Affinage

CTDSP1

Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 · UniProt Q9GZU7

Length
261 aa
Mass
29.2 kDa
Annotated
2026-06-09
38 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 Medium

    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

    PMID:14743429

    Open questions at the time
    • No phosphatase substrate identified at this stage
    • Functional consequence of the NLI complex not defined
  2. 2011 Medium

    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

    PMID:22210897

    Open questions at the time
    • CTDSP1 not always distinguished from CTDSP2/CTDSPL
    • Specific Rb phosphosites not resolved here
  3. 2014 High

    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

    PMID:25197063

    Open questions at the time
    • Relative contribution of the two phosphosites not quantified
    • In vivo requirement in neurogenesis not tested
  4. 2017 High

    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

    PMID:28440748

    Open questions at the time
    • Regulation of palmitoylation switch unknown
    • Relationship between nuclear and membrane pools unresolved
  5. 2018 High

    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

    PMID:30217818

    Open questions at the time
    • Structure with full-length REST not determined
    • How substrate selection is achieved among multiple CTD-type substrates unclear
  6. 2019 Medium

    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

    PMID:31774910

    Open questions at the time
    • Direct biochemical dephosphorylation of Rb not shown in this study
    • Single cell line
  7. 2020 Medium

    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

    PMID:32764831

    Open questions at the time
    • Direct substrate in the DNA-PKcs axis not identified
    • Mechanism of topoI stabilization unclear
  8. 2021 Medium

    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

    PMID:26732729 PMID:34262056

    Open questions at the time
    • Direct REST occupancy at neurotrophic promoters not shown
    • miRNA-based studies manipulate CTDSP1 indirectly
  9. 2023 Medium

    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

    PMID:34079082 PMID:37106272 PMID:37629167

    Open questions at the time
    • Tissue-specific dominance of nuclear vs membrane functions unclear
    • Some studies lack direct biochemical mechanism
  10. 2025 Medium

    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

    PMID:40103213

    Open questions at the time
    • Mammalian TORC1 substrate of CTDSP1 not identified
    • Physiological relevance in human cells not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No integrated model of substrate selection
  • Regulation of subcellular partitioning unknown
  • In vivo substrate hierarchy untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
AKTGOLLI-MBPNLIRBREST

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 25197063
2018 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. Kinetic phosphatase assay, X-ray crystallography of SCP1 with REST substrate, REST stability assay in HEK293 cells The Journal of biological chemistry High 30217818
2017 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. 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 eLife High 28440748
2011 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. Gain- and loss-of-function assays in primary fibroblasts, serum starvation-stimulation cell cycle assays, partial hepatectomy in mice, ppRb quantification by Western blot Nucleic acids research Medium 22210897
2019 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). CTDSP1 transfection/overexpression in A549 cells, Western blot for Rb phosphorylation at specific sites, cell growth and senescence assays Bioscience reports Medium 31774910
2020 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. Differentially expressing CTDSP1 cell lines, irinotecan sensitivity assays, topoI degradation measurement, CTDSP1 activity assay with rabeprazole, retrospective patient analysis PloS one Medium 32764831
2004 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. Yeast two-hybrid screen, co-immunoprecipitation from PC12 and N19 cell lysates, immunocytochemistry, Northern blot Journal of neuroscience research Medium 14743429
2021 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. siRNA knockdown of CTDSP1 in MPCs and DRG neurons, RT-qPCR, Western blot, BDNF ELISA, neurite outgrowth measurement Scientific reports Medium 34262056
2021 GPC5 transcriptionally upregulates CTDSP1 expression via the AhR-ARNT pathway, and the resulting CTDSP1 upregulation contributes to inhibited lung cancer cell proliferation. GPC5 overexpression in lung cancer cells, reporter assays for AhR-ARNT pathway activation, CTDSP1 expression quantification, cell proliferation assays Oncogene Medium 34079082
2023 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. Transfection of CTDSP1 expression construct into Caki-1 cells, cell growth assays, correlation analysis with RB1 expression in primary tumors International journal of molecular sciences Low 37629167
2016 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. Lentiviral miR-124-9-9* overexpression in murine Müller glia cultures, gene expression analysis, immunofluorescence for neuronal markers, Ctdsp1 protein level quantification Glia Low 26732729
2025 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. Genetic complementation assay in yeast (Psr1/Psr2 deletion strains expressing human CTDSP1), TORC1 activity and autophagy measurements Autophagy Medium 40103213
2023 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. 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 Cellular and molecular neurobiology Medium 37106272
2002 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. Genomic sequencing, Northern blot analysis of 15 human tissues Mammalian genome Low 10967134
2022 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. Dual-luciferase reporter assay, Western blot, RTCA proliferation assay, EdU assay, rescue experiment with CTDSP1 re-expression Iranian journal of basic medical sciences Low 36311195

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic acids research 179 22210897
2016 Crystal structure of an HIV assembly and maturation switch. eLife 115 27416583
2013 The role of microRNA-26b in human adipocyte differentiation and proliferation. Gene 77 24140453
2018 MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat. Proceedings of the National Academy of Sciences of the United States of America 73 30530702
2019 Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nature communications 67 31831742
2021 Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives. Journal of clinical medicine 55 34362013
2016 miR-124-9-9* potentiates Ascl1-induced reprogramming of cultured Müller glia. Glia 54 26732729
2014 C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of America 40 25197063
2002 Molecular cloning and characterization of dullard: a novel gene required for neural development. Biochemical and biophysical research communications 39 12083771
2016 Overexpression of miR-26b-5p regulates the cell cycle by targeting CCND2 in GC-2 cells under exposure to extremely low frequency electromagnetic fields. Cell cycle (Georgetown, Tex.) 32 26637059
2012 Serum autoantibodies to pancreatic cancer antigens as biomarkers of pancreatic cancer in a San Francisco Bay Area case-control study. Cancer 31 22517435
2012 Modulation of hsa-miR-26b levels following adipokine stimulation. Molecular biology reports 30 23275201
2024 Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases. Histopathology 23 38785043
2000 Complete nucleotide sequence and genomic structure of the human NRAMP1 gene region on chromosome region 2q35. Mammalian genome : official journal of the International Mammalian Genome Society 21 10967134
2017 Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis. eLife 18 28440748
2004 Identification of a protein that interacts with the golli-myelin basic protein and with nuclear LIM interactor in the nervous system. Journal of neuroscience research 18 14743429
2021 GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion. Oncogene 17 34079082
2020 Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions. International journal of molecular sciences 16 32316683
2018 Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST). The Journal of biological chemistry 16 30217818
2019 New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study. International journal of molecular sciences 15 31640137
2017 Transcriptomic signature predicts the distant relapse in patients with ER+ breast cancer treated with tamoxifen for five years. Molecular medicine reports 15 29257261
2017 miR-26b promoter analysis reveals regulatory mechanisms by lipid-related transcription factors in goat mammary epithelial cells. Journal of dairy science 13 28527797
2020 Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study. Biomolecules 12 32764519
2019 Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer. Bioscience reports 11 31774910
2023 Elabela, a Novel Peptide, Exerts Neuroprotective Effects Against Ischemic Stroke Through the APJ/miR-124-3p/CTDSP1/AKT Pathway. Cellular and molecular neurobiology 10 37106272
2020 CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer. PloS one 10 32764831
2020 Targeting the C-Terminal Domain Small Phosphatase 1. Life (Basel, Switzerland) 9 32397221
2022 Imputation to whole-genome sequence and its use in genome-wide association studies for pork colour traits in crossbred and purebred pigs. Frontiers in genetics 7 36303553
2021 C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue. Scientific reports 6 34262056
2002 Ethnic divergence and linkage disequilibrium of novel SNPs in the human NLI-IF gene: evidence of human origin and lack of association with tuberculosis susceptibility. Journal of human genetics 6 11950066
2019 Chloramphenicol inhibits eukaryotic Ser/Thr phosphatase and infection-specific cell differentiation in the rice blast fungus. Scientific reports 5 31243315
2023 Tumor Suppressor Properties of Small C-Terminal Domain Phosphatases in Clear Cell Renal Cell Carcinoma. International journal of molecular sciences 4 37629167
2022 MiR-574-5p promotes cell proliferation by negatively regulating small C-terminal domain phosphatase 1 in esophageal squamous cell carcinoma. Iranian journal of basic medical sciences 3 36311195
2022 Identification of microRNA editing sites in three subtypes of leukemia. Frontiers in molecular biosciences 3 36452459
2021 [SCP Phosphatases and Oncogenesis]. Molekuliarnaia biologiia 2 34432772
2025 The Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion. Autophagy 1 40103213
2015 Harnessing the master transcriptional repressor REST to reciprocally regulate neurogenesis. Neurogenesis (Austin, Tex.) 1 27535341
2026 Dual evidence reveals the therapeutic efficacy of exosome-delivered miR-124-3p in spinal cord injury via a novel CTDSP1/WNT/β-catenin mechanism. Spinal cord 0 42249107

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