{"gene":"PPP1CC","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"PP1γ dynamically relocalizes throughout the mammalian cell cycle: it accumulates in nucleoli during interphase, localizes to kinetochores in early mitosis (with rapid exchange with the cytoplasmic pool), redistributes to chromosome-containing regions at the early-to-late anaphase transition, and accumulates at the cleavage furrow and midbody by telophase, implicating it in nucleolar function, chromosome segregation, and cytokinesis.","method":"Stable HeLa cell lines expressing FP-PP1γ fusion proteins; time-lapse fluorescence imaging; FRAP","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with stable cell lines, FRAP for dynamics, multiple cell-cycle stages examined in one rigorous study","pmids":["12529430"],"is_preprint":false},{"year":2007,"finding":"URI forms stable complexes with PP1γ at mitochondria in growth-factor-deprived or rapamycin-treated cells, inhibiting the bound PP1γ activity. S6K1-mediated phosphorylation of URI at serine 371 upon growth factor stimulation disassembles the URI/PP1γ complex, releasing active PP1γ that then dephosphorylates and reduces S6K1 activity and BAD phosphorylation, thus activating a negative feedback loop that lowers the threshold for apoptosis.","method":"Co-immunoprecipitation, in vitro phosphatase activity assays, phosphospecific antibodies, S6K1 kinase assays, rapamycin treatment, MS identification","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro assays, mutagenesis of URI-S371, MS) in a single rigorous study with clear mechanistic dissection","pmids":["17936702"],"is_preprint":false},{"year":2011,"finding":"Plk1 phosphorylates Mst2 to prevent assembly of Nek2A–PP1γ–Mst2 complexes. In the absence of Plk1 phosphorylation of Mst2, PP1γ is recruited into the complex via Mst2 and counteracts Nek2A kinase activity (opposing centrosome disjunction). Plk1-phosphorylated Mst2 cannot bind PP1γ, thus allowing Nek2A activity to proceed and drive centrosome disjunction.","method":"Co-immunoprecipitation, kinase assays, Plk1 inhibitor/depletion, Mst2 phosphorylation-site mutants, centrosome separation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phosphomutant analysis, and functional centrosome-disjunction readout in one study","pmids":["21723128"],"is_preprint":false},{"year":1993,"finding":"Alternative splicing of the PPP1CC gene produces two PP1γ isoforms (PP1γ1 and PP1γ2) that differ at their C-termini. The gene was mapped to human chromosome 12q24.1–q24.2, distinct from the PP1α locus on chromosome 11.","method":"cDNA cloning from human teratocarcinoma library; somatic cell hybrid DNA analysis; in situ hybridization (FISH)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cDNA sequencing and chromosomal mapping; foundational structural characterization replicated by later chromosomal assignment studies","pmids":["8394140"],"is_preprint":false},{"year":1997,"finding":"Both PP1γ1 and PP1γ2 isoforms encoded by Ppp1cc retain phosphatase function, as demonstrated by their ability to complement the cold-sensitive PP1 defect (dis2-11 mutation) in fission yeast S. pombe.","method":"Complementation of fission yeast dis2-11 cold-sensitive mutant; Southern hybridization; FISH mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in yeast is a direct activity assay; single-lab study with clear genetic readout","pmids":["9339378"],"is_preprint":false},{"year":2007,"finding":"Targeted disruption of Ppp1cc in mice causes male infertility due to impaired spermiogenesis; PP1γ2 is the predominant isoform in spermatids and spermatozoa, and its loss produces malformed mitochondrial sheaths and extra outer dense fibers in sperm tails, implicating PP1γ2 in sperm tail morphogenesis in addition to motility.","method":"Ppp1cc knockout mice; isoform-specific immunohistochemistry; electron microscopy of sperm ultrastructure","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with ultrastructural phenotypic analysis; replicated in principle by multiple subsequent studies","pmids":["17301292"],"is_preprint":false},{"year":2009,"finding":"Transgenic expression of PPP1CC2 alone in Ppp1cc-null testes rescues spermatid viability and spermiation (anti-apoptotic effect) but fails to restore normal flagellar morphogenesis, sperm motility, or fertility, indicating that both PPP1CC isoforms are required for structurally normal spermatogenesis.","method":"Transgenic rescue experiment in Ppp1cc-/- mice; sperm morphology and motility analysis; fertility testing","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic rescue with isoform-specific construct, multiple functional readouts","pmids":["19420386"],"is_preprint":false},{"year":2010,"finding":"Loss of PP1γ in Ppp1cc knockout mice produces acrosomal defects and chromatin condensation defects in elongating spermatids, while junction complexes remain ultrastructurally normal, localizing PP1γ function to acrosome development and chromatin compaction during spermiogenesis.","method":"Light and electron microscopy of Ppp1cc knockout seminiferous epithelium; stage-specific analysis","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with electron microscopy phenotype; single-lab study","pmids":["20385779"],"is_preprint":false},{"year":2012,"finding":"PP1γ directly interacts with the SMN complex component Gemin8; PP1γ depletion by RNAi leads to hyperphosphorylation of SMN (revealed by 2D gel electrophoresis) and enhanced localization of the SMN complex and snRNPs to Cajal bodies, demonstrating that PP1γ dephosphorylates SMN to regulate SMN complex assembly and subnuclear localization.","method":"Co-immunoprecipitation from HeLa extracts, in vitro protein binding assays, RNAi knockdown, 2D gel electrophoresis, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP + in vitro binding + RNAi phenotype + 2D phospho-analysis in one study","pmids":["22454514"],"is_preprint":false},{"year":2013,"finding":"PP1γ is a direct interacting partner of hScrib (via a conserved PP1γ interaction motif on hScrib); this interaction is required for hScrib-mediated downregulation of ERK phosphorylation and for hScrib's ability to suppress oncogene-induced transformation. Loss of hScrib enhances nuclear translocation of PP1γ.","method":"Proteomic/mass spectrometry identification, co-immunoprecipitation, in vitro binding assays, ERK phosphorylation assays, oncogenic transformation assays, immunofluorescence","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated in vitro, functional rescue with motif mutants, multiple orthogonal readouts","pmids":["23359326"],"is_preprint":false},{"year":2013,"finding":"PP1γ (but not PP1α or PP1β) specifically enhances alternative splicing of CaMKIIδ by interacting with the splicing factor ASF; PP1γ overexpression or inhibition respectively promotes or suppresses CaMKIIδ splicing and associated cardiomyocyte apoptosis in OGD/R conditions.","method":"Co-immunoprecipitation of ASF-PP1γ, splicing reporter assays, PP1γ overexpression/siRNA in HEK293T and primary cardiomyocytes, pharmacological PP1 inhibition","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue; isoform specificity established; single-lab study","pmids":["24196533"],"is_preprint":false},{"year":2013,"finding":"Germ-cell-specific deletion of Ppp1cc (using Stra8-Cre) phenocopies global knockout, confirming that PPP1CC2 function in meiotic and postmeiotic germ cells is the critical determinant of male fertility; PPP1CC2 is the only PP1 isoform absent from Sertoli cells and spermatogonia but present in postmeiotic germ cells.","method":"Conditional (Stra8-Cre) Ppp1cc knockout mice; isoform-specific immunostaining; fertility assessment; sperm analysis","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout with precise cell-type mapping and fertility phenotyping, replicating global KO in same study","pmids":["24089200"],"is_preprint":false},{"year":2014,"finding":"PP1γ physically interacts with TRAF6 and enhances TRAF6 E3 ubiquitin ligase activity toward itself and substrates such as IKKγ, thereby promoting NF-κB-mediated innate immune signaling; enzymatically inactive PP1γ represses these events.","method":"Gain-of-function genetic screen, co-immunoprecipitation, ubiquitination assays with wild-type and catalytically inactive PP1γ, macrophage/monocyte innate immune activation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus catalytic-mutant analysis plus functional immune-response assay; single-lab study","pmids":["24586659"],"is_preprint":false},{"year":2016,"finding":"NEK1 phosphorylates PP1γ; phosphorylated PP1γ in turn dephosphorylates WAPL, retaining WAPL on chromosome cores to promote cohesin removal along chromosome arms during meiotic prophase I. This NEK1–PP1γ–WAPL axis operates through NEK1 interaction with PDS5B.","method":"Co-immunoprecipitation, phosphorylation assays, Nek1 knockout mice meiotic chromosome analysis, immunofluorescence of cohesin/WAPL localization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO phenotype plus Co-IP and phosphorylation assays; single-lab study","pmids":["27760328"],"is_preprint":false},{"year":2018,"finding":"α7 nicotinic acetylcholine receptor (α7nAChR) interacts with PP1γ in hepatocellular carcinoma cells; ligand-bound α7nAChR facilitates PP1γ-dependent ubiquitination and activation of TRAF6, leading to IκBα degradation, NF-κB nuclear accumulation, and upregulation of Cyclin D1 and PCNA.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, NF-κB reporter assays, proliferation assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and functional knockdown rescue; multiple pathway readouts; single-lab study","pmids":["30074282"],"is_preprint":false},{"year":2020,"finding":"Aurora B phosphorylates the PP1γ regulatory subunit Repo-Man to disrupt the PP1γ–Repo-Man interaction on chromatin, causing PP1γ dissociation from mitotic chromosomes; this dissociation is required to maintain the high chromatin phosphorylation state during mitosis. Repo-Man phosphorylation-site mutants or Aurora B inhibition retain PP1γ on chromatin and prolong chromosome condensation.","method":"Co-immunoprecipitation, immunofluorescence microscopy, Aurora B inhibitor treatment, Repo-Man phosphomutant overexpression, ectopic PP1γ targeting constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphomutant analysis plus functional chromatin-condensation readout; single-lab study","pmids":["32938714"],"is_preprint":false},{"year":2021,"finding":"PPP1R3G recruits PP1γ to RIPK1-containing complex I, where PP1γ removes inhibitory phosphorylations on RIPK1 (including serine 25), activating RIPK1 kinase activity and enabling apoptosis and necroptosis. A PPP1R3G mutant unable to bind PP1γ fails to rescue RIPK1 activation. Ppp1r3g-/- mice are protected from TNF-induced systemic inflammatory response syndrome.","method":"CRISPR whole-genome knockout screen, co-immunoprecipitation, phosphospecific antibodies for RIPK1-S25, PPP1R3G binding-mutant rescue, Ppp1r3g-/- mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen followed by mechanistic validation with mutants, in vivo mouse model, and multiple orthogonal methods in one study","pmids":["34862394"],"is_preprint":false},{"year":2022,"finding":"PP1γ is constitutively associated with HDAC1; the HDAC1/PP1γ complex dephosphorylates CREB at Ser133 during dopaminergic neurodegeneration, inactivating CREB and reducing expression of its target NURR1. CREB interacts with the HDAC1/PP1γ complex in PD, and disrupting CREB/HDAC1 interaction restores phospho-CREB and NURR1 levels.","method":"Co-immunoprecipitation, proximity ligation assay (PD patient tissue), MPTP mouse model, phosphospecific CREB-S133 antibodies, HDAC inhibitor (trichostatin A) treatment, GAL4-M1 CREB mutant overexpression","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, proximity ligation in human PD tissue, mouse disease model, pharmacological and genetic rescue; multiple orthogonal methods","pmids":["35501151"],"is_preprint":false},{"year":2022,"finding":"PP1γ (but not PP1α) and inhibitor-2 (I-2) positively regulate synaptic transmission in hippocampal neurons; I-2 enhances PP1γ interaction with its synaptic scaffold neurabin (measured by FRET/FLIM), and I-2 threonine-72 phosphorylation dictates its in vivo effect on PP1 activity.","method":"Electrophysiology in hippocampal neurons, FRET/FLIM to measure PP1γ–neurabin interaction, I-2 phosphorylation-site mutants, isoform-specific knockdown","journal":"Frontiers in synaptic neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET/FLIM plus electrophysiology plus phosphomutant analysis; single-lab study","pmids":["36276179"],"is_preprint":false},{"year":2023,"finding":"PP1γ (but not PP1α) regulates neuronal insulin signaling by dephosphorylating AKT2, modulating the AKT2–AS160–GLUT4 axis and GLUT4 translocation; it also regulates GSK3β phosphorylation via AKT2, and GSK3α phosphorylation via MLK3, with imbalance producing an Alzheimer's disease-like phenotype.","method":"siRNA knockdown of PP1α and PP1γ in N2a and SH-SY5Y cells, western blot for phospho-AKT2/AS160/GSK3, confocal microscopy for GLUT4 translocation, fluorescence-based glucose uptake assay, high-fat-diet diabetic mouse model brain lysates","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — isoform-specific siRNA with multiple phosphoprotein readouts and glucose metabolism assays; single-lab study","pmids":["37085815"],"is_preprint":false},{"year":2024,"finding":"gp78 E3 ubiquitin ligase degrades PPP1CC (and PPP2CA) via ubiquitination, thereby preventing dephosphorylation of KAP1 and promoting DNA damage repair and radioresistance in breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, western blot for phospho-KAP1, PPP1CC overexpression/knockdown, radiation survival assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay plus phospho-KAP1 readout plus functional radioresistance assay; single-lab study","pmids":["39297166"],"is_preprint":false},{"year":2025,"finding":"PPP1CC (Drosophila ortholog Pp1-87B) dephosphorylates substrates to suppress JNK signaling via the Moe-Rho1 axis; impaired Pp1-87B/PPP1CC activates JNK, which integrates apoptosis and ferroptosis-like cell death through Hippo pathway activation. In human liver tumor cells, PPP1CC similarly drives apoptosis and ferroptosis via JNK activation.","method":"Drosophila genetic screen, epistasis analysis (double mutants), human liver cancer cell overexpression/knockdown, JNK pathway reporters, cell death assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila plus functional validation in human tumor cells; single-lab study","pmids":["40906558"],"is_preprint":false},{"year":2025,"finding":"PPP1CC dephosphorylates YAP in outer cells of the mouse morula, promoting YAP nuclear translocation and trophectoderm (TE) lineage specification. PPP1CC localization to the TE is spatially restricted by its interaction with the lncRNA GAS5, which localizes to the subcortical region throughout early embryogenesis.","method":"PPP1CC knockdown in preimplantation mouse embryos, immunofluorescence for phospho-YAP and YAP localization, GAS5 knockdown/overexpression, blastomere fate tracing","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus rescue with YAP phosphorylation readout in mouse embryos; single-lab study","pmids":["41403070"],"is_preprint":false},{"year":2025,"finding":"PP1γ promotes ESCC progression by dephosphorylating YAP1, leading to reduced p-YAP1/YAP1 ratio, YAP1 activation, and upregulation of SOX2; silencing PPP1CC increases p-YAP1 and reduces SOX2, suppressing proliferation, migration, and invasion.","method":"PPP1CC siRNA knockdown in KYSE150 cells, western blot for p-YAP1/YAP1/SOX2, CCK-8 proliferation assay, colony formation, Transwell invasion/migration assays","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab knockdown study with downstream phosphoprotein readouts, no direct phosphatase-substrate interaction demonstrated","pmids":["40626009"],"is_preprint":false},{"year":2026,"finding":"PP1γ2 (testis-enriched isoform of PPP1CC) interacts with novel testicular partners including PIHI1D1 (part of the R2TP chaperone complex) and ZFR, NDUFB10, ILF2 (predicted via the C-terminal PP1γ2-specific sequence), as well as with SRPK1 interactome members ILF2 and TBLX1R1, suggesting additional roles in splicing, gene expression, and sperm formation.","method":"Immunoprecipitation followed by LC-MS/MS (testis tissue)","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown-MS experiment with no functional follow-up for most interactions; single-lab study","pmids":["41913519"],"is_preprint":false}],"current_model":"PPP1CC (PP1γ) is a serine/threonine phosphatase catalytic subunit that dynamically relocalizes throughout the cell cycle (nucleolus → kinetochores → chromosomes → cleavage furrow) and acts at multiple signaling nodes: it dephosphorylates RIPK1 (via PPP1R3G-mediated recruitment) to activate apoptosis/necroptosis, dephosphorylates CREB-Ser133 within an HDAC1 complex to regulate neuronal survival, counteracts Nek2A kinase activity at centrosomes under Plk1 control, is released from inhibitory URI complexes at mitochondria by S6K1 to create a negative feedback loop, dephosphorylates YAP to regulate Hippo signaling and trophectoderm specification, regulates cohesin removal during meiosis via a NEK1–PP1γ–WAPL axis, and in the testis the alternatively spliced PP1γ2 isoform is indispensable for spermiogenesis, chromatin condensation, acrosome development, and sperm motility."},"narrative":{"mechanistic_narrative":"PPP1CC encodes PP1γ, a serine/threonine protein phosphatase catalytic subunit whose specificity and subcellular targeting are dictated by interchangeable regulatory/scaffold partners, allowing it to act at distinct cell-cycle, signaling, and developmental nodes [PMID:12529430, PMID:21723128]. Across the mammalian cell cycle PP1γ dynamically relocalizes from nucleoli through kinetochores and chromosomes to the cleavage furrow [PMID:12529430], and its association with mitotic chromatin via the Repo-Man regulatory subunit is reversed by Aurora B phosphorylation to sustain the mitotic chromatin phosphorylation state [PMID:32938714]. At centrosomes it is recruited through Mst2 into a Nek2A–PP1γ complex that opposes centrosome disjunction, an assembly blocked by Plk1 phosphorylation of Mst2 [PMID:21723128], and in meiotic prophase NEK1-phosphorylated PP1γ dephosphorylates WAPL to drive cohesin removal [PMID:27760328]. PP1γ also dephosphorylates targeted substrates in diverse pathways: it is released from inhibitory mitochondrial URI complexes by S6K1 phosphorylation to set up an apoptotic negative-feedback loop [PMID:17936702], is recruited by PPP1R3G to dephosphorylate RIPK1 and license apoptosis/necroptosis [PMID:34862394], dephosphorylates CREB-Ser133 within an HDAC1 complex during dopaminergic neurodegeneration [PMID:35501151], and dephosphorylates YAP to control Hippo-dependent trophectoderm specification and tumor progression [PMID:41403070, PMID:40626009]. Additional substrate/partner relationships place PP1γ in SMN complex assembly via Gemin8 [PMID:22454514], ERK suppression via hScrib [PMID:23359326], and neuronal insulin signaling via AKT2 [PMID:37085815]. The gene generates two alternatively spliced isoforms, PP1γ1 and PP1γ2, both catalytically active [PMID:8394140, PMID:9339378]; the testis-enriched PP1γ2 is indispensable for spermiogenesis, with knockout mice showing chromatin condensation, acrosome, and flagellar defects and male infertility [PMID:17301292, PMID:20385779, PMID:24089200].","teleology":[{"year":1993,"claim":"Establishing that PPP1CC is a distinct PP1 gene generating two C-terminally divergent isoforms defined the molecular substrate for all later isoform-specific biology.","evidence":"cDNA cloning from a human teratocarcinoma library and chromosomal mapping by somatic cell hybrid and FISH analysis","pmids":["8394140"],"confidence":"High","gaps":["Did not establish functional differences between PP1γ1 and PP1γ2","No tissue-specific expression pattern defined"]},{"year":1997,"claim":"Demonstrating both isoforms are catalytically competent confirmed that alternative splicing alters targeting rather than abolishing phosphatase activity.","evidence":"Complementation of the fission yeast dis2-11 cold-sensitive PP1 mutant","pmids":["9339378"],"confidence":"Medium","gaps":["Yeast complementation does not reveal mammalian substrate specificity","Does not address isoform-specific regulatory partners"]},{"year":2003,"claim":"Mapping the dynamic cell-cycle relocalization of PP1γ placed the phosphatase at successive mitotic structures, framing it as a regulator of segregation and cytokinesis.","evidence":"Live-cell time-lapse imaging and FRAP of FP-PP1γ in stable HeLa lines","pmids":["12529430"],"confidence":"High","gaps":["Localization alone did not identify the targeting subunits driving each relocalization","No substrate dephosphorylated at each site identified"]},{"year":2007,"claim":"Identifying URI as an inhibitory mitochondrial partner released by S6K1 phosphorylation revealed how PP1γ activity is switched on to drive an apoptotic feedback loop, and a germline knockout established its essential role in spermiogenesis.","evidence":"Co-IP, in vitro phosphatase assays and URI-S371 mutagenesis (mitochondrial complex); Ppp1cc knockout mice with sperm ultrastructure EM","pmids":["17936702","17301292"],"confidence":"High","gaps":["URI study did not resolve whether other regulatory subunits compete for the same pool","Knockout did not distinguish PP1γ1 vs PP1γ2 contributions in vivo"]},{"year":2011,"claim":"Resolving the Plk1–Mst2–Nek2A–PP1γ circuit showed PP1γ is recruited via Mst2 to oppose centrosome disjunction, with Plk1 acting as the switch that excludes it.","evidence":"Reciprocal Co-IP, kinase assays, Mst2 phosphomutants and centrosome separation assays","pmids":["21723128"],"confidence":"High","gaps":["Direct Nek2A substrate dephosphorylated by PP1γ not defined","Quantitative contribution to disjunction timing unresolved"]},{"year":2009,"claim":"Isoform-specific transgenic rescue showed PP1γ2 alone restores spermatid viability but not flagellar morphogenesis, establishing non-redundant requirements for both isoforms in spermatogenesis.","evidence":"Transgenic PPP1CC2 rescue in Ppp1cc-null mice with morphology, motility and fertility readouts","pmids":["19420386"],"confidence":"High","gaps":["Substrates underlying flagellar morphogenesis not identified","Mechanism of the anti-apoptotic effect on spermatids unresolved"]},{"year":2010,"claim":"Stage-specific phenotyping localized PP1γ function to acrosome development and chromatin compaction in elongating spermatids.","evidence":"Light and electron microscopy of Ppp1cc knockout seminiferous epithelium","pmids":["20385779"],"confidence":"Medium","gaps":["No molecular substrate of chromatin condensation identified","Single-lab study"]},{"year":2012,"claim":"Linking PP1γ to the SMN complex through Gemin8 added a role in regulating SMN phosphorylation and subnuclear assembly.","evidence":"Reciprocal Co-IP, in vitro binding, RNAi and 2D phospho-gel analysis in HeLa cells","pmids":["22454514"],"confidence":"High","gaps":["Direct SMN phospho-site dephosphorylated not mapped","Physiological consequence for snRNP biogenesis not assayed"]},{"year":2013,"claim":"Three independent studies expanded PP1γ's isoform-specific partnerships — hScrib for ERK suppression and tumor restraint, ASF for CaMKIIδ splicing, and confirmation that germ-cell PP1γ2 alone dictates fertility.","evidence":"MS/Co-IP and motif-mutant binding (hScrib); Co-IP and splicing reporters (ASF/CaMKIIδ); Stra8-Cre conditional Ppp1cc knockout (germ cells)","pmids":["23359326","24196533","24089200"],"confidence":"High","gaps":["hScrib- and ASF-directed substrates not biochemically defined","Whether these signaling roles use PP1γ1 or PP1γ2 not fully resolved"]},{"year":2014,"claim":"PP1γ was shown to enhance TRAF6 E3 ligase activity and NF-κB innate immune signaling, an effect dependent on catalytic activity.","evidence":"Gain-of-function screen, Co-IP, ubiquitination assays with catalytically inactive PP1γ, immune activation assays","pmids":["24586659"],"confidence":"Medium","gaps":["Phosphatase substrate controlling TRAF6 activity unidentified","Single-lab study"]},{"year":2016,"claim":"Defining the NEK1–PP1γ–WAPL axis showed PP1γ phosphorylation by NEK1 enables WAPL dephosphorylation to drive meiotic cohesin removal.","evidence":"Co-IP, phosphorylation assays and Nek1 knockout mouse meiotic chromosome analysis","pmids":["27760328"],"confidence":"Medium","gaps":["WAPL phospho-sites targeted not mapped","Single-lab study"]},{"year":2018,"claim":"An α7nAChR–PP1γ interaction was shown to feed the TRAF6/NF-κB axis to promote hepatocellular carcinoma proliferation.","evidence":"Co-IP, siRNA, ubiquitination and NF-κB reporter assays in HCC cells","pmids":["30074282"],"confidence":"Medium","gaps":["Direct PP1γ substrate in the pathway undefined","Single-lab cancer-cell study"]},{"year":2020,"claim":"Showing Aurora B phosphorylates Repo-Man to evict PP1γ from mitotic chromatin explained how the chromatin phosphorylation state is held high during mitosis.","evidence":"Co-IP, Repo-Man phosphomutants, Aurora B inhibition and ectopic PP1γ targeting constructs","pmids":["32938714"],"confidence":"Medium","gaps":["Chromatin substrates kept phosphorylated not enumerated","Single-lab study"]},{"year":2021,"claim":"A genome-wide screen identified PPP1R3G as the targeting subunit that recruits PP1γ to dephosphorylate inhibitory RIPK1 phospho-sites and license apoptosis/necroptosis.","evidence":"CRISPR screen, Co-IP, RIPK1-S25 phospho-antibodies, binding-mutant rescue and Ppp1r3g knockout mice","pmids":["34862394"],"confidence":"High","gaps":["Full set of RIPK1 sites dephosphorylated not exhaustively mapped","Crosstalk with URI-controlled apoptotic pool not addressed"]},{"year":2022,"claim":"Two studies placed PP1γ in neuronal regulation — within an HDAC1/PP1γ complex that dephosphorylates CREB-Ser133 in dopaminergic neurodegeneration, and in isoform-specific control of synaptic transmission via I-2 and neurabin.","evidence":"Co-IP, proximity ligation in PD tissue, MPTP mouse model (CREB); electrophysiology and FRET/FLIM with I-2 phosphomutants (synapse)","pmids":["35501151","36276179"],"confidence":"High","gaps":["How HDAC1 complex assembly is regulated in disease unresolved","Synaptic substrate set of PP1γ not defined"]},{"year":2023,"claim":"PP1γ was shown to specifically regulate neuronal insulin signaling by dephosphorylating AKT2, tying PP1γ imbalance to an Alzheimer's-like phenotype.","evidence":"Isoform-specific siRNA, phospho-AKT2/AS160/GSK3 westerns, GLUT4 imaging and high-fat-diet mouse brain lysates","pmids":["37085815"],"confidence":"Medium","gaps":["Direct AKT2 phospho-site dephosphorylated not mapped","Single-lab study"]},{"year":2024,"claim":"Identifying gp78-mediated ubiquitin degradation of PPP1CC as a control on KAP1 dephosphorylation linked PP1γ turnover to DNA damage repair and radioresistance.","evidence":"Co-IP, ubiquitination assays, phospho-KAP1 westerns and radiation survival assays in breast cancer cells","pmids":["39297166"],"confidence":"Medium","gaps":["Whether KAP1 is a direct PP1γ substrate not demonstrated","Single-lab study"]},{"year":2025,"claim":"Multiple 2025 studies converged on PP1γ as a YAP/Hippo regulator — driving trophectoderm specification via GAS5-restricted localization, promoting ESCC progression through YAP1/SOX2, and integrating JNK-dependent apoptosis/ferroptosis.","evidence":"Embryo knockdown with phospho-YAP imaging and GAS5 manipulation; ESCC siRNA with p-YAP1/SOX2 readouts; Drosophila epistasis and human liver tumor cell assays","pmids":["41403070","40626009","40906558"],"confidence":"Medium","gaps":["Direct YAP phospho-sites dephosphorylated by PP1γ not biochemically mapped","ESCC finding is Low-confidence with no direct phosphatase-substrate demonstration"]},{"year":2026,"claim":"Proteomic profiling of the testis PP1γ2 interactome nominated novel partners (PIHI1D1, ZFR, NDUFB10, ILF2, TBLX1R1) implicating PP1γ2 in splicing and gene-expression machinery during sperm formation.","evidence":"Immunoprecipitation followed by LC-MS/MS from testis tissue","pmids":["41913519"],"confidence":"Low","gaps":["Single pulldown-MS with no functional validation of most interactions","Direct binding versus complex co-purification not distinguished"]},{"year":null,"claim":"How a single catalytic subunit achieves substrate selectivity at each site — the complete map of regulatory/targeting subunit, isoform identity, and the specific phospho-sites dephosphorylated — remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Most reported substrates lack mapped dephosphorylation sites","Isoform (PP1γ1 vs PP1γ2) responsible for each non-testis role often unresolved","Quantitative competition between regulatory subunits for the catalytic pool uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,8,13,16,17,19,22]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,1,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,12,15]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,15]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,22]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,16,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,19,22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,14]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,6,11,13]}],"complexes":["URI/PP1γ mitochondrial complex","HDAC1/PP1γ complex","Nek2A–PP1γ–Mst2 complex","SMN complex"],"partners":["URI","REPO-MAN","PPP1R3G","HDAC1","MST2","WAPL","GEMIN8","HSCRIB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P36873","full_name":"Serine/threonine-protein phosphatase PP1-gamma catalytic subunit","aliases":["Protein phosphatase 1C catalytic subunit"],"length_aa":323,"mass_kda":37.0,"function":"Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets (PubMed:17936702, PubMed:25012651). Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1 (PubMed:17936702). 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. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase (PubMed:20516061). 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 (By similarity). Regulates the recruitment of the SKA complex to kinetochores (PubMed:28982702). 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). Together with PPP1CA (PP1-alpha 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:35831509). 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:35831509). Dephosphorylates MKI67 at the onset of anaphase (PubMed:25012651). The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c (PubMed:35768504, PubMed:35831509)","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleolus; Nucleus, nucleoplasm; Nucleus speckle; Chromosome, centromere, kinetochore; Cleavage furrow; Midbody; Mitochondrion; Cytoplasm, cytoskeleton, microtubule organizing center","url":"https://www.uniprot.org/uniprotkb/P36873/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP1CC","classification":"Not Classified","n_dependent_lines":110,"n_total_lines":1208,"dependency_fraction":0.09105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP1CC","total_profiled":1310},"omim":[{"mim_id":"621430","title":"FIGNL1-INTERACTING REGULATOR OF RECOMBINATION AND MITOSIS; FIRRM","url":"https://www.omim.org/entry/621430"},{"mim_id":"618785","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 2; CDCA2","url":"https://www.omim.org/entry/618785"},{"mim_id":"618068","title":"SPERMATOGENIC LEUCINE ZIPPER PROTEIN 1; SPZ1","url":"https://www.omim.org/entry/618068"},{"mim_id":"615479","title":"MYOSIN XVI; MYO16","url":"https://www.omim.org/entry/615479"},{"mim_id":"614032","title":"TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 4; TOX4","url":"https://www.omim.org/entry/614032"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPP1CC"},"hgnc":{"alias_symbol":["PP1C","PP1gamma"],"prev_symbol":[]},"alphafold":{"accession":"P36873","domains":[{"cath_id":"3.60.21.10","chopping":"29-182_189-295","consensus_level":"high","plddt":98.0995,"start":29,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P36873","model_url":"https://alphafold.ebi.ac.uk/files/AF-P36873-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P36873-F1-predicted_aligned_error_v6.png","plddt_mean":92.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP1CC","jax_strain_url":"https://www.jax.org/strain/search?query=PPP1CC"},"sequence":{"accession":"P36873","fasta_url":"https://rest.uniprot.org/uniprotkb/P36873.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P36873/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P36873"}},"corpus_meta":[{"pmid":"12529430","id":"PMC_12529430","title":"Time-lapse 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and midbody by telophase, implicating it in nucleolar function, chromosome segregation, and cytokinesis.\",\n      \"method\": \"Stable HeLa cell lines expressing FP-PP1γ fusion proteins; time-lapse fluorescence imaging; FRAP\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with stable cell lines, FRAP for dynamics, multiple cell-cycle stages examined in one rigorous study\",\n      \"pmids\": [\"12529430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"URI forms stable complexes with PP1γ at mitochondria in growth-factor-deprived or rapamycin-treated cells, inhibiting the bound PP1γ activity. S6K1-mediated phosphorylation of URI at serine 371 upon growth factor stimulation disassembles the URI/PP1γ complex, releasing active PP1γ that then dephosphorylates and reduces S6K1 activity and BAD phosphorylation, thus activating a negative feedback loop that lowers the threshold for apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase activity assays, phosphospecific antibodies, S6K1 kinase assays, rapamycin treatment, MS identification\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro assays, mutagenesis of URI-S371, MS) in a single rigorous study with clear mechanistic dissection\",\n      \"pmids\": [\"17936702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Plk1 phosphorylates Mst2 to prevent assembly of Nek2A–PP1γ–Mst2 complexes. In the absence of Plk1 phosphorylation of Mst2, PP1γ is recruited into the complex via Mst2 and counteracts Nek2A kinase activity (opposing centrosome disjunction). Plk1-phosphorylated Mst2 cannot bind PP1γ, thus allowing Nek2A activity to proceed and drive centrosome disjunction.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, Plk1 inhibitor/depletion, Mst2 phosphorylation-site mutants, centrosome separation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phosphomutant analysis, and functional centrosome-disjunction readout in one study\",\n      \"pmids\": [\"21723128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Alternative splicing of the PPP1CC gene produces two PP1γ isoforms (PP1γ1 and PP1γ2) that differ at their C-termini. The gene was mapped to human chromosome 12q24.1–q24.2, distinct from the PP1α locus on chromosome 11.\",\n      \"method\": \"cDNA cloning from human teratocarcinoma library; somatic cell hybrid DNA analysis; in situ hybridization (FISH)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cDNA sequencing and chromosomal mapping; foundational structural characterization replicated by later chromosomal assignment studies\",\n      \"pmids\": [\"8394140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Both PP1γ1 and PP1γ2 isoforms encoded by Ppp1cc retain phosphatase function, as demonstrated by their ability to complement the cold-sensitive PP1 defect (dis2-11 mutation) in fission yeast S. pombe.\",\n      \"method\": \"Complementation of fission yeast dis2-11 cold-sensitive mutant; Southern hybridization; FISH mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in yeast is a direct activity assay; single-lab study with clear genetic readout\",\n      \"pmids\": [\"9339378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Targeted disruption of Ppp1cc in mice causes male infertility due to impaired spermiogenesis; PP1γ2 is the predominant isoform in spermatids and spermatozoa, and its loss produces malformed mitochondrial sheaths and extra outer dense fibers in sperm tails, implicating PP1γ2 in sperm tail morphogenesis in addition to motility.\",\n      \"method\": \"Ppp1cc knockout mice; isoform-specific immunohistochemistry; electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with ultrastructural phenotypic analysis; replicated in principle by multiple subsequent studies\",\n      \"pmids\": [\"17301292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transgenic expression of PPP1CC2 alone in Ppp1cc-null testes rescues spermatid viability and spermiation (anti-apoptotic effect) but fails to restore normal flagellar morphogenesis, sperm motility, or fertility, indicating that both PPP1CC isoforms are required for structurally normal spermatogenesis.\",\n      \"method\": \"Transgenic rescue experiment in Ppp1cc-/- mice; sperm morphology and motility analysis; fertility testing\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic rescue with isoform-specific construct, multiple functional readouts\",\n      \"pmids\": [\"19420386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of PP1γ in Ppp1cc knockout mice produces acrosomal defects and chromatin condensation defects in elongating spermatids, while junction complexes remain ultrastructurally normal, localizing PP1γ function to acrosome development and chromatin compaction during spermiogenesis.\",\n      \"method\": \"Light and electron microscopy of Ppp1cc knockout seminiferous epithelium; stage-specific analysis\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with electron microscopy phenotype; single-lab study\",\n      \"pmids\": [\"20385779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PP1γ directly interacts with the SMN complex component Gemin8; PP1γ depletion by RNAi leads to hyperphosphorylation of SMN (revealed by 2D gel electrophoresis) and enhanced localization of the SMN complex and snRNPs to Cajal bodies, demonstrating that PP1γ dephosphorylates SMN to regulate SMN complex assembly and subnuclear localization.\",\n      \"method\": \"Co-immunoprecipitation from HeLa extracts, in vitro protein binding assays, RNAi knockdown, 2D gel electrophoresis, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP + in vitro binding + RNAi phenotype + 2D phospho-analysis in one study\",\n      \"pmids\": [\"22454514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PP1γ is a direct interacting partner of hScrib (via a conserved PP1γ interaction motif on hScrib); this interaction is required for hScrib-mediated downregulation of ERK phosphorylation and for hScrib's ability to suppress oncogene-induced transformation. Loss of hScrib enhances nuclear translocation of PP1γ.\",\n      \"method\": \"Proteomic/mass spectrometry identification, co-immunoprecipitation, in vitro binding assays, ERK phosphorylation assays, oncogenic transformation assays, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated in vitro, functional rescue with motif mutants, multiple orthogonal readouts\",\n      \"pmids\": [\"23359326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PP1γ (but not PP1α or PP1β) specifically enhances alternative splicing of CaMKIIδ by interacting with the splicing factor ASF; PP1γ overexpression or inhibition respectively promotes or suppresses CaMKIIδ splicing and associated cardiomyocyte apoptosis in OGD/R conditions.\",\n      \"method\": \"Co-immunoprecipitation of ASF-PP1γ, splicing reporter assays, PP1γ overexpression/siRNA in HEK293T and primary cardiomyocytes, pharmacological PP1 inhibition\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue; isoform specificity established; single-lab study\",\n      \"pmids\": [\"24196533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Germ-cell-specific deletion of Ppp1cc (using Stra8-Cre) phenocopies global knockout, confirming that PPP1CC2 function in meiotic and postmeiotic germ cells is the critical determinant of male fertility; PPP1CC2 is the only PP1 isoform absent from Sertoli cells and spermatogonia but present in postmeiotic germ cells.\",\n      \"method\": \"Conditional (Stra8-Cre) Ppp1cc knockout mice; isoform-specific immunostaining; fertility assessment; sperm analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout with precise cell-type mapping and fertility phenotyping, replicating global KO in same study\",\n      \"pmids\": [\"24089200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PP1γ physically interacts with TRAF6 and enhances TRAF6 E3 ubiquitin ligase activity toward itself and substrates such as IKKγ, thereby promoting NF-κB-mediated innate immune signaling; enzymatically inactive PP1γ represses these events.\",\n      \"method\": \"Gain-of-function genetic screen, co-immunoprecipitation, ubiquitination assays with wild-type and catalytically inactive PP1γ, macrophage/monocyte innate immune activation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus catalytic-mutant analysis plus functional immune-response assay; single-lab study\",\n      \"pmids\": [\"24586659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NEK1 phosphorylates PP1γ; phosphorylated PP1γ in turn dephosphorylates WAPL, retaining WAPL on chromosome cores to promote cohesin removal along chromosome arms during meiotic prophase I. This NEK1–PP1γ–WAPL axis operates through NEK1 interaction with PDS5B.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, Nek1 knockout mice meiotic chromosome analysis, immunofluorescence of cohesin/WAPL localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO phenotype plus Co-IP and phosphorylation assays; single-lab study\",\n      \"pmids\": [\"27760328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"α7 nicotinic acetylcholine receptor (α7nAChR) interacts with PP1γ in hepatocellular carcinoma cells; ligand-bound α7nAChR facilitates PP1γ-dependent ubiquitination and activation of TRAF6, leading to IκBα degradation, NF-κB nuclear accumulation, and upregulation of Cyclin D1 and PCNA.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, NF-κB reporter assays, proliferation assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and functional knockdown rescue; multiple pathway readouts; single-lab study\",\n      \"pmids\": [\"30074282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aurora B phosphorylates the PP1γ regulatory subunit Repo-Man to disrupt the PP1γ–Repo-Man interaction on chromatin, causing PP1γ dissociation from mitotic chromosomes; this dissociation is required to maintain the high chromatin phosphorylation state during mitosis. Repo-Man phosphorylation-site mutants or Aurora B inhibition retain PP1γ on chromatin and prolong chromosome condensation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, Aurora B inhibitor treatment, Repo-Man phosphomutant overexpression, ectopic PP1γ targeting constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphomutant analysis plus functional chromatin-condensation readout; single-lab study\",\n      \"pmids\": [\"32938714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPP1R3G recruits PP1γ to RIPK1-containing complex I, where PP1γ removes inhibitory phosphorylations on RIPK1 (including serine 25), activating RIPK1 kinase activity and enabling apoptosis and necroptosis. A PPP1R3G mutant unable to bind PP1γ fails to rescue RIPK1 activation. Ppp1r3g-/- mice are protected from TNF-induced systemic inflammatory response syndrome.\",\n      \"method\": \"CRISPR whole-genome knockout screen, co-immunoprecipitation, phosphospecific antibodies for RIPK1-S25, PPP1R3G binding-mutant rescue, Ppp1r3g-/- mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen followed by mechanistic validation with mutants, in vivo mouse model, and multiple orthogonal methods in one study\",\n      \"pmids\": [\"34862394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PP1γ is constitutively associated with HDAC1; the HDAC1/PP1γ complex dephosphorylates CREB at Ser133 during dopaminergic neurodegeneration, inactivating CREB and reducing expression of its target NURR1. CREB interacts with the HDAC1/PP1γ complex in PD, and disrupting CREB/HDAC1 interaction restores phospho-CREB and NURR1 levels.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PD patient tissue), MPTP mouse model, phosphospecific CREB-S133 antibodies, HDAC inhibitor (trichostatin A) treatment, GAL4-M1 CREB mutant overexpression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, proximity ligation in human PD tissue, mouse disease model, pharmacological and genetic rescue; multiple orthogonal methods\",\n      \"pmids\": [\"35501151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PP1γ (but not PP1α) and inhibitor-2 (I-2) positively regulate synaptic transmission in hippocampal neurons; I-2 enhances PP1γ interaction with its synaptic scaffold neurabin (measured by FRET/FLIM), and I-2 threonine-72 phosphorylation dictates its in vivo effect on PP1 activity.\",\n      \"method\": \"Electrophysiology in hippocampal neurons, FRET/FLIM to measure PP1γ–neurabin interaction, I-2 phosphorylation-site mutants, isoform-specific knockdown\",\n      \"journal\": \"Frontiers in synaptic neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET/FLIM plus electrophysiology plus phosphomutant analysis; single-lab study\",\n      \"pmids\": [\"36276179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PP1γ (but not PP1α) regulates neuronal insulin signaling by dephosphorylating AKT2, modulating the AKT2–AS160–GLUT4 axis and GLUT4 translocation; it also regulates GSK3β phosphorylation via AKT2, and GSK3α phosphorylation via MLK3, with imbalance producing an Alzheimer's disease-like phenotype.\",\n      \"method\": \"siRNA knockdown of PP1α and PP1γ in N2a and SH-SY5Y cells, western blot for phospho-AKT2/AS160/GSK3, confocal microscopy for GLUT4 translocation, fluorescence-based glucose uptake assay, high-fat-diet diabetic mouse model brain lysates\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — isoform-specific siRNA with multiple phosphoprotein readouts and glucose metabolism assays; single-lab study\",\n      \"pmids\": [\"37085815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"gp78 E3 ubiquitin ligase degrades PPP1CC (and PPP2CA) via ubiquitination, thereby preventing dephosphorylation of KAP1 and promoting DNA damage repair and radioresistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, western blot for phospho-KAP1, PPP1CC overexpression/knockdown, radiation survival assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay plus phospho-KAP1 readout plus functional radioresistance assay; single-lab study\",\n      \"pmids\": [\"39297166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPP1CC (Drosophila ortholog Pp1-87B) dephosphorylates substrates to suppress JNK signaling via the Moe-Rho1 axis; impaired Pp1-87B/PPP1CC activates JNK, which integrates apoptosis and ferroptosis-like cell death through Hippo pathway activation. In human liver tumor cells, PPP1CC similarly drives apoptosis and ferroptosis via JNK activation.\",\n      \"method\": \"Drosophila genetic screen, epistasis analysis (double mutants), human liver cancer cell overexpression/knockdown, JNK pathway reporters, cell death assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila plus functional validation in human tumor cells; single-lab study\",\n      \"pmids\": [\"40906558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPP1CC dephosphorylates YAP in outer cells of the mouse morula, promoting YAP nuclear translocation and trophectoderm (TE) lineage specification. PPP1CC localization to the TE is spatially restricted by its interaction with the lncRNA GAS5, which localizes to the subcortical region throughout early embryogenesis.\",\n      \"method\": \"PPP1CC knockdown in preimplantation mouse embryos, immunofluorescence for phospho-YAP and YAP localization, GAS5 knockdown/overexpression, blastomere fate tracing\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus rescue with YAP phosphorylation readout in mouse embryos; single-lab study\",\n      \"pmids\": [\"41403070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP1γ promotes ESCC progression by dephosphorylating YAP1, leading to reduced p-YAP1/YAP1 ratio, YAP1 activation, and upregulation of SOX2; silencing PPP1CC increases p-YAP1 and reduces SOX2, suppressing proliferation, migration, and invasion.\",\n      \"method\": \"PPP1CC siRNA knockdown in KYSE150 cells, western blot for p-YAP1/YAP1/SOX2, CCK-8 proliferation assay, colony formation, Transwell invasion/migration assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab knockdown study with downstream phosphoprotein readouts, no direct phosphatase-substrate interaction demonstrated\",\n      \"pmids\": [\"40626009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PP1γ2 (testis-enriched isoform of PPP1CC) interacts with novel testicular partners including PIHI1D1 (part of the R2TP chaperone complex) and ZFR, NDUFB10, ILF2 (predicted via the C-terminal PP1γ2-specific sequence), as well as with SRPK1 interactome members ILF2 and TBLX1R1, suggesting additional roles in splicing, gene expression, and sperm formation.\",\n      \"method\": \"Immunoprecipitation followed by LC-MS/MS (testis tissue)\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown-MS experiment with no functional follow-up for most interactions; single-lab study\",\n      \"pmids\": [\"41913519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP1CC (PP1γ) is a serine/threonine phosphatase catalytic subunit that dynamically relocalizes throughout the cell cycle (nucleolus → kinetochores → chromosomes → cleavage furrow) and acts at multiple signaling nodes: it dephosphorylates RIPK1 (via PPP1R3G-mediated recruitment) to activate apoptosis/necroptosis, dephosphorylates CREB-Ser133 within an HDAC1 complex to regulate neuronal survival, counteracts Nek2A kinase activity at centrosomes under Plk1 control, is released from inhibitory URI complexes at mitochondria by S6K1 to create a negative feedback loop, dephosphorylates YAP to regulate Hippo signaling and trophectoderm specification, regulates cohesin removal during meiosis via a NEK1–PP1γ–WAPL axis, and in the testis the alternatively spliced PP1γ2 isoform is indispensable for spermiogenesis, chromatin condensation, acrosome development, and sperm motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP1CC encodes PP1\\u03b3, a serine/threonine protein phosphatase catalytic subunit whose specificity and subcellular targeting are dictated by interchangeable regulatory/scaffold partners, allowing it to act at distinct cell-cycle, signaling, and developmental nodes [#0, #2]. Across the mammalian cell cycle PP1\\u03b3 dynamically relocalizes from nucleoli through kinetochores and chromosomes to the cleavage furrow [#0], and its association with mitotic chromatin via the Repo-Man regulatory subunit is reversed by Aurora B phosphorylation to sustain the mitotic chromatin phosphorylation state [#15]. At centrosomes it is recruited through Mst2 into a Nek2A\\u2013PP1\\u03b3 complex that opposes centrosome disjunction, an assembly blocked by Plk1 phosphorylation of Mst2 [#2], and in meiotic prophase NEK1-phosphorylated PP1\\u03b3 dephosphorylates WAPL to drive cohesin removal [#13]. PP1\\u03b3 also dephosphorylates targeted substrates in diverse pathways: it is released from inhibitory mitochondrial URI complexes by S6K1 phosphorylation to set up an apoptotic negative-feedback loop [#1], is recruited by PPP1R3G to dephosphorylate RIPK1 and license apoptosis/necroptosis [#16], dephosphorylates CREB-Ser133 within an HDAC1 complex during dopaminergic neurodegeneration [#17], and dephosphorylates YAP to control Hippo-dependent trophectoderm specification and tumor progression [#22, #23]. Additional substrate/partner relationships place PP1\\u03b3 in SMN complex assembly via Gemin8 [#8], ERK suppression via hScrib [#9], and neuronal insulin signaling via AKT2 [#19]. The gene generates two alternatively spliced isoforms, PP1\\u03b31 and PP1\\u03b32, both catalytically active [#3, #4]; the testis-enriched PP1\\u03b32 is indispensable for spermiogenesis, with knockout mice showing chromatin condensation, acrosome, and flagellar defects and male infertility [#5, #7, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that PPP1CC is a distinct PP1 gene generating two C-terminally divergent isoforms defined the molecular substrate for all later isoform-specific biology.\",\n      \"evidence\": \"cDNA cloning from a human teratocarcinoma library and chromosomal mapping by somatic cell hybrid and FISH analysis\",\n      \"pmids\": [\"8394140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish functional differences between PP1\\u03b31 and PP1\\u03b32\", \"No tissue-specific expression pattern defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating both isoforms are catalytically competent confirmed that alternative splicing alters targeting rather than abolishing phosphatase activity.\",\n      \"evidence\": \"Complementation of the fission yeast dis2-11 cold-sensitive PP1 mutant\",\n      \"pmids\": [\"9339378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Yeast complementation does not reveal mammalian substrate specificity\", \"Does not address isoform-specific regulatory partners\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the dynamic cell-cycle relocalization of PP1\\u03b3 placed the phosphatase at successive mitotic structures, framing it as a regulator of segregation and cytokinesis.\",\n      \"evidence\": \"Live-cell time-lapse imaging and FRAP of FP-PP1\\u03b3 in stable HeLa lines\",\n      \"pmids\": [\"12529430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization alone did not identify the targeting subunits driving each relocalization\", \"No substrate dephosphorylated at each site identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying URI as an inhibitory mitochondrial partner released by S6K1 phosphorylation revealed how PP1\\u03b3 activity is switched on to drive an apoptotic feedback loop, and a germline knockout established its essential role in spermiogenesis.\",\n      \"evidence\": \"Co-IP, in vitro phosphatase assays and URI-S371 mutagenesis (mitochondrial complex); Ppp1cc knockout mice with sperm ultrastructure EM\",\n      \"pmids\": [\"17936702\", \"17301292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"URI study did not resolve whether other regulatory subunits compete for the same pool\", \"Knockout did not distinguish PP1\\u03b31 vs PP1\\u03b32 contributions in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolving the Plk1\\u2013Mst2\\u2013Nek2A\\u2013PP1\\u03b3 circuit showed PP1\\u03b3 is recruited via Mst2 to oppose centrosome disjunction, with Plk1 acting as the switch that excludes it.\",\n      \"evidence\": \"Reciprocal Co-IP, kinase assays, Mst2 phosphomutants and centrosome separation assays\",\n      \"pmids\": [\"21723128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Nek2A substrate dephosphorylated by PP1\\u03b3 not defined\", \"Quantitative contribution to disjunction timing unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Isoform-specific transgenic rescue showed PP1\\u03b32 alone restores spermatid viability but not flagellar morphogenesis, establishing non-redundant requirements for both isoforms in spermatogenesis.\",\n      \"evidence\": \"Transgenic PPP1CC2 rescue in Ppp1cc-null mice with morphology, motility and fertility readouts\",\n      \"pmids\": [\"19420386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates underlying flagellar morphogenesis not identified\", \"Mechanism of the anti-apoptotic effect on spermatids unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Stage-specific phenotyping localized PP1\\u03b3 function to acrosome development and chromatin compaction in elongating spermatids.\",\n      \"evidence\": \"Light and electron microscopy of Ppp1cc knockout seminiferous epithelium\",\n      \"pmids\": [\"20385779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular substrate of chromatin condensation identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking PP1\\u03b3 to the SMN complex through Gemin8 added a role in regulating SMN phosphorylation and subnuclear assembly.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro binding, RNAi and 2D phospho-gel analysis in HeLa cells\",\n      \"pmids\": [\"22454514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SMN phospho-site dephosphorylated not mapped\", \"Physiological consequence for snRNP biogenesis not assayed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Three independent studies expanded PP1\\u03b3's isoform-specific partnerships \\u2014 hScrib for ERK suppression and tumor restraint, ASF for CaMKII\\u03b4 splicing, and confirmation that germ-cell PP1\\u03b32 alone dictates fertility.\",\n      \"evidence\": \"MS/Co-IP and motif-mutant binding (hScrib); Co-IP and splicing reporters (ASF/CaMKII\\u03b4); Stra8-Cre conditional Ppp1cc knockout (germ cells)\",\n      \"pmids\": [\"23359326\", \"24196533\", \"24089200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"hScrib- and ASF-directed substrates not biochemically defined\", \"Whether these signaling roles use PP1\\u03b31 or PP1\\u03b32 not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PP1\\u03b3 was shown to enhance TRAF6 E3 ligase activity and NF-\\u03baB innate immune signaling, an effect dependent on catalytic activity.\",\n      \"evidence\": \"Gain-of-function screen, Co-IP, ubiquitination assays with catalytically inactive PP1\\u03b3, immune activation assays\",\n      \"pmids\": [\"24586659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase substrate controlling TRAF6 activity unidentified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining the NEK1\\u2013PP1\\u03b3\\u2013WAPL axis showed PP1\\u03b3 phosphorylation by NEK1 enables WAPL dephosphorylation to drive meiotic cohesin removal.\",\n      \"evidence\": \"Co-IP, phosphorylation assays and Nek1 knockout mouse meiotic chromosome analysis\",\n      \"pmids\": [\"27760328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WAPL phospho-sites targeted not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An \\u03b17nAChR\\u2013PP1\\u03b3 interaction was shown to feed the TRAF6/NF-\\u03baB axis to promote hepatocellular carcinoma proliferation.\",\n      \"evidence\": \"Co-IP, siRNA, ubiquitination and NF-\\u03baB reporter assays in HCC cells\",\n      \"pmids\": [\"30074282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PP1\\u03b3 substrate in the pathway undefined\", \"Single-lab cancer-cell study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing Aurora B phosphorylates Repo-Man to evict PP1\\u03b3 from mitotic chromatin explained how the chromatin phosphorylation state is held high during mitosis.\",\n      \"evidence\": \"Co-IP, Repo-Man phosphomutants, Aurora B inhibition and ectopic PP1\\u03b3 targeting constructs\",\n      \"pmids\": [\"32938714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin substrates kept phosphorylated not enumerated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A genome-wide screen identified PPP1R3G as the targeting subunit that recruits PP1\\u03b3 to dephosphorylate inhibitory RIPK1 phospho-sites and license apoptosis/necroptosis.\",\n      \"evidence\": \"CRISPR screen, Co-IP, RIPK1-S25 phospho-antibodies, binding-mutant rescue and Ppp1r3g knockout mice\",\n      \"pmids\": [\"34862394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of RIPK1 sites dephosphorylated not exhaustively mapped\", \"Crosstalk with URI-controlled apoptotic pool not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two studies placed PP1\\u03b3 in neuronal regulation \\u2014 within an HDAC1/PP1\\u03b3 complex that dephosphorylates CREB-Ser133 in dopaminergic neurodegeneration, and in isoform-specific control of synaptic transmission via I-2 and neurabin.\",\n      \"evidence\": \"Co-IP, proximity ligation in PD tissue, MPTP mouse model (CREB); electrophysiology and FRET/FLIM with I-2 phosphomutants (synapse)\",\n      \"pmids\": [\"35501151\", \"36276179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HDAC1 complex assembly is regulated in disease unresolved\", \"Synaptic substrate set of PP1\\u03b3 not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PP1\\u03b3 was shown to specifically regulate neuronal insulin signaling by dephosphorylating AKT2, tying PP1\\u03b3 imbalance to an Alzheimer's-like phenotype.\",\n      \"evidence\": \"Isoform-specific siRNA, phospho-AKT2/AS160/GSK3 westerns, GLUT4 imaging and high-fat-diet mouse brain lysates\",\n      \"pmids\": [\"37085815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AKT2 phospho-site dephosphorylated not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying gp78-mediated ubiquitin degradation of PPP1CC as a control on KAP1 dephosphorylation linked PP1\\u03b3 turnover to DNA damage repair and radioresistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, phospho-KAP1 westerns and radiation survival assays in breast cancer cells\",\n      \"pmids\": [\"39297166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KAP1 is a direct PP1\\u03b3 substrate not demonstrated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies converged on PP1\\u03b3 as a YAP/Hippo regulator \\u2014 driving trophectoderm specification via GAS5-restricted localization, promoting ESCC progression through YAP1/SOX2, and integrating JNK-dependent apoptosis/ferroptosis.\",\n      \"evidence\": \"Embryo knockdown with phospho-YAP imaging and GAS5 manipulation; ESCC siRNA with p-YAP1/SOX2 readouts; Drosophila epistasis and human liver tumor cell assays\",\n      \"pmids\": [\"41403070\", \"40626009\", \"40906558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct YAP phospho-sites dephosphorylated by PP1\\u03b3 not biochemically mapped\", \"ESCC finding is Low-confidence with no direct phosphatase-substrate demonstration\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Proteomic profiling of the testis PP1\\u03b32 interactome nominated novel partners (PIHI1D1, ZFR, NDUFB10, ILF2, TBLX1R1) implicating PP1\\u03b32 in splicing and gene-expression machinery during sperm formation.\",\n      \"evidence\": \"Immunoprecipitation followed by LC-MS/MS from testis tissue\",\n      \"pmids\": [\"41913519\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pulldown-MS with no functional validation of most interactions\", \"Direct binding versus complex co-purification not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single catalytic subunit achieves substrate selectivity at each site \\u2014 the complete map of regulatory/targeting subunit, isoform identity, and the specific phospho-sites dephosphorylated \\u2014 remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most reported substrates lack mapped dephosphorylation sites\", \"Isoform (PP1\\u03b31 vs PP1\\u03b32) responsible for each non-testis role often unresolved\", \"Quantitative competition between regulatory subunits for the catalytic pool uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 8, 13, 16, 17, 19, 22]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 1, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 12, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 16, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 19, 22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 14]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 6, 11, 13]}\n    ],\n    \"complexes\": [\n      \"URI/PP1\\u03b3 mitochondrial complex\",\n      \"HDAC1/PP1\\u03b3 complex\",\n      \"Nek2A\\u2013PP1\\u03b3\\u2013Mst2 complex\",\n      \"SMN complex\"\n    ],\n    \"partners\": [\n      \"URI\",\n      \"Repo-Man\",\n      \"PPP1R3G\",\n      \"HDAC1\",\n      \"Mst2\",\n      \"WAPL\",\n      \"Gemin8\",\n      \"hScrib\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}