity purification-MS (identifying PP1A holoenzyme components), co-immunoprecipitation in HEK293T and MC3T3-E1 cells, phosphosite MS analysis, phosphomimetic and alanine substitution mutants, AP-1 reporter assays, osteogenic differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — AP-MS plus co-IP for complex identification, MS mapping of dephosphorylation sites, phosphomimetic mutagenesis abolishing transcriptional activity, functional osteogenic readout, multiple orthogonal methods\",\n      \"pmids\": [\"30948508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Taperin (C9orf75) preferentially docks the alpha isoform of PP1 over PP1beta via a classic RVxF motif, suppresses the general phosphatase activity of PP1α, and is found complexed to PP1α in both nuclear and cytoplasmic compartments. Taperin shuttles between nucleus and cytoplasm and is recruited to sites of DNA damage, interacting with Ku70, Ku80, PARP and topoisomerases.\",\n      \"method\": \"Biochemical binding assays, co-immunoprecipitation, SILAC MS for interactors, PP1 isoform specificity assays, subcellular fractionation, DNA damage recruitment assays\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay distinguishing PP1alpha from PP1beta, PP1 activity suppression assay, SILAC MS, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23213405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PP1α is a negative regulator of TRPV1 (transient receptor potential vanilloid 1) channel activity. HSV-based coexpression of PP1α rescued viral replication suppressed by TRPV1 in a cell-based screen. In vivo, HSV vectors expressing PP1α reduced thermal sensitivity in rat footpads, demonstrating functional specificity for thermal but not chemical pain modalities.\",\n      \"method\": \"HSV-based cDNA library screen for TRPV1 negative regulators, viral rescue of replication, in vivo rat thermal sensitivity assays\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with in vitro and in vivo validation, single lab, mechanism of TRPV1 regulation not fully defined at biochemical level\",\n      \"pmids\": [\"27382601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LACTB directly binds PP1A and attenuates the interaction between PP1A and YAP, reducing YAP dephosphorylation and increasing phospho-YAP (Ser127), which prevents YAP nuclear translocation in a LATS1-independent manner. This constitutes an SOX10/LACTB/PP1A signaling cascade controlling melanoma progression.\",\n      \"method\": \"Co-immunoprecipitation (LACTB-PP1A and PP1A-YAP interactions), western blotting for YAP phosphorylation, subcellular fractionation, siRNA/overexpression, in vivo xenograft experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing LACTB-PP1A binding and competitive displacement of YAP from PP1A, YAP phosphorylation readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33675985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNORD12B interacts with PP1α, disrupts the interaction between 14-3-3ζ and PP1α, and causes PP1α to relocalize from the cytosol to the nucleus. Nuclear sequestration of PP1α leads to enhanced cytosolic AKT phosphorylation and activation of AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (SNORD12B-PP1α and 14-3-3ζ-PP1α interactions), subcellular fractionation, western blotting for AKT phosphorylation, RNA interference and overexpression, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for RNA-protein and protein-protein interactions, subcellular localization with functional AKT phosphorylation consequence, single lab\",\n      \"pmids\": [\"33941854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The peptide PDHK1-241aa (encoded by circPDHK1) interacts with PPP1CA and causes its relocation to the nucleus. This nuclear relocation of PPP1CA inhibits AKT dephosphorylation and activates the AKT-mTOR signaling pathway to promote clear cell renal cell carcinoma progression.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (identifying PPP1CA as PDHK1-241aa interactor), co-immunoprecipitation, immunofluorescence, subcellular fractionation, AKT phosphorylation western blot, functional assays in ccRCC cells and nude mice\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus co-IP validation, subcellular localization change with functional AKT phosphorylation consequence, single lab with multiple methods; note: circRNA study but mechanism is through encoded peptide interaction with PPP1CA protein\",\n      \"pmids\": [\"38360682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MIIP interacts with PP1α via its C-terminal domain but does not affect PP1α protein level. MIIP interaction with PP1α enhances PP1α-mediated AKT dephosphorylation. Silencing PP1α reverses MIIP's inhibitory effect on AKT phosphorylation and cell growth; MIIPC lacking the PP1α-interacting C-terminus loses MIIP's tumor-suppressive function.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, western blotting for AKT phosphorylation, siRNA knockdown of PP1α, MIIP deletion mutants (MIIP∆C), xenograft assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, deletion mutant mapping of interaction domain, epistasis rescue experiment (PP1α knockdown reverses MIIP effect), single lab\",\n      \"pmids\": [\"31092266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PP1α is phosphorylated by PKC at Ser-325 (in its C-terminal region) in response to B-cell receptor (IgM) stimulation. PP1 activity transiently decreases after B-cell stimulation. PP1alpha undergoes isoform-specific modification (altered isoelectric point pattern on 2D gels) upon BCR stimulation or PMA treatment, while PP1delta does not. The C-terminal peptide of PP1alpha is a better PKC substrate than PP1gamma1/2.\",\n      \"method\": \"2D electrophoresis + western blot, in vitro phosphorylation of C-terminal peptides by PKC with [gamma-32P]ATP, PP1 activity assays, B-cell stimulation model\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro PKC phosphorylation assay identifying specific site (Ser-325), B-cell stimulation model with PP1 activity readout, isoform specificity demonstrated, single lab\",\n      \"pmids\": [\"9399575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Zika virus infection, NS2B acts as a scaffold protein mediating interaction between PP1α and eIF2α. This NS2B-PP1α complex promotes eIF2α dephosphorylation by PP1α, inhibiting stress granule formation and promoting viral replication. The NS2B-PP1α complex is stabilized against ubiquitin-induced degradation. The NS2BV35A mutant interacts only with eIF2α and fails to inhibit stress granule formation.\",\n      \"method\": \"Co-immunoprecipitation of NS2B-PP1α-eIF2α complex, eIF2α dephosphorylation assays, stress granule formation assays, NS2BV35A mutagenesis, ubiquitination resistance assay, viral replication assays, brain organoid experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — complex reconstitution/co-IP, mutagenesis (NS2BV35A) abolishing complex function, dephosphorylation assay, specific functional readout (SG formation and viral replication), multiple orthogonal methods\",\n      \"pmids\": [\"38935808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NY-ESO-1 acts as a scaffold protein recruiting the deubiquitinase OTUB1 to PP1α, forming a ternary NY-ESO-1/OTUB1/PP1α complex. OTUB1 deubiquitinase activity (not its E2-suppressing function) prevents PP1α polyubiquitination and promotes its stability. Accumulated PP1α then activates ERK1/2 signaling to promote anoikis resistance and tumor metastasis.\",\n      \"method\": \"Co-immunoprecipitation of ternary complex, ubiquitination assays, OTUB1 deubiquitinase activity assay, PP1α knockdown rescue experiments, ERK1/2 activity measurements, in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of ternary complex, deubiquitination assay, knockdown epistasis experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41053024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP1A dephosphorylates Keap1 at site Ser104 (site 104), disrupting the Keap1-Nrf2 interaction, enhancing transcription of ferroptosis-related markers and immune checkpoint PD-L1, thereby inhibiting Lenvatinib-induced ferroptosis in hepatocellular carcinoma.\",\n      \"method\": \"Transcriptomic analysis, ferroptosis metabolite profiling (ROS, Fe2+, lipid-ROS, GSH), PP1A knockdown, western blotting for Keap1-Nrf2 interaction, PD-L1 expression, single-cell sequencing, co-culture T-cell exhaustion assays, in vivo tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific substrate site (Keap1 Ser104) identified with functional pathway consequence, PP1A KD experiments, multiple assays in single lab\",\n      \"pmids\": [\"40344394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP1α selectively removes activation-loop phosphorylation from AMPK (dephosphorylating the activation-loop sites) while autophosphorylation sites remain protected, establishing asymmetric phosphatase control of AMPK regulatory states.\",\n      \"method\": \"Phosphatase competition assay (PP1A treatment of phosphorylated AMPK), integrated bottom-up and top-down mass spectrometry for site-specific kinetics, proteoform characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase competition assay with site-specific MS readout, rigorous biochemical characterization, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681638\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PPP1CA (PP1α) is a broadly active serine/threonine phosphatase whose substrate specificity, localization, and activity are tightly controlled by regulatory/targeting subunits and post-translational modifications: it dephosphorylates a diverse array of substrates including Cdk9-Thr186 (releasing P-TEFb from 7SK snRNP), pRb, Akt, eIF2α, caspase-9-Thr125, YAP/TAZ-Ser127, SRSF1, NCC, NACA, PAK1-Thr423, Keap1, and H4S47; its activity is inhibited by Cdk2-mediated phosphorylation at Thr320 (cell cycle), PKC phosphorylation at Ser325 (B-cell signaling), GSH-dependent disulfide formation (redox stress), CARM1-mediated arginine methylation at R23, and SUV39H2-mediated lysine methylation at K141; its subcellular distribution between cytoplasm and nucleus is regulated by 14-3-3ζ (cytoplasmic retention), PML (nuclear sequestration), and various viral/oncogenic proteins; and it is stabilized by deubiquitinases USP11 and OTUB1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP1CA (PP1α) is a broadly acting serine/threonine phosphatase whose substrate selection, subcellular localization, and activity are dictated by interchangeable regulatory/targeting subunits and a layered code of post-translational modifications, allowing one catalytic core to control transcription, cell-cycle progression, survival signaling, the translational stress response, and ion transport [#0, #14, #18]. Its substrate repertoire is dictated by partner-directed targeting: it dephosphorylates Cdk9-Thr186 to release active P-TEFb from the 7SK snRNP downstream of Ca2+/PP2B signaling [#0], caspase-9-Thr125 to license apoptosis upon IL-2 withdrawal [#2], YAP-Ser127 and TAZ to drive Hippo-effector nuclear accumulation [#5, #4], PAK1-Thr423 within a Smad4–MYO18A–PP1A holoenzyme [#11], the NaCl cotransporter NCC in a potassium-regulated manner to modulate blood pressure [#14], NACA to potentiate AP-1 transcription [#22], and eIF2α (via the GADD34/PP1α complex) to restore translation after oxidative stress [#18]. Activity and access to substrates are gated by inhibitory phosphorylation at Thr320 by Cdk2 across cell-cycle transitions [#1] and at Ser325 by PKC during B-cell receptor signaling [#29], by redox-driven intramolecular disulfide formation protected by glutathione [#16], and by CARM1-mediated arginine-23 methylation and SUV39H2-mediated lysine-141 methylation, the latter disrupting PP1α–TFEB and PP1α–spinophilin engagement to impair autophagy [#12, #13]. Nucleocytoplasmic partitioning is set by competing interactors—14-3-3ζ enforces cytoplasmic retention while diverse RNAs, peptides, and viral/oncogenic proteins (SNORD12B, PDHK1-241aa, PML) relocalize the enzyme [#20, #26, #27, #7]—and its abundance is stabilized by the deubiquitinases USP11 and OTUB1, which feed ERK/MAPK-driven tumor progression [#8, #31]. PP1α functions as a regulatory node in oncogenic Ras-induced senescence, requiring PPP1CA for p53/p21-dependent pRb dephosphorylation [#6], and is hijacked by HSV-1 (γ34.5) and Zika virus (NS2B) to dephosphorylate eIF2α and overcome translational arrest during infection [#21, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that PP1α activity is regulated by signal-dependent C-terminal phosphorylation, identifying PKC-Ser325 as an isoform-specific modification linking BCR signaling to transient phosphatase suppression.\",\n      \"evidence\": \"In vitro PKC phosphorylation of C-terminal peptides, 2D electrophoresis, PP1 activity assays in a B-cell stimulation model\",\n      \"pmids\": [\"9399575\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream substrate consequences of Ser325 phosphorylation not defined\", \"Physiological PP1α targets in BCR signaling not mapped\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined Cdk2-mediated Thr320 phosphorylation as a cell-cycle switch creating distinct PP1α subpopulations governing G1/S versus M-phase transitions.\",\n      \"evidence\": \"In vitro kinase assay with Cdk2/Cdk4, phospho-specific antibodies, co-IP with pRB, T320A mutagenesis, cell-cycle synchronization\",\n      \"pmids\": [\"10506210\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct cell-cycle substrates dephosphorylated by the Thr320-controlled pool not enumerated\", \"Phosphatase that reverses Thr320 not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated isoform-selective targeting of PP1α by inhibitor-3 to centrosomes, an early example of regulatory-subunit-driven spatial control distinguishing PP1α from PP1β/γ.\",\n      \"evidence\": \"Immunofluorescence co-localization, co-IP, mutagenesis of nuclear/nucleolar targeting signals in HEK293 cells\",\n      \"pmids\": [\"16256067\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of centrosomal PP1α localization unresolved\", \"Centrosomal substrates not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked PP1α to apoptotic commitment by showing it directly dephosphorylates caspase-9-Thr125 upon survival-signal withdrawal, with novel non-RVxF binding sites on the substrate.\",\n      \"evidence\": \"In vivo/in vitro co-IP, cell-free caspase activation reconstitution, siRNA knockdown in an IL-2 deprivation model\",\n      \"pmids\": [\"16888006\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Regulatory subunit directing PP1α to caspase-9 not identified\", \"Upstream signal activating PP1α after IL-2 withdrawal not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed PP1α as the effector phosphatase that releases active P-TEFb from the 7SK snRNP, connecting Ca2+/PP2B signaling to transcriptional elongation via Cdk9-Thr186 dephosphorylation.\",\n      \"evidence\": \"Co-IP, in vitro phosphatase assays on Cdk9 T186, siRNA knockdown, UV/HMBA stimulation\",\n      \"pmids\": [\"18483222\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Targeting subunit recruiting PP1α to 7SK snRNP not defined\", \"How PP2B-induced conformational change grants PP1α access at structural level unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established PP1α as a positive effector of oncogene-induced senescence, required for p53/p21-driven pRb dephosphorylation and ceramide-mediated growth arrest.\",\n      \"evidence\": \"Retroviral genetic screen, shRNA knockdown, p21/pRb phospho-blotting, ceramide addition, tumor growth assays\",\n      \"pmids\": [\"18204081\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs indirect role of PP1α in pRb dephosphorylation not separated\", \"Mechanism linking ceramide to PP1α activation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated conserved isoform-discriminating binding of URI for PP1α over PP1β, reinforcing that PP1α partner selectivity has functional consequences for transcription and genome stability.\",\n      \"evidence\": \"Binding affinity measurements (Drosophila and human URI), uri loss-of-function allele, viability/transcription/DNA-damage assays\",\n      \"pmids\": [\"18412953\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Human URI–PP1α functional consequences not directly tested\", \"Substrates of the URI–PP1α complex not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PP1α as a Hippo-pathway phosphatase dephosphorylating YAP-Ser127 to drive nuclear accumulation and transcriptional activation, opposing cytoplasmic sequestration.\",\n      \"evidence\": \"Co-IP, in vitro dephosphorylation, subcellular fractionation, okadaic acid treatment, reporter assays, siRNA knockdown\",\n      \"pmids\": [\"21909427\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Regulatory subunit targeting PP1α to YAP not identified\", \"Relationship to LATS kinase signaling not delineated here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined PP1α as an Akt1-dephosphorylating phosphatase at integrin adhesions whose activity is restrained by direct binding of PINCH1, coupling adhesion signaling to survival/radioresistance.\",\n      \"evidence\": \"Direct binding assay, PP1α activity assays, Akt1 phospho-measurement, siRNA knockdown, in vivo irradiation survival\",\n      \"pmids\": [\"20530873\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Akt residue dephosphorylated by PP1α not specified\", \"Generalizability beyond adhesion-site context untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated PP1α in chromatin regulation by showing it binds H3-H4 and the Pak2 kinase and controls histone H4S47 phosphorylation and H3.3 deposition.\",\n      \"evidence\": \"siRNA knockdown, co-IP for H3-H4 and Pak2, ChIP for H3.3 occupancy, H4S47ph blotting\",\n      \"pmids\": [\"23828041\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct dephosphorylation of H4S47 by PP1α not isolated from Pak2 regulation\", \"Targeting subunit for chromatin localization unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PP1α's Hippo-effector role to TAZ during Wnt3a signaling, showing dephosphorylation blocks 14-3-3 binding, stabilizes TAZ, and drives osteoblastic differentiation.\",\n      \"evidence\": \"siRNA knockdown, TAZ phospho-blotting, 14-3-3 co-IP, nuclear fractionation, osteogenic differentiation assays\",\n      \"pmids\": [\"24510127\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Targeting subunit recruiting PP1α to TAZ not identified\", \"Crosstalk with the YAP arm not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established 14-3-3ζ as a phosphorylation-independent cytoplasmic retention factor for PP1α, defining a key node in PP1α nucleocytoplasmic partitioning without affecting catalytic activity.\",\n      \"evidence\": \"Co-IP, GST pulldown, deletion mapping (residues 159-279), in vitro activity assay, subcellular fractionation, dominant-negative 14-3-3ζ (K49E)\",\n      \"pmids\": [\"24956593\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signals that release PP1α from 14-3-3ζ not defined here\", \"Substrate consequences of localization shift not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed redox control of PP1α via reversible intramolecular disulfide formation (Cys39/Cys127) that, under glutathione, protects the enzyme from irreversible over-oxidation while lowering activity.\",\n      \"evidence\": \"Disulfide-targeted mass spectrometry, in vitro activity assays under oxidative conditions, site-specific cysteine analysis\",\n      \"pmids\": [\"30531830\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological redox conditions triggering this in cells not established\", \"Substrate-level consequences not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the GADD34/PP1α complex acts on dual stress substrates—eIF2α-pSer51 and SIRT1-pSer47—coupling translational recovery to SIRT1 deacetylase activation after oxidative stress.\",\n      \"evidence\": \"GADD34 acetylation MS, co-IP of GADD34/PP1α/eIF2α/SIRT1, rescue in GADD34-/- MEFs with PP1α-binding-deficient mutant, deacetylase activity assays\",\n      \"pmids\": [\"28984870\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether SIRT1 is a direct PP1α substrate vs GADD34-bridged not fully separated\", \"Selectivity over CReP-targeted PP1α not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that HSV-1 γ34.5 hijacks PP1α to dephosphorylate eIF2α and reverse translational arrest, with PP1α-binding required for disseminated neonatal disease in vivo.\",\n      \"evidence\": \"Neonatal murine infection, PP1α-binding mutant virus, type I IFN-deficient rescue, brain-slice pharmacologic inhibition\",\n      \"pmids\": [\"26621722\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of γ34.5–PP1α recruitment not detailed\", \"Host eIF2α kinase counteracted not specified in this work\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PP1α as a negative regulator of TRPV1 thermal channel activity, expanding its role to sensory signaling.\",\n      \"evidence\": \"HSV-based cDNA screen, viral replication rescue, in vivo rat thermal sensitivity assays\",\n      \"pmids\": [\"27382601\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Biochemical mechanism of TRPV1 regulation (direct dephosphorylation?) not defined\", \"TRPV1 phosphosite not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped a multi-site PP1α–NACA dephosphorylation event (Thr89, Ser151, Thr174) through a defined holoenzyme (PPP1R9B/R12A/R18) that drives NACA nuclear localization and AP-1 transcriptional potentiation.\",\n      \"evidence\": \"AP-MS of holoenzyme, co-IP, phosphosite MS, phosphomimetic/alanine mutants, AP-1 reporter and osteogenic assays\",\n      \"pmids\": [\"30948508\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which specific regulatory subunit targets NACA in vivo not isolated\", \"Kinase counteracted on NACA not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined deubiquitinase-mediated stabilization of PP1α by USP11, linking PP1α abundance to ERK/MAPK-driven colorectal cancer progression.\",\n      \"evidence\": \"LC-MS/MS interactome, co-IP, ubiquitination assays, proteasome inhibition, in vitro/in vivo tumor assays\",\n      \"pmids\": [\"31521612\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ubiquitin ligase targeting PP1α not identified\", \"How ERK activation links to PP1α catalytic substrates unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Cavin-3, released from caveolae upon UV stress, binds and inhibits PP1α to promote H2AX phosphorylation and apoptosis, defining a surface-to-nucleus pro-apoptotic relay.\",\n      \"evidence\": \"Biotin affinity proteomics, MS, cell-free binding, co-IP, UV stress, H2AX phospho-measurement\",\n      \"pmids\": [\"31332168\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether H2AX is a direct PP1α substrate not established\", \"Quantitative contribution of PP1α inhibition to apoptosis not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established MIIP as a positive regulator that enhances PP1α-mediated Akt dephosphorylation, with its tumor-suppressive function dependent on the PP1α-interacting C-terminus.\",\n      \"evidence\": \"Co-IP, co-localization, Akt phospho-blotting, PP1α siRNA epistasis, MIIPΔC mutants, xenografts\",\n      \"pmids\": [\"31092266\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Akt residue targeted not specified\", \"Direct vs scaffolding role of MIIP not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PP1α as a regulator of SRSF1 phosphorylation/localization opposing SRPK1/2, controlling MKNK2 alternative splicing in colon cancer.\",\n      \"evidence\": \"PP1α activity assays, siRNA knockdown, splicing PCR, IHC, xenografts\",\n      \"pmids\": [\"33602301\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct SRSF1 dephosphorylation site by PP1α not mapped\", \"Targeting subunit for SRSF1 not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted a Smad4–MYO18A–PP1A holoenzyme in which MYO18A serves as the RVFFR-motif regulatory subunit directing PP1A to dephosphorylate PAK1-Thr423 and suppress β-catenin nuclear translocation.\",\n      \"evidence\": \"LC-MS/MS, co-IP, complex reconstitution, RVFFR mutagenesis, PAK1/β-catenin phospho-assays, in vivo functional assays\",\n      \"pmids\": [\"34799729\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Generalizability of the ternary complex beyond cholangiocarcinoma untested\", \"Structural detail of substrate presentation absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed competing interactors reposition PP1α: LACTB displaces PP1A from YAP to increase phospho-YAP, while the noncoding RNA SNORD12B disrupts the 14-3-3ζ–PP1α interaction to drive nuclear relocalization and cytosolic AKT-mTOR activation.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, YAP/AKT phospho-blotting, RNAi/overexpression, xenografts\",\n      \"pmids\": [\"33675985\", \"33941854\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Quantitative kinetics of competitive displacement not measured\", \"Direct vs indirect AKT regulation upon relocalization not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated arginine methylation of PP1α at R23 by CARM1 reprograms substrate output toward AKT-T450/AMPK-T172 dephosphorylation and glycolytic flux, controlling bone-cell differentiation.\",\n      \"evidence\": \"In vitro methylation assays, CRISPR KO, lentiviral OE, transcriptomic/metabolomic profiling, AKT/AMPK phospho-blotting\",\n      \"pmids\": [\"37649137\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which R23 methylation alters substrate selectivity unresolved\", \"Whether methylation alters partner binding not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established lysine methylation of PP1α at K141 by SUV39H2 as an inhibitory mark that disrupts PP1α–TFEB and PP1α–spinophilin (PPP1R9B) engagement, blocking TFEB dephosphorylation, autophagy, and accelerating senescence.\",\n      \"evidence\": \"Proteomics, in vitro methylation, co-IP disruption, TFEB phospho/localization assays, CRISPR KO/OE, autophagy assays, IDD animal models\",\n      \"pmids\": [\"37605006\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Demethylase reversing K141 not identified\", \"Structural basis for K141-dependent partner discrimination unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined PP1A as the potassium-regulated NCC phosphatase in kidney, directly dephosphorylating NCC with its negative regulator I1 (PPP1R1A) suppressed by dietary potassium, modulating blood pressure.\",\n      \"evidence\": \"Transcriptomics, direct binding assay, in vivo dephosphorylation in SPAK-constitutively-active mice, high-K diet, blood pressure measurement\",\n      \"pmids\": [\"37676724\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Targeting subunit directing PP1A to NCC not fully defined\", \"Relative contribution vs PP3/calcineurin not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed the circPDHK1-encoded peptide PDHK1-241aa relocalizes PPP1CA to the nucleus to relieve cytoplasmic AKT dephosphorylation and activate AKT-mTOR in renal cell carcinoma, a second relocalization-based hijack mechanism.\",\n      \"evidence\": \"IP-MS, co-IP, immunofluorescence, fractionation, AKT phospho-blotting, ccRCC cell and nude-mouse assays\",\n      \"pmids\": [\"38360682\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"AKT residue and direct substrate status not specified\", \"Competition with 14-3-3ζ for PP1α not examined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated Zika NS2B scaffolds PP1α onto eIF2α to promote dephosphorylation, suppress stress granules, and stabilize PP1α against degradation, mirroring viral subversion of the translational stress response.\",\n      \"evidence\": \"Co-IP of NS2B-PP1α-eIF2α complex, eIF2α dephosphorylation and stress-granule assays, NS2BV35A mutagenesis, ubiquitination-resistance and viral replication assays, brain organoids\",\n      \"pmids\": [\"38935808\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether NS2B alters PP1α catalytic activity vs only localization unresolved\", \"Host factors competing for PP1α during infection not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified OTUB1 (recruited by NY-ESO-1) as a second PP1α-stabilizing deubiquitinase whose catalytic, not E2-suppressing, activity prevents PP1α polyubiquitination and drives ERK1/2-dependent metastasis.\",\n      \"evidence\": \"Ternary-complex co-IP, ubiquitination/deubiquitination assays, PP1α knockdown rescue, ERK1/2 activity, in vivo metastasis assays\",\n      \"pmids\": [\"41053024\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ubiquitin ligase opposing OTUB1 on PP1α not identified\", \"Link between PP1α accumulation and ERK substrates not mechanistically detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PP1A dephosphorylates Keap1-Ser104 to disrupt Keap1-Nrf2, upregulating ferroptosis markers and PD-L1 and limiting Lenvatinib-induced ferroptosis in hepatocellular carcinoma.\",\n      \"evidence\": \"Transcriptomics, ferroptosis metabolite profiling, PP1A knockdown, Keap1-Nrf2 co-IP, PD-L1 blotting, single-cell sequencing, T-cell exhaustion co-culture, in vivo models\",\n      \"pmids\": [\"40344394\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Targeting subunit recruiting PP1A to Keap1 not defined\", \"Direct dephosphorylation of Keap1 vs indirect effect not fully isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided site-resolved kinetics showing PP1α asymmetrically removes AMPK activation-loop phosphorylation while sparing autophosphorylation sites, refining how PP1α shapes AMPK regulatory states.\",\n      \"evidence\": \"In vitro phosphatase competition assay with integrated bottom-up/top-down MS proteoform analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.10.681638\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Cellular relevance of site selectivity not validated\", \"Regulatory subunit directing AMPK dephosphorylation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the combinatorial PTM code (Thr320/Ser325 phosphorylation, R23/K141 methylation, Cys oxidation) is integrated with the >100 possible regulatory subunits to specify substrate choice and localization in any given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model linking PP1α PTM state to subunit selectivity\", \"Quantitative subunit occupancy in vivo not measured\", \"Reciprocal regulation between localization controllers (14-3-3ζ, PML, RNAs) not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 5, 11, 14, 18, 22, 32, 33]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 5, 14, 18, 22]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 26, 27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20, 26, 27, 23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 7, 11, 28]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 31, 18]}\n    ],\n    \"complexes\": [\n      \"GADD34/PP1\\u03b1 complex\",\n      \"Smad4-MYO18A-PP1A complex\",\n      \"7SK snRNP\",\n      \"NY-ESO-1/OTUB1/PP1\\u03b1 complex\"\n    ],\n    \"partners\": [\n      \"GADD34\",\n      \"MYO18A\",\n      \"PINCH1\",\n      \"14-3-3\\u03b6\",\n      \"USP11\",\n      \"OTUB1\",\n      \"PPP1R9B\",\n      \"NACA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}