{"gene":"CTDSP1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2014,"finding":"CTDSP1 (SCP1) physically associates with REST immunocomplexes, dephosphorylates REST at phosphoserines 861/864 (a proline-directed phosphorylation motif), and thereby stabilizes REST protein levels. Mutation at S861/864 stabilizes REST and inhibits its degradation, while CTDSP1 counteracts ERK1/2-mediated phosphorylation that promotes REST degradation via Pin1 and βTrCP.","method":"Co-immunoprecipitation of CTDSP1 in REST immunocomplexes, phosphatase activity assay on REST peptide substrates, site-directed mutagenesis of S861/864, neural progenitor REST peptide overexpression assay for neuronal differentiation inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro dephosphorylation assay, Co-IP, mutagenesis of substrate sites, and functional neuronal differentiation readout, all in single rigorous study","pmids":["25197063"],"is_preprint":false},{"year":2018,"finding":"SCP1/CTDSP1 dephosphorylates two degron phosphosites of REST with a clear kinetic preference for phosphoserine 861 (pSer-861). Crystal structure of SCP1 was obtained and shows direct engagement with REST degron sites. SCP1 stabilizes REST protein levels and sustains REST gene-silencing function in HEK293 cells.","method":"Kinetic phosphatase assay, X-ray crystallography of SCP1 with REST substrate, REST stability assay in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinetic assay, crystal structure, and cellular REST stability assay; single lab but three orthogonal methods","pmids":["30217818"],"is_preprint":false},{"year":2017,"finding":"SCP1/CTDSP1 localizes to the plasma membrane in cancer cells via palmitoylation of a conserved cysteine motif in its NH2 terminus. Membrane-localized SCP1 dephosphorylates AKT at serine 473, suppressing angiogenesis and tumor growth. Ctdsp1 knockout mice show increased AKT phosphorylation, angiogenesis, and tumorigenesis.","method":"EGFP/epitope-tagged SCP1 live-cell imaging and fractionation, palmitoylation site mutagenesis, in vitro AKT dephosphorylation assay, Ctdsp1 knockout mouse model with AKT phosphorylation and angiogenesis readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — subcellular localization by imaging/fractionation linked to functional AKT dephosphorylation assay, knockout mouse with multiple orthogonal phenotypic readouts","pmids":["28440748"],"is_preprint":false},{"year":2011,"finding":"CTDSP1 and its family members (CTDSP2, CTDSPL) synergistically decrease the phosphorylated form of pRb (ppRb) and block G1/S-phase progression. Both CTDSP family members and miR-26a/b are co-expressed during cell cycle quiescence and are downregulated during proliferation.","method":"Gain- and loss-of-function assays in primary fibroblasts, serum starvation-stimulation cell cycle assays, partial hepatectomy in mice, ppRb quantification by Western blot","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with ppRb readout, in vivo and in vitro, but CTDSP1 not always distinguished from paralogs","pmids":["22210897"],"is_preprint":false},{"year":2019,"finding":"CTDSP1 overexpression in A549 lung adenocarcinoma cells significantly slows growth and induces senescence, mediated through dephosphorylation of Rb at Ser807/811, Ser780, and Ser795 (increasing the proportion of active, hypophosphorylated Rb).","method":"CTDSP1 transfection/overexpression in A549 cells, Western blot for Rb phosphorylation at specific sites, cell growth and senescence assays","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression with specific phospho-Rb site quantification and growth/senescence phenotype; single lab","pmids":["31774910"],"is_preprint":false},{"year":2020,"finding":"CTDSP1 acts as a primary upstream regulator of DNA-PKcs in response to topoisomerase I (topoI) inhibitors including irinotecan. CTDSP1 promotes irinotecan sensitivity by preventing rapid topoI degradation; knockdown of CTDSP1 accelerates topoI degradation and confers drug resistance. Rabeprazole inhibits CTDSP1 activity and thereby promotes resistance to irinotecan.","method":"Differentially expressing CTDSP1 cell lines, irinotecan sensitivity assays, topoI degradation measurement, CTDSP1 activity assay with rabeprazole, retrospective patient analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional CTDSP1 manipulation with topoI degradation and drug resistance readouts; single lab with cell-based and patient data","pmids":["32764831"],"is_preprint":false},{"year":2004,"finding":"CTDSP1 (human NLI-IF/GIP) co-immunoprecipitates with both golli-MBP and nuclear LIM interactor (NLI) under physiological conditions in PC12 cells and N19 cells. CTDSP1 is predominantly nuclear and forms a complex with golli and NLI, linking it to NLI-associated transcriptional regulation.","method":"Yeast two-hybrid screen, co-immunoprecipitation from PC12 and N19 cell lysates, immunocytochemistry, Northern blot","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP under physiological conditions in multiple cell lines, yeast two-hybrid confirmation; nuclear localization by IHC","pmids":["14743429"],"is_preprint":false},{"year":2021,"finding":"CTDSP1 knockdown in mesenchymal progenitor cells (MPCs) and dorsal root ganglion (DRG) neurons promotes neurotrophic factor (including BDNF) expression and promotes DRG neuron regeneration (neurite outgrowth). This mechanism is mediated through CTDSP1's role in stabilizing REST, which suppresses neurotrophic gene expression.","method":"siRNA knockdown of CTDSP1 in MPCs and DRG neurons, RT-qPCR, Western blot, BDNF ELISA, neurite outgrowth measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple quantitative readouts (gene expression, protein, BDNF secretion, neurite growth); single lab","pmids":["34262056"],"is_preprint":false},{"year":2021,"finding":"GPC5 transcriptionally upregulates CTDSP1 expression via the AhR-ARNT pathway, and the resulting CTDSP1 upregulation contributes to inhibited lung cancer cell proliferation.","method":"GPC5 overexpression in lung cancer cells, reporter assays for AhR-ARNT pathway activation, CTDSP1 expression quantification, cell proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway activation with expression and functional readout; single lab","pmids":["34079082"],"is_preprint":false},{"year":2023,"finding":"CTDSP1 overexpression in Caki-1 clear cell renal cell carcinoma cells inhibits cell growth in vitro. This tumor-suppressive activity is consistent with CTDSP1's role in Rb dephosphorylation.","method":"Transfection of CTDSP1 expression construct into Caki-1 cells, cell growth assays, correlation analysis with RB1 expression in primary tumors","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with growth readout, no direct biochemical mechanism demonstrated in this paper","pmids":["37629167"],"is_preprint":false},{"year":2016,"finding":"Reduction of Ctdsp1 levels in Müller glia (via miR-124-9-9* overexpression) is associated with decreased REST pathway activity and facilitated neuronal reprogramming. This places CTDSP1 in the REST pathway as a repressor of neuronal gene expression in glia.","method":"Lentiviral miR-124-9-9* overexpression in murine Müller glia cultures, gene expression analysis, immunofluorescence for neuronal markers, Ctdsp1 protein level quantification","journal":"Glia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect manipulation of CTDSP1 via miRNA overexpression; CTDSP1 not directly targeted, and mechanistic link to REST is inferred","pmids":["26732729"],"is_preprint":false},{"year":2025,"finding":"Human CTDSP1 (along with CTDSP2 and CTDSPL) can functionally replace yeast Psr1/Psr2 HAD-type phosphatases in restoring TORC1 inhibition and autophagy induction in response to low leucine conditions in Saccharomyces cerevisiae, demonstrating conservation of phosphatase function across species in the TORC1 signaling pathway.","method":"Genetic complementation assay in yeast (Psr1/Psr2 deletion strains expressing human CTDSP1), TORC1 activity and autophagy measurements","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic complementation of yeast deletion with human CTDSP1, functional TORC1/autophagy readout; single study","pmids":["40103213"],"is_preprint":false},{"year":2023,"finding":"CTDSP1 directly suppresses AKT phosphorylation; overexpression of CTDSP1 in neuronal cells exacerbates apoptosis and axonal damage and suppresses AKT phosphorylation under oxygen-glucose deprivation conditions, while miR-124-3p (which targets CTDSP1 3'-UTR) reverses these effects. Dual-luciferase reporter assay confirmed CTDSP1 is a direct target of miR-124-3p.","method":"Adenovirus-mediated CTDSP1 overexpression, dual-luciferase reporter assay for miR-124-3p targeting CTDSP1 3'-UTR, flow cytometry for apoptosis, immunofluorescence, Western blot for p-AKT","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase reporter validation of miR-124-3p/CTDSP1 interaction, CTDSP1 overexpression with AKT phosphorylation and apoptosis readouts; single lab","pmids":["37106272"],"is_preprint":false},{"year":2002,"finding":"CTDSP1 (NLI-IF) gene was identified adjacent to NRAMP1 on chromosome 2q35, encoding a 261-amino acid nuclear protein of 29.2 kDa with ubiquitous expression. Northern blot revealed a 2.6-kb transcript ubiquitously expressed across 15 tissues and a 7-kb placenta-specific transcript.","method":"Genomic sequencing, Northern blot analysis of 15 human tissues","journal":"Mammalian genome","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene identification and expression survey; no direct functional mechanistic experiment","pmids":["10967134"],"is_preprint":false},{"year":2022,"finding":"miR-574-5p negatively regulates CTDSP1 by directly targeting CTDSP1; overexpression of miR-574-5p promotes ESCC cell proliferation in a CTDSP1-dependent manner, confirmed by luciferase reporter assay and rescue experiment.","method":"Dual-luciferase reporter assay, Western blot, RTCA proliferation assay, EdU assay, rescue experiment with CTDSP1 re-expression","journal":"Iranian journal of basic medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase validation of miRNA-target relationship and proliferation rescue; CTDSP1 mechanism not explored beyond being a miR-574-5p target","pmids":["36311195"],"is_preprint":false}],"current_model":"CTDSP1 (SCP1/NLI-IF) is a nuclear HAD-type serine/threonine phosphatase that directly dephosphorylates the REST transcription factor at degron phosphosites (preferentially pSer-861), thereby stabilizing REST and maintaining repression of neuronal genes in non-neuronal cells and stem cells; it also dephosphorylates the C-terminal domain of RNA Pol II to regulate transcription, dephosphorylates Rb to promote G1/S arrest, and—when palmitoylated and targeted to the plasma membrane—dephosphorylates AKT at Ser473 to suppress angiogenesis, while additionally functioning upstream of DNA-PKcs to regulate topoisomerase I stability and irinotecan sensitivity."},"narrative":{"mechanistic_narrative":"CTDSP1 (SCP1/NLI-IF) is a nuclear HAD-type serine/threonine phosphatase that controls neuronal gene repression and cell-cycle progression through site-specific dephosphorylation of key substrates [PMID:25197063, PMID:22210897]. Its central role in neuronal lineage restriction is to dephosphorylate the transcription factor REST at degron phosphoserines 861/864, with a kinetic preference for pSer-861, thereby antagonizing ERK1/2-driven, Pin1/βTrCP-mediated REST degradation and stabilizing REST to sustain repression of neuronal genes; a crystal structure of SCP1 captures direct engagement with the REST degron [PMID:25197063, PMID:30217818]. Consistent with this axis, lowering CTDSP1 destabilizes REST and de-represses neurotrophic genes including BDNF, promoting neurite outgrowth and neuronal reprogramming [PMID:34262056]. CTDSP1 also acts as a growth suppressor by dephosphorylating Rb at multiple inhibitory sites (Ser780, Ser795, Ser807/811), increasing the active hypophosphorylated pool to enforce G1/S arrest and senescence [PMID:22210897, PMID:31774910]. When palmitoylated on an N-terminal cysteine motif and targeted to the plasma membrane, SCP1 dephosphorylates AKT at Ser473 to suppress angiogenesis and tumor growth, a phenotype confirmed by Ctdsp1-knockout mice showing elevated AKT phosphorylation and tumorigenesis [PMID:28440748]. Additional functions include acting upstream of DNA-PKcs to stabilize topoisomerase I and confer irinotecan sensitivity [PMID:32764831], and a conserved phosphatase activity capable of restoring yeast TORC1-dependent autophagy regulation [PMID:40103213].","teleology":[{"year":2004,"claim":"Established CTDSP1 as a predominantly nuclear protein partnering with nuclear LIM interactor, placing it in transcriptional regulatory complexes.","evidence":"Yeast two-hybrid, reciprocal Co-IP, and immunocytochemistry in PC12 and N19 cells","pmids":["14743429"],"confidence":"Medium","gaps":["No phosphatase substrate identified at this stage","Functional consequence of the NLI complex not defined"]},{"year":2011,"claim":"Showed CTDSP1 (with paralogs) drives G1/S arrest, linking the phosphatase to cell-cycle control via Rb.","evidence":"Gain/loss-of-function in primary fibroblasts, serum starvation assays, partial hepatectomy, ppRb Western blot","pmids":["22210897"],"confidence":"Medium","gaps":["CTDSP1 not always distinguished from CTDSP2/CTDSPL","Specific Rb phosphosites not resolved here"]},{"year":2014,"claim":"Identified REST as a direct CTDSP1 substrate, explaining how the phosphatase maintains neuronal gene repression by stabilizing REST against degradation.","evidence":"Co-IP, in vitro phosphatase assay on REST peptides, S861/864 mutagenesis, neural progenitor differentiation readout","pmids":["25197063"],"confidence":"High","gaps":["Relative contribution of the two phosphosites not quantified","In vivo requirement in neurogenesis not tested"]},{"year":2017,"claim":"Revealed a membrane-localized, palmitoylation-dependent pool of SCP1 that dephosphorylates AKT-Ser473, extending CTDSP1 function beyond the nucleus to angiogenesis suppression.","evidence":"Live-cell imaging/fractionation, palmitoylation-site mutagenesis, in vitro AKT dephosphorylation, Ctdsp1 knockout mouse phenotyping","pmids":["28440748"],"confidence":"High","gaps":["Regulation of palmitoylation switch unknown","Relationship between nuclear and membrane pools unresolved"]},{"year":2018,"claim":"Defined the kinetic preference (pSer-861) and structural basis of REST recognition, providing a molecular model for substrate engagement.","evidence":"Kinetic phosphatase assay, X-ray crystallography of SCP1 with REST substrate, HEK293 REST stability assay","pmids":["30217818"],"confidence":"High","gaps":["Structure with full-length REST not determined","How substrate selection is achieved among multiple CTD-type substrates unclear"]},{"year":2019,"claim":"Resolved the specific Rb phosphosites dephosphorylated by CTDSP1, connecting its activity to senescence induction.","evidence":"CTDSP1 overexpression in A549 cells, site-specific phospho-Rb Western blot, growth/senescence assays","pmids":["31774910"],"confidence":"Medium","gaps":["Direct biochemical dephosphorylation of Rb not shown in this study","Single cell line"]},{"year":2020,"claim":"Placed CTDSP1 upstream of DNA-PKcs in controlling topoisomerase I stability, providing a mechanism for irinotecan sensitivity.","evidence":"CTDSP1-differential cell lines, irinotecan sensitivity and topoI degradation assays, rabeprazole inhibition, patient analysis","pmids":["32764831"],"confidence":"Medium","gaps":["Direct substrate in the DNA-PKcs axis not identified","Mechanism of topoI stabilization unclear"]},{"year":2021,"claim":"Confirmed the REST-stabilizing role functionally in neural contexts, showing CTDSP1 loss de-represses neurotrophic genes and promotes regeneration.","evidence":"siRNA knockdown in MPCs and DRG neurons, RT-qPCR, BDNF ELISA, neurite outgrowth; and miR-124-9-9* manipulation in Muller glia","pmids":["34262056","26732729"],"confidence":"Medium","gaps":["Direct REST occupancy at neurotrophic promoters not shown","miRNA-based studies manipulate CTDSP1 indirectly"]},{"year":2023,"claim":"Identified upstream regulation of CTDSP1 (miR-124-3p, miR-574-5p, GPC5-AhR) and reinforced its AKT-suppressive, growth-inhibitory output across cancer and ischemic neuronal contexts.","evidence":"Luciferase reporter assays, overexpression with p-AKT/apoptosis readouts, growth assays in renal and lung cancer cells","pmids":["37106272","34079082","37629167"],"confidence":"Medium","gaps":["Tissue-specific dominance of nuclear vs membrane functions unclear","Some studies lack direct biochemical mechanism"]},{"year":2025,"claim":"Demonstrated functional conservation of CTDSP1 phosphatase activity in TORC1-dependent autophagy control via yeast complementation.","evidence":"Genetic complementation of yeast Psr1/Psr2 deletion with human CTDSP1, TORC1/autophagy readouts","pmids":["40103213"],"confidence":"Medium","gaps":["Mammalian TORC1 substrate of CTDSP1 not identified","Physiological relevance in human cells not established"]},{"year":null,"claim":"How CTDSP1 selects among its diverse substrates (REST, Rb, AKT, Pol II CTD) and how the palmitoylation switch partitions nuclear versus membrane functions remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of substrate selection","Regulation of subcellular partitioning unknown","In vivo substrate hierarchy untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12]}],"complexes":[],"partners":["REST","NLI","GOLLI-MBP","AKT","RB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZU7","full_name":"Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1","aliases":["Nuclear LIM interactor-interacting factor 3","NLI-IF","NLI-interacting factor 3","Small C-terminal domain phosphatase 1","SCP1","Small CTD phosphatase 1"],"length_aa":261,"mass_kda":29.2,"function":"Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation. Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9GZU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTDSP1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTDSP1","total_profiled":1310},"omim":[{"mim_id":"618626","title":"PHOSPHORYLATED C-TERMINAL DOMAIN-INTERACTING FACTOR 1; PCIF1","url":"https://www.omim.org/entry/618626"},{"mim_id":"612152","title":"MICRO RNA 26B; MIR26B","url":"https://www.omim.org/entry/612152"},{"mim_id":"610684","title":"C-TERMINAL DOMAIN NUCLEAR ENVELOPE PHOSPHATASE 1; CTDNEP1","url":"https://www.omim.org/entry/610684"},{"mim_id":"609867","title":"UBIQUITIN-LIKE DOMAIN-CONTAINING CTD PHOSPHATASE 1; UBLCP1","url":"https://www.omim.org/entry/609867"},{"mim_id":"608711","title":"CTD SMALL PHOSPHATASE 2; CTDSP2","url":"https://www.omim.org/entry/608711"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTDSP1"},"hgnc":{"alias_symbol":["NLIIF","SCP1"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZU7","domains":[{"cath_id":"3.40.50.1000","chopping":"83-103_133-254","consensus_level":"high","plddt":97.9891,"start":83,"end":254}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZU7-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTDSP1","jax_strain_url":"https://www.jax.org/strain/search?query=CTDSP1"},"sequence":{"accession":"Q9GZU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZU7"}},"corpus_meta":[{"pmid":"22210897","id":"PMC_22210897","title":"MicroRNA-26a/b and 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Mutation at S861/864 stabilizes REST and inhibits its degradation, while CTDSP1 counteracts ERK1/2-mediated phosphorylation that promotes REST degradation via Pin1 and βTrCP.\",\n      \"method\": \"Co-immunoprecipitation of CTDSP1 in REST immunocomplexes, phosphatase activity assay on REST peptide substrates, site-directed mutagenesis of S861/864, neural progenitor REST peptide overexpression assay for neuronal differentiation inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro dephosphorylation assay, Co-IP, mutagenesis of substrate sites, and functional neuronal differentiation readout, all in single rigorous study\",\n      \"pmids\": [\"25197063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCP1/CTDSP1 dephosphorylates two degron phosphosites of REST with a clear kinetic preference for phosphoserine 861 (pSer-861). Crystal structure of SCP1 was obtained and shows direct engagement with REST degron sites. SCP1 stabilizes REST protein levels and sustains REST gene-silencing function in HEK293 cells.\",\n      \"method\": \"Kinetic phosphatase assay, X-ray crystallography of SCP1 with REST substrate, REST stability assay in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinetic assay, crystal structure, and cellular REST stability assay; single lab but three orthogonal methods\",\n      \"pmids\": [\"30217818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCP1/CTDSP1 localizes to the plasma membrane in cancer cells via palmitoylation of a conserved cysteine motif in its NH2 terminus. Membrane-localized SCP1 dephosphorylates AKT at serine 473, suppressing angiogenesis and tumor growth. Ctdsp1 knockout mice show increased AKT phosphorylation, angiogenesis, and tumorigenesis.\",\n      \"method\": \"EGFP/epitope-tagged SCP1 live-cell imaging and fractionation, palmitoylation site mutagenesis, in vitro AKT dephosphorylation assay, Ctdsp1 knockout mouse model with AKT phosphorylation and angiogenesis readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — subcellular localization by imaging/fractionation linked to functional AKT dephosphorylation assay, knockout mouse with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"28440748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTDSP1 and its family members (CTDSP2, CTDSPL) synergistically decrease the phosphorylated form of pRb (ppRb) and block G1/S-phase progression. Both CTDSP family members and miR-26a/b are co-expressed during cell cycle quiescence and are downregulated during proliferation.\",\n      \"method\": \"Gain- and loss-of-function assays in primary fibroblasts, serum starvation-stimulation cell cycle assays, partial hepatectomy in mice, ppRb quantification by Western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with ppRb readout, in vivo and in vitro, but CTDSP1 not always distinguished from paralogs\",\n      \"pmids\": [\"22210897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTDSP1 overexpression in A549 lung adenocarcinoma cells significantly slows growth and induces senescence, mediated through dephosphorylation of Rb at Ser807/811, Ser780, and Ser795 (increasing the proportion of active, hypophosphorylated Rb).\",\n      \"method\": \"CTDSP1 transfection/overexpression in A549 cells, Western blot for Rb phosphorylation at specific sites, cell growth and senescence assays\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression with specific phospho-Rb site quantification and growth/senescence phenotype; single lab\",\n      \"pmids\": [\"31774910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTDSP1 acts as a primary upstream regulator of DNA-PKcs in response to topoisomerase I (topoI) inhibitors including irinotecan. CTDSP1 promotes irinotecan sensitivity by preventing rapid topoI degradation; knockdown of CTDSP1 accelerates topoI degradation and confers drug resistance. Rabeprazole inhibits CTDSP1 activity and thereby promotes resistance to irinotecan.\",\n      \"method\": \"Differentially expressing CTDSP1 cell lines, irinotecan sensitivity assays, topoI degradation measurement, CTDSP1 activity assay with rabeprazole, retrospective patient analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional CTDSP1 manipulation with topoI degradation and drug resistance readouts; single lab with cell-based and patient data\",\n      \"pmids\": [\"32764831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CTDSP1 (human NLI-IF/GIP) co-immunoprecipitates with both golli-MBP and nuclear LIM interactor (NLI) under physiological conditions in PC12 cells and N19 cells. CTDSP1 is predominantly nuclear and forms a complex with golli and NLI, linking it to NLI-associated transcriptional regulation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from PC12 and N19 cell lysates, immunocytochemistry, Northern blot\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP under physiological conditions in multiple cell lines, yeast two-hybrid confirmation; nuclear localization by IHC\",\n      \"pmids\": [\"14743429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTDSP1 knockdown in mesenchymal progenitor cells (MPCs) and dorsal root ganglion (DRG) neurons promotes neurotrophic factor (including BDNF) expression and promotes DRG neuron regeneration (neurite outgrowth). This mechanism is mediated through CTDSP1's role in stabilizing REST, which suppresses neurotrophic gene expression.\",\n      \"method\": \"siRNA knockdown of CTDSP1 in MPCs and DRG neurons, RT-qPCR, Western blot, BDNF ELISA, neurite outgrowth measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple quantitative readouts (gene expression, protein, BDNF secretion, neurite growth); single lab\",\n      \"pmids\": [\"34262056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPC5 transcriptionally upregulates CTDSP1 expression via the AhR-ARNT pathway, and the resulting CTDSP1 upregulation contributes to inhibited lung cancer cell proliferation.\",\n      \"method\": \"GPC5 overexpression in lung cancer cells, reporter assays for AhR-ARNT pathway activation, CTDSP1 expression quantification, cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway activation with expression and functional readout; single lab\",\n      \"pmids\": [\"34079082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CTDSP1 overexpression in Caki-1 clear cell renal cell carcinoma cells inhibits cell growth in vitro. This tumor-suppressive activity is consistent with CTDSP1's role in Rb dephosphorylation.\",\n      \"method\": \"Transfection of CTDSP1 expression construct into Caki-1 cells, cell growth assays, correlation analysis with RB1 expression in primary tumors\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with growth readout, no direct biochemical mechanism demonstrated in this paper\",\n      \"pmids\": [\"37629167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Reduction of Ctdsp1 levels in Müller glia (via miR-124-9-9* overexpression) is associated with decreased REST pathway activity and facilitated neuronal reprogramming. This places CTDSP1 in the REST pathway as a repressor of neuronal gene expression in glia.\",\n      \"method\": \"Lentiviral miR-124-9-9* overexpression in murine Müller glia cultures, gene expression analysis, immunofluorescence for neuronal markers, Ctdsp1 protein level quantification\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect manipulation of CTDSP1 via miRNA overexpression; CTDSP1 not directly targeted, and mechanistic link to REST is inferred\",\n      \"pmids\": [\"26732729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human CTDSP1 (along with CTDSP2 and CTDSPL) can functionally replace yeast Psr1/Psr2 HAD-type phosphatases in restoring TORC1 inhibition and autophagy induction in response to low leucine conditions in Saccharomyces cerevisiae, demonstrating conservation of phosphatase function across species in the TORC1 signaling pathway.\",\n      \"method\": \"Genetic complementation assay in yeast (Psr1/Psr2 deletion strains expressing human CTDSP1), TORC1 activity and autophagy measurements\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic complementation of yeast deletion with human CTDSP1, functional TORC1/autophagy readout; single study\",\n      \"pmids\": [\"40103213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CTDSP1 directly suppresses AKT phosphorylation; overexpression of CTDSP1 in neuronal cells exacerbates apoptosis and axonal damage and suppresses AKT phosphorylation under oxygen-glucose deprivation conditions, while miR-124-3p (which targets CTDSP1 3'-UTR) reverses these effects. Dual-luciferase reporter assay confirmed CTDSP1 is a direct target of miR-124-3p.\",\n      \"method\": \"Adenovirus-mediated CTDSP1 overexpression, dual-luciferase reporter assay for miR-124-3p targeting CTDSP1 3'-UTR, flow cytometry for apoptosis, immunofluorescence, Western blot for p-AKT\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase reporter validation of miR-124-3p/CTDSP1 interaction, CTDSP1 overexpression with AKT phosphorylation and apoptosis readouts; single lab\",\n      \"pmids\": [\"37106272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CTDSP1 (NLI-IF) gene was identified adjacent to NRAMP1 on chromosome 2q35, encoding a 261-amino acid nuclear protein of 29.2 kDa with ubiquitous expression. Northern blot revealed a 2.6-kb transcript ubiquitously expressed across 15 tissues and a 7-kb placenta-specific transcript.\",\n      \"method\": \"Genomic sequencing, Northern blot analysis of 15 human tissues\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene identification and expression survey; no direct functional mechanistic experiment\",\n      \"pmids\": [\"10967134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-574-5p negatively regulates CTDSP1 by directly targeting CTDSP1; overexpression of miR-574-5p promotes ESCC cell proliferation in a CTDSP1-dependent manner, confirmed by luciferase reporter assay and rescue experiment.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, RTCA proliferation assay, EdU assay, rescue experiment with CTDSP1 re-expression\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase validation of miRNA-target relationship and proliferation rescue; CTDSP1 mechanism not explored beyond being a miR-574-5p target\",\n      \"pmids\": [\"36311195\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTDSP1 (SCP1/NLI-IF) is a nuclear HAD-type serine/threonine phosphatase that directly dephosphorylates the REST transcription factor at degron phosphosites (preferentially pSer-861), thereby stabilizing REST and maintaining repression of neuronal genes in non-neuronal cells and stem cells; it also dephosphorylates the C-terminal domain of RNA Pol II to regulate transcription, dephosphorylates Rb to promote G1/S arrest, and—when palmitoylated and targeted to the plasma membrane—dephosphorylates AKT at Ser473 to suppress angiogenesis, while additionally functioning upstream of DNA-PKcs to regulate topoisomerase I stability and irinotecan sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTDSP1 (SCP1/NLI-IF) is a nuclear HAD-type serine/threonine phosphatase that controls neuronal gene repression and cell-cycle progression through site-specific dephosphorylation of key substrates [#0, #3]. Its central role in neuronal lineage restriction is to dephosphorylate the transcription factor REST at degron phosphoserines 861/864, with a kinetic preference for pSer-861, thereby antagonizing ERK1/2-driven, Pin1/\\u03b2TrCP-mediated REST degradation and stabilizing REST to sustain repression of neuronal genes; a crystal structure of SCP1 captures direct engagement with the REST degron [#0, #1]. Consistent with this axis, lowering CTDSP1 destabilizes REST and de-represses neurotrophic genes including BDNF, promoting neurite outgrowth and neuronal reprogramming [#7]. CTDSP1 also acts as a growth suppressor by dephosphorylating Rb at multiple inhibitory sites (Ser780, Ser795, Ser807/811), increasing the active hypophosphorylated pool to enforce G1/S arrest and senescence [#3, #4]. When palmitoylated on an N-terminal cysteine motif and targeted to the plasma membrane, SCP1 dephosphorylates AKT at Ser473 to suppress angiogenesis and tumor growth, a phenotype confirmed by Ctdsp1-knockout mice showing elevated AKT phosphorylation and tumorigenesis [#2]. Additional functions include acting upstream of DNA-PKcs to stabilize topoisomerase I and confer irinotecan sensitivity [#5], and a conserved phosphatase activity capable of restoring yeast TORC1-dependent autophagy regulation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established CTDSP1 as a predominantly nuclear protein partnering with nuclear LIM interactor, placing it in transcriptional regulatory complexes.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, and immunocytochemistry in PC12 and N19 cells\",\n      \"pmids\": [\"14743429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No phosphatase substrate identified at this stage\", \"Functional consequence of the NLI complex not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CTDSP1 (with paralogs) drives G1/S arrest, linking the phosphatase to cell-cycle control via Rb.\",\n      \"evidence\": \"Gain/loss-of-function in primary fibroblasts, serum starvation assays, partial hepatectomy, ppRb Western blot\",\n      \"pmids\": [\"22210897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CTDSP1 not always distinguished from CTDSP2/CTDSPL\", \"Specific Rb phosphosites not resolved here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified REST as a direct CTDSP1 substrate, explaining how the phosphatase maintains neuronal gene repression by stabilizing REST against degradation.\",\n      \"evidence\": \"Co-IP, in vitro phosphatase assay on REST peptides, S861/864 mutagenesis, neural progenitor differentiation readout\",\n      \"pmids\": [\"25197063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of the two phosphosites not quantified\", \"In vivo requirement in neurogenesis not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a membrane-localized, palmitoylation-dependent pool of SCP1 that dephosphorylates AKT-Ser473, extending CTDSP1 function beyond the nucleus to angiogenesis suppression.\",\n      \"evidence\": \"Live-cell imaging/fractionation, palmitoylation-site mutagenesis, in vitro AKT dephosphorylation, Ctdsp1 knockout mouse phenotyping\",\n      \"pmids\": [\"28440748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of palmitoylation switch unknown\", \"Relationship between nuclear and membrane pools unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the kinetic preference (pSer-861) and structural basis of REST recognition, providing a molecular model for substrate engagement.\",\n      \"evidence\": \"Kinetic phosphatase assay, X-ray crystallography of SCP1 with REST substrate, HEK293 REST stability assay\",\n      \"pmids\": [\"30217818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure with full-length REST not determined\", \"How substrate selection is achieved among multiple CTD-type substrates unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the specific Rb phosphosites dephosphorylated by CTDSP1, connecting its activity to senescence induction.\",\n      \"evidence\": \"CTDSP1 overexpression in A549 cells, site-specific phospho-Rb Western blot, growth/senescence assays\",\n      \"pmids\": [\"31774910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical dephosphorylation of Rb not shown in this study\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CTDSP1 upstream of DNA-PKcs in controlling topoisomerase I stability, providing a mechanism for irinotecan sensitivity.\",\n      \"evidence\": \"CTDSP1-differential cell lines, irinotecan sensitivity and topoI degradation assays, rabeprazole inhibition, patient analysis\",\n      \"pmids\": [\"32764831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in the DNA-PKcs axis not identified\", \"Mechanism of topoI stabilization unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed the REST-stabilizing role functionally in neural contexts, showing CTDSP1 loss de-represses neurotrophic genes and promotes regeneration.\",\n      \"evidence\": \"siRNA knockdown in MPCs and DRG neurons, RT-qPCR, BDNF ELISA, neurite outgrowth; and miR-124-9-9* manipulation in Muller glia\",\n      \"pmids\": [\"34262056\", \"26732729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct REST occupancy at neurotrophic promoters not shown\", \"miRNA-based studies manipulate CTDSP1 indirectly\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified upstream regulation of CTDSP1 (miR-124-3p, miR-574-5p, GPC5-AhR) and reinforced its AKT-suppressive, growth-inhibitory output across cancer and ischemic neuronal contexts.\",\n      \"evidence\": \"Luciferase reporter assays, overexpression with p-AKT/apoptosis readouts, growth assays in renal and lung cancer cells\",\n      \"pmids\": [\"37106272\", \"34079082\", \"37629167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific dominance of nuclear vs membrane functions unclear\", \"Some studies lack direct biochemical mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated functional conservation of CTDSP1 phosphatase activity in TORC1-dependent autophagy control via yeast complementation.\",\n      \"evidence\": \"Genetic complementation of yeast Psr1/Psr2 deletion with human CTDSP1, TORC1/autophagy readouts\",\n      \"pmids\": [\"40103213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian TORC1 substrate of CTDSP1 not identified\", \"Physiological relevance in human cells not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CTDSP1 selects among its diverse substrates (REST, Rb, AKT, Pol II CTD) and how the palmitoylation switch partitions nuclear versus membrane functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of substrate selection\", \"Regulation of subcellular partitioning unknown\", \"In vivo substrate hierarchy untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"REST\", \"NLI\", \"golli-MBP\", \"AKT\", \"Rb\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}