CTDSP2 (SCP2, OS4, NIF2) is a small nuclear protein phosphatase of the FCP/SCP branch of the haloacid dehalogenase (HAD) superfamily. Its C-terminal FCP1-homology domain uses a Mg2+-dependent DXDX(T/V) motif, with Asp107 forming a phosphoaspartyl intermediate, to hydrolyse phosphoserine on protein substrates. Like its paralogs CTDSP1 and CTDSPL, it dephosphorylates the C-terminal heptad repeats of the RNA polymerase II largest subunit with a preference for phospho-Ser5, and it is recruited to promoters by transcription factors such as the androgen receptor and REST, where it restrains promoter clearance and contributes to silencing of neuronal genes in non-neuronal cells. CTDSP2 also removes the activating C-terminal phosphates from Smad1 in the nucleus, terminating BMP signalling. CTDSP2 is a FOXO target gene, and its intron hosts miR-26a-2.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein serine/threonine phosphatase activity is correct and is the most precise existing term that covers both known substrate classes (RNA polymerase II CTD and Smad1 C-terminal phosphoserines). Reason: CTDSP2 carries the FCP1-homology HAD-family catalytic domain (residues 97-255) with the DXDX(T/V) nucleophile Asp107 and proton donor Asp109, and SCP-family enzymes dephosphorylate phosphoserine in the RNA polymerase II CTD heptad repeats (PMID:12721286). Human SCP2 also dephosphorylates the C-terminal SSXS phosphoserines of Smad1 (PMID:16882717), a non-CTD protein substrate for which GO has no substrate-specific child term. GO:0008420 (is_a this term) captures the CTD activity; this broader term remains as precise as warranted for the Smad1 activity, so it is not refined away. Supporting Evidence: file:human/CTDSP2/CTDSP2-uniprot.txt /note="4-aspartylphosphate intermediate" file:human/CTDSP2/CTDSP2-uniprot.txt /note="Proton donor" PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. PMID:16882717 In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription |
| GO:0005515 protein binding | IPI PMID:16724108 Small carboxyl-terminal domain phosphatase 2 attenuates andr... | MODIFY | Summary: Binding to androgen receptor (AR) is a characterised, functional interaction through which CTDSP2 is recruited to AR target promoters. Reason: Per the GO:0005515 policy, bare protein binding is replaced by an informative term where the paper supports one. PMID:16724108 identified SCP2 as an AR interactor, showed AR- and androgen-dependent recruitment to the PSA promoter, and found that SCP2 attenuates AR transcriptional activity. Nuclear androgen receptor binding (GO:0050681) captures this. Proposed replacements: nuclear androgen receptor binding Supporting Evidence: PMID:16724108 Small carboxyl-terminal domain (CTD) phosphatase 2 (SCP2) was identified and verified as a protein that interacts with the androgen receptor (AR). PMID:16724108 Silencing SCP2 and SCP1 by short hairpin RNAs increased androgen-dependent transcription of the PSA gene |
| GO:0005515 protein binding | IPI PMID:16882717 Unique players in the BMP pathway: small C-terminal domain p... | MODIFY | Summary: Smad1 is a substrate of CTDSP2; the interaction reflects enzyme-substrate engagement. Reason: Per the GO:0005515 policy, the bare binding row is replaced by the informative activity that the cited paper supports. PMID:16882717 shows that human SCP2 dephosphorylates the BMP-receptor-phosphorylated C-terminus of Smad1, so the interaction is best represented as the protein serine/threonine phosphatase activity acting on Smad1. Proposed replacements: protein serine/threonine phosphatase activity Supporting Evidence: PMID:16882717 In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription PMID:16882717 In human cells, RNAi-mediated depletion of SCP1 and SCP2 increases the extent and duration of Smad1 phosphorylation in response to BMP |
| GO:0005515 protein binding | IPI PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retrovir... | REMOVE | Summary: High-throughput interaction with HTLV-1 Tax (host-pathogen yeast two-hybrid screen); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with HTLV-1 Tax (host-pathogen yeast two-hybrid screen); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interaction with N4BP3 (proteome-scale binary interactome screen); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with N4BP3 (proteome-scale binary interactome screen); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interaction with LCN2 (proteome-scale binary interactome screen); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with LCN2 (proteome-scale binary interactome screen); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: High-throughput interaction with CDCA3 (proteome-scale binary interactome screens); uninformative about CTDSP2 function. Reason: Bare GO:0005515 is removed under the repository protein-binding policy because it conveys no functional information. Removal does not dispute the reported interaction with CDCA3 (proteome-scale binary interactome screens); no study links this partner to CTDSP2 catalytic or regulatory activity, so there is no more informative MF to substitute. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization is supported and is where CTDSP2 meets its substrates. Reason: UniProt records nuclear localization (by similarity) and the SCP family is described as nuclear phosphatases that dephosphorylate Smad1 and RNA polymerase II CTD; CTDSP2 is recruited to AR- and REST-bound promoters. Accept as the core location. Supporting Evidence: PMID:16882717 identifying the SCP (small C-terminal domain phosphatase) family of nuclear phosphatases as mediators of Smad1 dephosphorylation file:human/CTDSP2/CTDSP2-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1791130 | ACCEPT | Summary: Nucleoplasm is consistent with chromatin-associated CTD and Smad1 dephosphorylation. Reason: The Reactome TAS comes from the generic "Expression of CTDSP2" event, which itself says nothing about compartment beyond placing the product in the nucleoplasm. The location is nevertheless consistent with recruitment of CTDSP2 to promoters (PMID:16724108, PMID:15681389) and with the nuclear SCP family (PMID:16882717). Accepted as a refinement of nucleus. Supporting Evidence: PMID:16882717 identifying the SCP (small C-terminal domain phosphatase) family of nuclear phosphatases as mediators of Smad1 dephosphorylation PMID:15681389 We show that REST/NRSF recruits SCPs to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000108 | MODIFY | Summary: CTDSP2 regulates RNA polymerase II transcription, and the evidence indicates the direction is negative. Reason: This IEA is a logical inference from GO:0008420 and is correct but less specific than the evidence. CTDSP2 attenuates androgen- and glucocorticoid-receptor-dependent transcription and its silencing increases PSA transcription with earlier Ser5 CTD phosphorylation (PMID:16724108); SCPs recruited by REST silence RE-1-containing neuronal genes (PMID:15681389); UniProt summarizes CTDSP2 as a negative regulator of RNA polymerase II transcription. CTDSP2 does the work in these processes by dephosphorylating the polymerase CTD, so negative regulation of transcription by RNA polymerase II is the supported refinement. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:16724108 Silencing SCP2 and SCP1 by short hairpin RNAs increased androgen-dependent transcription of the PSA gene PMID:16724108 Ser 5 phosphorylation of the RNA polymerase II CTD, a process necessary for initiation of transcription elongation, occurred significantly earlier in SCP2-silenced than parental LNCaP cells. PMID:15681389 We show that REST/NRSF recruits SCPs to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. file:human/CTDSP2/CTDSP2-uniprot.txt Negatively regulates RNA polymerase II transcription |
| GO:0006470 protein dephosphorylation | IDA PMID:12721286 A novel RNA polymerase II C-terminal domain phosphatase that... | ACCEPT | Summary: CTDSP2 directly dephosphorylates protein substrates (RNA polymerase II CTD, Smad1). Reason: Protein dephosphorylation is the process directly executed by the catalytic activity. The more specific process term for CTD dephosphorylation (GO:0070940) is obsolete, so this is as precise as GO allows. Supporting Evidence: PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. PMID:16882717 In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription |
| GO:0008420 RNA polymerase II CTD heptapeptide repeat phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: RNA polymerase II CTD heptapeptide repeat phosphatase activity is the defining catalytic activity of the small CTD phosphatases. Reason: The PAINT IBD for GO:0008420 sits at PANTHER node PTN000954535, seeded by experimental annotations of human CTDSP2 (O14595) and CTDSP1 (Q9GZU7); CTDSP2 descends from that node (PTHR12210 subfamily SF187, whereas CTDSP1 is SF139 and CTDSPL SF43, all inside the SCP clade). The target appearing in its own WITH/FROM is the expected marker that it has its own experimental grounding (PMID:12721286), not circularity. The catalytic Asp107/Asp109 DXDX(T/V) motif is intact, so there is no evidence of loss in this lineage. PAINT propagated only the MF from this node and no process or location terms; that restraint is respected here. Supporting Evidence: file:human/CTDSP2/CTDSP2-uniprot.txt 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. PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. file:human/CTDSP2/CTDSP2-uniprot.txt /note="4-aspartylphosphate intermediate" file:human/CTDSP2/CTDSP2-uniprot.txt /note="Proton donor" |
| GO:0008420 RNA polymerase II CTD heptapeptide repeat phosphatase activity | IDA PMID:12721286 A novel RNA polymerase II C-terminal domain phosphatase that... | ACCEPT | Summary: RNA polymerase II CTD heptapeptide repeat phosphatase activity is the defining catalytic activity of the small CTD phosphatases. Reason: Yeo et al. (2003) describe the SCP family as RNAPII CTD phosphatases that prefer phospho-Ser5; UniProt cites this paper (ECO:0000269) for the CTDSP2 Ser5 CTD phosphatase function. The cached abstract foregrounds SCP1 and full text is not available locally, so the experimental annotation of CTDSP2 is deferred to the curator who read the full paper. Independent CTDSP2-specific support comes from AR-dependent transcription, where SCP2 silencing caused earlier Ser5 CTD phosphorylation at the PSA promoter (PMID:16724108). Supporting Evidence: PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. file:human/CTDSP2/CTDSP2-uniprot.txt 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. PMID:16724108 Ser 5 phosphorylation of the RNA polymerase II CTD, a process necessary for initiation of transcription elongation, occurred significantly earlier in SCP2-silenced than parental LNCaP cells. |
| GO:0008420 RNA polymerase II CTD heptapeptide repeat phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: RNA polymerase II CTD heptapeptide repeat phosphatase activity is the defining catalytic activity of the small CTD phosphatases. Reason: The ARBA/InterPro (IPR040078 RNA polymerase II CTD phosphatase) electronic mapping agrees with the experimental and phylogenetic annotation of this activity; consistent with the IDA and IBA rows. Supporting Evidence: file:human/CTDSP2/CTDSP2-uniprot.txt 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. PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. file:human/CTDSP2/CTDSP2-uniprot.txt /note="4-aspartylphosphate intermediate" file:human/CTDSP2/CTDSP2-uniprot.txt /note="Proton donor" |
| GO:0016791 phosphatase activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but very general; CTDSP2 is a protein serine phosphatase acting on RNA polymerase II CTD and Smad1. Reason: The InterPro (Dullard-like phosphatase, IPR011948) mapping is correct but less specific than the evidence supports. Replace with the specific activities supported for CTDSP2 and already carried by the gene: RNA polymerase II CTD heptapeptide repeat phosphatase activity (GO:0008420) and protein serine/threonine phosphatase activity (GO:0004722) for the Smad1 C-terminal phosphatase activity. Proposed replacements: RNA polymerase II CTD heptapeptide repeat phosphatase activity protein serine/threonine phosphatase activity Supporting Evidence: file:human/CTDSP2/CTDSP2-uniprot.txt /note="4-aspartylphosphate intermediate" PMID:12721286 This study describes a family of small CTD phosphatases (SCPs) that preferentially catalyze the dephosphorylation of Ser5 within the consensus repeat. PMID:16882717 In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription |
| GO:0030514 negative regulation of BMP signaling pathway | IDA PMID:16882717 Unique players in the BMP pathway: small C-terminal domain p... | NEW | Summary: CTDSP2 terminates BMP signaling by dephosphorylating the receptor-phosphorylated C-terminus of Smad1 in the nucleus. Reason: Participation test: CTDSP2 itself performs the inactivating step (removal of the activating C-terminal phosphates of Smad1), so this is not a substrate or necessity claim. Human SCP2 selectively dephosphorylated Smad1 and inhibited BMP/Smad1-dependent transcription, and SCP1/SCP2 depletion prolonged BMP-induced Smad1 phosphorylation in human cells. The only GOA row from this paper is an IntAct IPI, so the absence of a process annotation reflects absent GO curation rather than a curator decision. Comparator check: the Smad2/3 C-terminal phosphatase PPM1A carries the analogous negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512, IDA, PMID:16751101), while no SCP paralog yet carries the BMP term; flagged as a suggested question. Part of the loss-of-function data combine SCP1 and SCP2 knockdown. Supporting Evidence: PMID:16882717 In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription PMID:16882717 In human cells, RNAi-mediated depletion of SCP1 and SCP2 increases the extent and duration of Smad1 phosphorylation in response to BMP |
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Download this section (compressed HTML)Q: None of the SCP paralogs (CTDSP1, CTDSP2, CTDSPL) carries a BMP-signalling process annotation despite PMID:16882717; should GO curators annotate negative regulation of BMP signaling pathway to the family, and is it inherited from the SCP ancestral node?
Q: Which genes in non-neuronal cells depend specifically on CTDSP2 rather than on redundant CTDSP1/CTDSPL for CTD Ser5 dephosphorylation?
Experiment: CTDSP2-only knockout (versus CTDSP1/CTDSPL single and compound knockouts) in a BMP-responsive cell line, with phospho-Smad1 kinetics and catalytic-dead (D107A) rescue, to separate CTDSP2-specific from redundant SCP activity.
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