Cubitus interruptus (Ci) is the sole Gli-family C2H2 zinc-finger transcription factor of Drosophila melanogaster and the terminal effector of Hedgehog signalling; cells lacking it show no Hedgehog output at all. The 1397-residue full-length protein, Ci-155, is a latent transcriptional activator. In cells not receiving Hedgehog it is held in the cytoplasm in a microtubule-associated complex with the kinesin-related protein Costal-2, the Ser/Thr kinase Fused and Suppressor of fused, where Costal-2-recruited protein kinase A, glycogen synthase kinase 3 and casein kinase 1 phosphorylate it on clustered, successively primed sites. The resulting extended phosphodegron is read by Slimb, the F-box substrate receptor of an SCF ubiquitin ligase, and commits Ci-155 to partial proteasomal proteolysis that removes the C-terminal activation and tethering domains. The product, the roughly 75 kDa Ci-75, is constitutively nuclear and acts as a sequence-specific transcriptional repressor of hedgehog itself and of other Hedgehog target genes; this repressor state is the default output of the pathway. Hedgehog reception blocks the processing, so Ci-155 accumulates, is further phosphorylated by Fused and casein kinase 1, is released from Suppressor of fused, and is imported through a bipartite nuclear localisation signal and a PY-NLS read by Transportin. Nuclear Ci-155 then activates targets such as decapentaplegic, patched, wingless and knot/collier, recruiting the coactivator CBP (nejire) to do so, and is in turn limited by the Cullin-3 substrate adaptor Roadkill/HIB. Both forms recognise the same GLI/Ci consensus sequence in RNA polymerase II cis-regulatory regions through five C2H2 zinc fingers, so the dose and duration of Hedgehog exposure is translated into a graded ratio of activator to repressor. Through these two opposing outputs Ci patterns the anterior compartment of every embryonic segment and imaginal disc, and contributes to eye, wing, leg, labial, genital and posterior spiracle morphogenesis, to ovarian and hindgut stem-cell behaviour, and to Hedgehog-dependent epithelial immunity in the gut.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic ARBA annotation of the Ci/GLI family to negative regulation of RNA polymerase II transcription. Ci-75, the N-terminal fragment produced by phosphorylation-dependent partial proteolysis of Ci-155, is constitutively nuclear and represses hedgehog itself and other Hedgehog target genes. Repression of RNA polymerase II transcription is one of the two core outputs of this gene product. Reason: Accepted. The electronic assertion coincides with the directly demonstrated repressor output of this gene: proteolysis converts Ci-155 into a nuclear repressor form (PMID:9215627), and repressor and activator forms control overlapping but distinct subsets of Hedgehog targets (PMID:10102270). The term is at the right level of specificity for a Pol II transcription factor. Supporting Evidence: PMID:9215627 This form translocates to the nucleus where it represses hh and other target genes. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IGI PMID:16386907 Processing of the Drosophila hedgehog signaling effector Ci-... | ACCEPT | Summary: IGI with smoothened (FB:FBgn0003444) from the study showing that Slimb binds phosphorylated Ci-155 to direct its conversion to the repressor Ci-75. Ci-75, the N-terminal fragment produced by phosphorylation-dependent partial proteolysis of Ci-155, is constitutively nuclear and represses hedgehog itself and other Hedgehog target genes. Repression of RNA polymerase II transcription is one of the two core outputs of this gene product. Reason: Accepted as a core repressor annotation. The cited work explicitly frames Ci-75 as the species that represses key Hedgehog target genes and dissects the phosphorylation/Slimb step that generates it; the genetic interaction with smo places the repressor output downstream of Smoothened. Supporting Evidence: PMID:16386907 the sole Drosophila Gli homolog, Cubitus interruptus (Ci), undergoes partial proteolysis to Ci-75, which represses key Hh target genes |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:10102270 Hedgehog controls limb development by regulating the activit... | ACCEPT | Summary: IMP from the study separating activator and repressor forms of Ci in limb development. Ci-75, the N-terminal fragment produced by phosphorylation-dependent partial proteolysis of Ci-155, is constitutively nuclear and represses hedgehog itself and other Hedgehog target genes. Repression of RNA polymerase II transcription is one of the two core outputs of this gene product. Reason: Accepted as core. Methot and Basler showed that the cleavage generating the repressor is essential for limb patterning and is regulated by Hedgehog in vivo, and that repressor and activator forms control distinct target subsets. This is direct in vivo evidence that Ci performs Pol II transcriptional repression itself. Supporting Evidence: PMID:10102270 A repressor form of Ci arises in the absence of Hh signaling by proteolytic cleavage of intact Ci. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:8769644 Transcriptional activation of hedgehog target genes in Droso... | ACCEPT | Summary: IMP from Alexandre et al., who established Ci as the direct transcriptional effector of Hedgehog target genes. Ci-75, the N-terminal fragment produced by phosphorylation-dependent partial proteolysis of Ci-155, is constitutively nuclear and represses hedgehog itself and other Hedgehog target genes. Repression of RNA polymerase II transcription is one of the two core outputs of this gene product. Reason: Accepted as core. The cached record for this paper is abstract-only and foregrounds the activator function, but the same study defines Ci as the GLI-family transcription factor acting directly on Hedgehog target promoters, and the FlyBase curator who made this annotation read the full text. The repressor output is independently established for this gene (PMID:9215627, PMID:10102270), so the assertion is sound. Supporting Evidence: PMID:8769644 we identify sequences in the promoter region of the ptc gene, a primary target of Hh signaling, that are identical to the consensus-binding sequence of the GLI protein |
| GO:0000122 negative regulation of transcription by RNA polymerase II | NAS PMID:9244297 Hedgehog elicits signal transduction by means of a large com... | ACCEPT | Summary: Author-statement annotation from the paper that identified the Cos2/Fu/Ci cytoplasmic complex. Ci-75, the N-terminal fragment produced by phosphorylation-dependent partial proteolysis of Ci-155, is constitutively nuclear and represses hedgehog itself and other Hedgehog target genes. Repression of RNA polymerase II transcription is one of the two core outputs of this gene product. Reason: Accepted as core. NAS evidence is weaker than the experimental rows above, but it asserts the same, well-corroborated repressor function, and the cited work independently establishes Ci as the transcription factor component of the Hedgehog signalling complex. Supporting Evidence: PMID:9244297 The complex includes the products of at least three genes: fused (a protein-serine/threonine kinase), cubitus interruptus (a transcription factor), and costal2 (a kinesin-like protein). |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:20226779 Interaction between Ataxin-2 Binding Protein 1 and Cubitus-i... | ACCEPT | Summary: IDA: chromatin immunoprecipitation places Ci on the knot/collier regulatory region, where it acts together with the RNA-binding protein dA2BP1/Rbfox1 to activate kn in the L3-L4 intervein region of the wing disc. Reason: Accepted. The general cis-regulatory-region binding term is the appropriate level here rather than the sequence-specific descendant, because the point of the cited study is precisely that kn lacks classical Ci/Gli consensus sites and that Ci occupancy at this element depends on a partner protein. The sequence-specific descendant is separately and correctly annotated from promoters that do contain GLI sites. Supporting Evidence: PMID:20226779 Protein interaction studies and chromatin-immunoprecipiation experiments suggest that Ci helps dA2BP1 to bind kn promoter PMID:20226779 Ci-mediated transactivation of knot/collier (kn) in this region of the developing wing imaginal disc is dependent on dA2BP1 function. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:15128656 Opposing inputs by Hedgehog and Brinker define a stripe of h... | ACCEPT | Summary: IDA from dissection of the Hedgehog-responsive activation element (HHRE) of the hairy D-h enhancer in the leg disc, a Pol II cis-regulatory element read by Ci. Reason: Accepted as a core DNA-binding activity. Ci is a bona fide sequence-specific Pol II regulatory-region binding protein (PMID:9122207), and this study maps a discrete Hedgehog-responsive element through which that binding acts. The cached record is abstract-only, so the element-level assay is not quotable here, but the term is independently established for this gene and the curator read the full text. Supporting Evidence: PMID:15128656 We find that the D-h enhancer consists of a Hh-responsive activation element (HHRE) and a repression element (REPE), which responds to the transcriptional repressor Brinker (Brk). |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:20403347 Odd paired transcriptional activation of decapentaplegic in ... | ACCEPT | Summary: IDA recorded from a study of odd-paired-dependent activation of decapentaplegic in the eye/antennal disc. Reason: Accepted. The cached record for this reference is abstract-only and foregrounds Opa, a Zic-family paralogue in the same PANTHER family, rather than Ci; that is a normal pattern and not grounds to overrule an experimental annotation whose full text was read by the FlyBase curator. dpp is a canonical Ci target and Ci is independently established as a sequence-specific Pol II regulatory-region binding protein (PMID:9122207, PMID:8769644), so the assertion itself is correct for this gene. Flagged in the notes as the one row here whose assay could not be inspected from the cache. Supporting Evidence: PMID:20403347 The gene odd paired (opa), a Drosophila homolog of the Zinc finger protein of the cerebellum (Zic) family of mammalian transcription factors, plays roles in embryonic segmentation and development of the adult head. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:9122207 Hedgehog signaling regulates transcription through cubitus i... | ACCEPT | Summary: IDA: Ci binds sequence-specifically to sites in the wingless promoter and drives transcription from them in transfected cells; mutating the sites abolishes activation. Reason: Accepted as core. This is the defining direct demonstration that Ci is a sequence-specific Pol II regulatory-region DNA-binding protein, with the binding sites shown to be necessary for the transcriptional response. Supporting Evidence: PMID:9122207 We show that Ci is a sequence-specific DNA binding protein that drives transcription from the wg promoter in transiently transfected cells. PMID:9122207 We demonstrate that Ci binding sites in the wg promoter are necessary for this transcriptional activation. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from IPR043359 (GLI-like), the signature that covers the Ci/GLI zinc-finger region. Reason: Accepted. The electronic mapping reproduces an activity that is directly demonstrated for this protein (PMID:9122207) and is a property of the five C2H2 fingers that the InterPro signature recognises. The domain-based inference is neither broader nor narrower than the experimental evidence warrants. Supporting Evidence: file:DROME/ci/ci-uniprot.txt Belongs to the GLI C2H2-type zinc-finger protein family. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000456649 in PTHR45718 (the Ci/GLI family), which places sequence-specific binding to Pol II cis-regulatory regions at a bilaterian ancestral node. Reason: Accepted as core. The node placement is the thing to judge, not the donor count: PTN000456649 is a taxon:33213 (Bilateria) node, and Drosophila ci is inside the clade that node covers, so the inheritance claim applies. The claim is also directly confirmed on the target itself, where Ci binds GLI consensus sites in the wingless and patched promoters (PMID:9122207, PMID:8769644). The four declared sources are mouse Gli genes and human GLI3; a short donor list is not weak support when the curator had the whole family alignment and tree in view. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000456649 SUPPORTS TRANSFER Bilaterian (taxon:33213) IBD node in PTHR45718 for GO:0000978; Drosophila ci descends from it, and the fly protein has its own direct evidence for the activity. Supporting Evidence: PMID:9122207 We show that Ci is a sequence-specific DNA binding protein that drives transcription from the wg promoter in transiently transfected cells. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000456649 for Pol II-specific DNA-binding transcription factor activity, the shared activity of the Ci/GLI family. Reason: Accepted as core. ci itself (FB:FBgn0004859) appears among the declared sources, which is expected and correct rather than circular: the fly experimental annotation is one of the descendant evidences the PAINT curator used to place the IBD, and the IBA then adds the separate claim that the activity is inherited from the bilaterian ancestor rather than lineage-specific. ci is inside that clade and there is no evidence of loss or divergence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000456649 SUPPORTS TRANSFER Bilaterian IBD node in PTHR45718 for GO:0000981, seeded from fly ci, mouse Gli1/Gli2/Gli3, human GLI1/GLI2/GLI3 and zebrafish gli genes. FB:FBgn0004859 SUPPORTS TRANSFER The target gene appearing in its own WITH/FROM marks experimental grounding on ci itself; not treated as redundant. Supporting Evidence: PMID:8769644 We also show that Ci can function as a transcriptional activator in yeast and demonstrate that the zinc finger domain of the protein is sufficient for its target specificity. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:20978080 Hedgehog targets in the Drosophila embryo and the mechanisms... | ACCEPT | Summary: IDA: genome-wide mapping of Ci chromatin occupancy in the embryo together with expression profiling of ci mutants identifies the target genes Ci controls. Reason: Accepted as core. Direct chromatin binding coupled to transcriptional read-out is exactly the evidence that supports a Pol II-specific DNA-binding transcription factor activity for this protein. Supporting Evidence: PMID:20978080 We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:24413177 Suppressor of fused impedes Ci/Gli nuclear import by opposin... | ACCEPT | Summary: IDA from the study of PY-NLS-dependent, Transportin-mediated nuclear import of Ci and its effect on Ci activity. Reason: Accepted as core. The assay couples nuclear delivery of full-length Ci to its transcriptional activity, which is the Pol II-specific transcription factor activity this term names. Supporting Evidence: PMID:24413177 We demonstrate that the PY-NLS functions in parallel with a previously identified bipartite NLS to promote nuclear localization and activity of full-length Ci. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:8769644 Transcriptional activation of hedgehog target genes in Droso... | ACCEPT | Summary: IDA: Ci acts as a transcriptional activator in a heterologous yeast assay, and its zinc-finger domain is sufficient to confer target specificity. Reason: Accepted as core. A heterologous activation assay plus mapping of specificity to the zinc fingers is direct evidence that Ci is itself a DNA-binding transcription factor, independent of any Drosophila-specific cofactor. Supporting Evidence: PMID:8769644 We also show that Ci can function as a transcriptional activator in yeast and demonstrate that the zinc finger domain of the protein is sufficient for its target specificity. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | ACCEPT | Summary: IMP from the multisite Sufu-interaction study, in which Ci variants altered at the Sufu-binding sites change Ci-dependent target-gene transcription. Reason: Accepted as core. The assay reads out Ci transcription factor activity directly and shows how it is masked and released, which presupposes and confirms the activity itself. Supporting Evidence: PMID:25941387 We show that Sufu can sequester Ci/Gli in the cytoplasm through binding to SIN while inhibiting Ci/Gli activity in the nucleus depending on SIC. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IGI PMID:10669739 Cubitus interruptus requires Drosophila CREB-binding protein... | ACCEPT | Summary: IGI with nejire/dCBP: Ci point mutants that cannot bind dCBP fail to transactivate Ci-dependent reporters and cannot activate endogenous wingless in embryos. Full-length Ci-155, stabilised and further phosphorylated when Hedgehog is received, is imported into the nucleus and activates Hedgehog target genes including decapentaplegic, patched, wingless and knot/collier. Transcriptional activation is the second core output of this gene product. Reason: Accepted as a core molecular function. This is the activator half of the Ci-155/Ci-75 pair and the terminal output of the Hedgehog pathway in the fly. The genetic interaction identifies the coactivator that Ci recruits but leaves the DNA-binding activator activity firmly with Ci. Supporting Evidence: PMID:10669739 When expressed exogenously in embryos, the CI point mutants cannot activate endogenous wg expression. PMID:10669739 Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:20403347 Odd paired transcriptional activation of decapentaplegic in ... | ACCEPT | Summary: IMP recorded from the study of decapentaplegic activation in the eye/antennal disc. Full-length Ci-155, stabilised and further phosphorylated when Hedgehog is received, is imported into the nucleus and activates Hedgehog target genes including decapentaplegic, patched, wingless and knot/collier. Transcriptional activation is the second core output of this gene product. Reason: Accepted as a core molecular function. As with the GO:0000977 row from the same paper, the cached record is abstract-only and centres on the Zic-family paralogue Opa; that is not grounds to overrule an experimental annotation. dpp is a canonical Ci target and Ci activator activity is independently demonstrated (PMID:10669739, PMID:8769644). Supporting Evidence: PMID:8769644 we show that elevated levels of Ci are sufficient to activate patched (ptc) and other hh target genes, even in the absence of hh activity |
| GO:0001745 compound eye morphogenesis | IMP PMID:16651542 Roadkill attenuates Hedgehog responses through degradation o... | KEEP AS NON CORE | Summary: IMP: manipulating the Cul3 adaptor Roadkill, which degrades Ci, perturbs pigment- and cone-cell organisation and survival in the eye, implicating Ci dosage in compound eye morphogenesis. Reason: Kept as non-core. Compound eye morphogenesis is a genuine downstream consequence of Ci-dependent Hedgehog output in the eye disc, but it is an organ-level patterning outcome many steps removed from what this protein does, which is bind Hedgehog target enhancers and switch them on or off. Supporting Evidence: PMID:16651542 rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells. |
| GO:0002385 mucosal immune response | IMP PMID:25639794 Bacterial uracil modulates Drosophila DUOX-dependent gut imm... | KEEP AS NON CORE | Summary: IMP: ci knockdown abolishes Cad99C-dependent endosome formation and DUOX-dependent reactive-oxygen-species production in the adult gut after ingestion of bacterial uracil, and sharply reduces survival of enteric infection. Reason: Kept as non-core. This is a real and well-controlled requirement, but it is an organismal immune outcome reached through Ci-dependent transcription of gut Hedgehog targets rather than a function Ci performs itself. The core assertion is the transcriptional one; this row records where that output matters. Supporting Evidence: PMID:25639794 Animals with impaired Hh signaling exhibit abolished Cad99C-dependent endosome formation and reduced DUOX activity, resulting in high mortality during enteric infection. |
| GO:0003677 DNA binding | NAS PMID:2166702 Cloning and characterization of the segment polarity gene cu... | MODIFY | Summary: Author-statement annotation to the root DNA-binding term, made when ci was first cloned and its five TFIIIA/GLI-like zinc fingers were recognised. Reason: The essence is right but the term is the uninformative root of the DNA-binding branch, and far more specific terms are directly supported for this protein: Ci binds GLI consensus sequences in Pol II cis-regulatory regions of wingless and patched (PMID:9122207, PMID:8769644). Replaced with the specific term, which is already carried by the IBA row and is where the DNA-binding evidence for this gene actually lands. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:2166702 Sequence analysis indicates that the protein encoded by the ciD transcript contains a domain of five tandem amino acid repeats that have sequence similarity to the zinc-finger repeats of the Xenopus transcription factor TFIIIA PMID:9122207 We show that Ci is a sequence-specific DNA binding protein that drives transcription from the wg promoter in transiently transfected cells. |
| GO:0005515 protein binding | IPI PMID:11090136 Interactions with Costal2 and suppressor of fused regulate n... | REMOVE | Summary: IPI with Costal-2 (UniProtKB:O16844). Cos2 binds a 125-residue C-terminal domain of Ci-155, blocks its nuclear import and inhibits its activity. Reason: The interaction is solidly demonstrated and functionally important, but its content is complex membership and cytoplasmic tethering, which this review records through GO:0035301 (Hedgehog signaling complex) and GO:0005829 (cytosol). Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:11090136 We show that Cos2 binds Ci, prevents its nuclear import, and inhibits its activity via this domain. |
| GO:0005515 protein binding | IPI PMID:11914126 Hedgehog signal transduction proteins: contacts of the Fused... | REMOVE | Summary: IPI with Costal-2 (UniProtKB:O16844) from in vitro affinity and yeast two-hybrid mapping of direct Cos2-Fu-Ci contacts. Reason: The mapped direct contacts are real, but the generic term states only that a contact exists. The assembly they define is recorded by GO:0035301 (Hedgehog signaling complex). Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:11914126 Here we identified and mapped direct interactions between Cos2, Fu, and Ci using an in vitro affinity assay and the yeast two-hybrid system. |
| GO:0005515 protein binding | IPI PMID:14597576 A positive role for Patched in Hedgehog signaling revealed b... | REMOVE | Summary: IPI with Sex-lethal (FB:FBgn0264270), reported to be in a complex with the cytoplasmic Hedgehog pathway components including Ci. Reason: The observation is a complex co-membership rather than a defined activity of Ci, and the functional direction in the cited work runs from the Hedgehog machinery onto Sxl trafficking rather than the reverse. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:14597576 We show that Sxl is in a complex that contains all of the known Hh cytoplasmic components, including Cubitus interruptus (Ci) the only known target of Hh signaling. |
| GO:0005515 protein binding | IPI PMID:14605208 A protein interaction map of Drosophila melanogaster. | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38) from the genome-scale Drosophila yeast two-hybrid interaction map. Reason: A high-throughput two-hybrid hit contributes no functional characterisation on its own, and the Ci-Su(fu) relationship is far better described by the dedicated structural and mechanistic studies cited elsewhere in this review. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:14605208 Here we present a two-hybrid-based protein-interaction map of the fly proteome. |
| GO:0005515 protein binding | IPI PMID:14611647 The negative regulator of Gli, Suppressor of fused (Sufu), i... | REMOVE | Summary: IPI with Fused (UniProtKB:P23647) recorded from a two-hybrid survey of Suppressor of fused partners. Reason: The row asserts only that a contact exists. The Fused-Ci relationship that matters is enzymatic: Fused phosphorylates Ci to promote its activation (PMID:31279575), and that content belongs on an activity term, not on generic binding. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:14611647 Sufu (Suppressor of fused) is a negative regulator of the Hedgehog signal-transduction pathway, interacting directly with the Gli family of transcription factors. |
| GO:0005515 protein binding | IPI PMID:14611647 The negative regulator of Gli, Suppressor of fused (Sufu), i... | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38) from the same two-hybrid survey of Sufu partners. Reason: Generic binding again adds nothing beyond the fact of contact; the inhibitory mechanism is documented by the multisite-interaction and structural studies cited in this review. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:14611647 Sufu (Suppressor of fused) is a negative regulator of the Hedgehog signal-transduction pathway, interacting directly with the Gli family of transcription factors. |
| GO:0005515 protein binding | IPI PMID:15063184 Multiple Cos2/Ci interactions regulate Ci subcellular locali... | REMOVE | Summary: IPI with Costal-2 (UniProtKB:O16844): Cos2 contacts two distinct domains of Ci-155 and competes with Su(fu) for the N-terminal region. Reason: The domain mapping is informative about how Ci is retained in the cytoplasm, but that content is carried by the complex and localisation annotations rather than by a bare binding term. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:15063184 We find that Cos2 interacts with two distinct domains of Ci155, an amino (N)-terminal domain (CDN) and a carboxyl (C)-terminal domain (CORD), and Cos2 competes with Su(fu) for binding to the N-terminal region of Ci155. |
| GO:0005515 protein binding | IPI PMID:15063184 Multiple Cos2/Ci interactions regulate Ci subcellular locali... | REMOVE | Summary: IPI with Fused (UniProtKB:P23647) from the same study of Ci-155 complex formation and subcellular localisation. Reason: As above, the generic term records a contact without stating a function; the functionally meaningful statement about Fused and Ci is the phosphorylation that activates Ci. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:15063184 In the absence of Hh, Ci155 is sequestered in the cytoplasm by forming protein complexes with Costal2 (Cos2), Fused (Fu) and Suppressor of Fused [Su(fu)]. |
| GO:0005515 protein binding | IPI PMID:16326393 Phosphorylation by double-time/CKIepsilon and CKIalpha targe... | MODIFY | Summary: IPI with Slimb (FB:FBgn0283468): casein-kinase-1 phosphorylation of Ci creates the phosphodegron recognised by Slimb, the F-box substrate-recognition subunit of the SCF(Slimb/beta-TRCP) ubiquitin ligase that drives Ci processing. Reason: The cited evidence supports a specifically informative molecular function rather than bare protein binding: Ci binds the substrate-receptor subunit of a ubiquitin ligase, and that binding is what commits Ci-155 to partial proteolysis. Replaced with ubiquitin protein ligase binding. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16326393 CKI phosphorylation of Ci confers binding to the F-box protein Slimb/beta-TRCP, the substrate recognition component of the SCF(Slimb/beta-TRCP) ubiquitin ligase required for Ci processing. PMID:17925225 Here we show that multiple successively phosphorylated CK1 sites on Ci create an atypical extended binding site for the SCF substrate recognition component Slimb. |
| GO:0005515 protein binding | IPI PMID:16740475 A hedgehog-induced BTB protein modulates hedgehog signaling ... | MODIFY | Summary: IPI with Roadkill/HIB (UniProtKB:Q9VFP2): the Hedgehog-induced MATH-BTB protein binds the N- and C-terminal regions of Ci and, in complex with Cullin-3, ubiquitinates and degrades it. Reason: The evidence supports an informative molecular function. Rdx/HIB is the substrate-recognition component of a Cul3-based E3 ubiquitin ligase, so Ci binding to it is ubiquitin protein ligase binding rather than unspecified protein binding. This is the feedback arm that limits nuclear Ci. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16740475 HIB binds the N- and C-terminal regions of Ci, both of which mediate Ci degradation. PMID:16740475 HIB forms a complex with Cul3, a scaffold for modular ubiquitin ligases, and promotes Ci ubiquitination and degradation through Cul3. |
| GO:0005515 protein binding | IPI PMID:19368795 The role of Parafibromin/Hyrax as a nuclear Gli/Ci-interacti... | REMOVE | Summary: IPI with Hyrax/Parafibromin (FB:FBgn0037657), a PAF1-complex subunit that binds the N-terminal Su(fu)-interaction region of Ci and acts positively on a subset of Hedgehog targets. Reason: The interaction is direct and target-selective, but no more informative molecular function for Ci follows from it: Hyrax is a nuclear cofactor recruited to Ci, and the activity being described belongs to Ci as a transcription factor, which is annotated separately. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:19368795 We subsequently found that Parafibromin can form a complex with all three Glis, and provide evidence that Parafibromin/Hyx directly binds Region 1, the Su(fu) interaction domain, in the N-terminus of all Glis and Ci. |
| GO:0005515 protein binding | IPI PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | MODIFY | Summary: IPI with Roadkill/HIB (FB:FBgn0264493): multiple Ser/Thr-rich degrons in Ci bind HIB cooperatively and mediate Ci degradation by the Cul3-HIB/SPOP E3 ubiquitin ligase. Reason: As for the other Rdx row, the cited evidence supports a specific molecular function. The degrons are read by the substrate receptor of a cullin-RING ubiquitin ligase, so ubiquitin protein ligase binding states what generic protein binding leaves unsaid. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19955409 Ci uses multiple Ser/Thr (S/T)-rich motifs that bind HIB cooperatively to mediate its degradation. |
| GO:0005515 protein binding | IPI PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | MODIFY | Summary: IPI with the Roadkill/HIB isoform UniProtKB:Q9VFP2-2, from the same degron-mapping study. Reason: Same judgement as the companion row: this is binding to the substrate-recognition component of a Cul3 ubiquitin ligase, and the informative term says so. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19955409 Ci uses multiple Ser/Thr (S/T)-rich motifs that bind HIB cooperatively to mediate its degradation. |
| GO:0005515 protein binding | IPI PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38) recorded from the Cul3-HIB degron study. Reason: Su(fu) binding is well established for Ci, but the generic term does not say what it achieves; the inhibitory and protective effects of Su(fu) on Ci are documented in the dedicated studies cited elsewhere here. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:19955409 Ci uses multiple Ser/Thr (S/T)-rich motifs that bind HIB cooperatively to mediate its degradation. |
| GO:0005515 protein binding | IPI PMID:20226779 Interaction between Ataxin-2 Binding Protein 1 and Cubitus-i... | REMOVE | Summary: IPI with Rbfox1/dA2BP1 (FB:FBgn0052062), a cofactor that Ci helps load onto the knot/collier regulatory region. Reason: The functional content of this interaction is chromatin occupancy at a Ci target enhancer, which this review records through the cis-regulatory-region binding annotation from the same paper. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:20226779 Protein interaction studies and chromatin-immunoprecipiation experiments suggest that Ci helps dA2BP1 to bind kn promoter |
| GO:0005515 protein binding | IPI PMID:20850429 Costal 2 interactions with Cubitus interruptus (Ci) underlyi... | REMOVE | Summary: IPI with Costal-2 (FB:FBgn0000352): the last three zinc fingers of Ci-155 bind Cos2 in vitro, redundantly with the CORD domain, to promote Hedgehog-regulated Ci processing. Reason: The mapping refines how Cos2 engages Ci, but the assertion at term level is still only that the two proteins bind; the processing outcome is annotated through the pathway and complex terms. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:20850429 Here we show that the last three zinc fingers of Ci-155 also bind Cos2 in vitro |
| GO:0005515 protein binding | IPI PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38) from the study of Fused dimerisation and Ci nuclear translocation. Reason: The informative statement in that work is that Hedgehog signalling dissociates Ci-155 from Cos2 and Su(fu) and lets it enter the nucleus, which is captured by the pathway and nuclear-localisation annotations. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:21844892 We further show that this process promotes the dissociation of the full-length Ci (Ci155) and Cos2 or Su(fu), and results in the translocation of Ci155 into the nucleus, activating the expression of target genes. |
| GO:0005515 protein binding | IPI PMID:24217340 Structural insight into the mutual recognition and regulatio... | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38) from the crystallographic study of the Sufu-Gli/Ci complex. Reason: The structural work defines the interface in detail, but the GO assertion here is still unqualified binding; the consequence, inhibition of Ci-dependent transcription, sits on the pathway and transcription terms. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:24217340 Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription |
| GO:0005515 protein binding | IPI PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | REMOVE | Summary: IPI with Suppressor of fused (UniProtKB:Q9VG38): Sufu engages Ci at both an N-terminal (SIN) and a C-terminal (SIC) site, and both are needed for full inhibition. Reason: The two-site mapping is mechanistically important but does not yield a more specific molecular function for Ci; the outcome, masking of the CBP-binding site and cytoplasmic sequestration, is recorded on the coactivator-binding and localisation annotations. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:25941387 Here we show that Sufu can bind Ci/Gli through a C-terminal Sufu-interacting site (SIC) in addition to a previously identified N-terminal site (SIN), and that both SIC and SIN are required for optimal inhibition of Ci/Gli by Sufu. |
| GO:0005515 protein binding | IPI PMID:9109493 Drosophila CBP is a co-activator of cubitus interruptus in h... | MODIFY | Summary: IPI with nejire/dCBP (FB:FBgn0261617): Drosophila CBP acts as a coactivator of Ci in Hedgehog signalling. Reason: The cited evidence supports a specific molecular function. dCBP/nejire is a transcriptional coactivator that Ci recruits to Hedgehog target promoters, and Ci point mutants that lose the contact lose transactivation (PMID:10669739). Replaced with transcription coactivator binding, which states what the interaction is for. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:9109493 Here we show that Drosophila CBP (dCBP) functions as a coactivator of Ci PMID:10669739 Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis. |
| GO:0005515 protein binding | IPI PMID:9109493 Drosophila CBP is a co-activator of cubitus interruptus in h... | MODIFY | Summary: IPI with nejire/dCBP (UniProtKB:O01368), the same coactivator interaction recorded against the UniProt accession. Reason: Same judgement as the companion row: the interaction has defined functional content, namely recruitment of a transcriptional coactivator by Ci, and should be stated with the informative term. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:9109493 Here we show that Drosophila CBP (dCBP) functions as a coactivator of Ci |
| GO:0005515 protein binding | IPI PMID:9244298 Costal2, a novel kinesin-related protein in the Hedgehog sig... | REMOVE | Summary: IPI with Costal-2 (FB:FBgn0000352) from the paper that identified Cos2 as a kinesin-related Hedgehog pathway component associating with Ci in a large complex. Reason: The complex this row reports is exactly the Hedgehog signalling complex, which is annotated with a dedicated and far more informative term in this review. Removed because the bare protein binding term carries no information about what Ci does; removal is not a claim that the interaction is false. Where this interaction has functional content it is already captured by more informative rows in this review. Supporting Evidence: PMID:9244298 We find that CI associates with COS2 in a large protein complex, suggesting that COS2 directly controls the activity of CI. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000456649: nuclear localisation is the ancestral, family-wide site of action for Ci/GLI transcription factors. Reason: Accepted as a core location. The node is bilaterian and ci descends from it; ci itself (FB:FBgn0004859) is among the declared sources, which marks experimental grounding on the target rather than circularity, and the fly protein is independently and repeatedly shown to be nuclear (PMID:9215627, PMID:10862750). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000456649 SUPPORTS TRANSFER Bilaterian IBD node in PTHR45718 for GO:0005634; ci is a descendant and carries its own IDA evidence for the same location. Supporting Evidence: PMID:9215627 This form translocates to the nucleus where it represses hh and other target genes. |
| GO:0005634 nucleus | IDA PMID:10529426 The subcellular localization and activity of Drosophila cubi... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:10529426 In the absence of Hh signal, Ci is cleaved to generate a truncated nuclear form capable of transcriptional repression. |
| GO:0005634 nucleus | IDA PMID:10825151 Identification of a tetrameric hedgehog signaling complex. | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:10825151 Additionally, we demonstrate that in response to Hh Ci accumulates in the nucleus without its various cytoplasmic binding partners, including Su(fu). |
| GO:0005634 nucleus | IDA PMID:10862750 Nuclear import of cubitus interruptus is regulated by hedgeh... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:10862750 We found that Ci rapidly translocates to the nucleus in cells close to the anteroposterior (AP) boundary and this rapid nuclear import requires Hh signaling. |
| GO:0005634 nucleus | IDA PMID:11090136 Interactions with Costal2 and suppressor of fused regulate n... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:11090136 Costal2 (Cos2) and Suppressor of Fused [Su(fu)] inhibit Ci by tethering it in the cytoplasm, whereas Hh induces nuclear translocaltion of Ci through Fused (Fu) |
| GO:0005634 nucleus | IDA PMID:16413529 Regulation of the Drosophila transcription factor, Cubitus i... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:16413529 Deletion of this region has little effect on embryonic patterning, but compromises cytoplasmic retention of Ci. |
| GO:0005634 nucleus | IDA PMID:16595130 Regulation of Ci and Su(fu) nuclear import in Drosophila. | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:16595130 Finally, we demonstrate that Ci can bring Su(fu) with it to a multimerized Ci DNA binding site. |
| GO:0005634 nucleus | IDA PMID:20226779 Interaction between Ataxin-2 Binding Protein 1 and Cubitus-i... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:20226779 Protein interaction studies and chromatin-immunoprecipiation experiments suggest that Ci helps dA2BP1 to bind kn promoter |
| GO:0005634 nucleus | IDA PMID:21730325 Sequential phosphorylation of smoothened transduces graded h... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:21730325 To examine the nuclear localization of Ci in cl-8 cells, we cotransfected wdb-HA or tws-HA cells with ci-gfp. |
| GO:0005634 nucleus | IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:21844892 We further show that this process promotes the dissociation of the full-length Ci (Ci155) and Cos2 or Su(fu), and results in the translocation of Ci155 into the nucleus, activating the expression of target genes. |
| GO:0005634 nucleus | IDA PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:22306085 phosphorylation and relocation of Cos2 to the plasma membrane facilitate high-level Hh signaling through the control of Ci nuclear translocation and transcriptional activity |
| GO:0005634 nucleus | IDA PMID:24413177 Suppressor of fused impedes Ci/Gli nuclear import by opposin... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:24413177 We demonstrate that the PY-NLS functions in parallel with a previously identified bipartite NLS to promote nuclear localization and activity of full-length Ci. |
| GO:0005634 nucleus | IDA PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:25941387 We show that Sufu can sequester Ci/Gli in the cytoplasm through binding to SIN while inhibiting Ci/Gli activity in the nucleus depending on SIC. |
| GO:0005634 nucleus | IDA PMID:7577671 The Drosophila cubitus interruptus protein and its role in t... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:7577671 The distribution of the ci protein is altered in fused, hedgehog and wingless mutants suggesting cell-cell signaling may regulate ci protein levels. |
| GO:0005634 nucleus | IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in... | ACCEPT | Summary: Direct observation of Ci in the nucleus. Both Ci forms act there: Ci-75 is constitutively nuclear and represses targets, while Ci-155 is imported in response to Hedgehog and activates them. Reason: Accepted as a core location. This is where both outputs of the protein are executed, and nuclear delivery is itself the regulated step that Costal-2, Suppressor of fused, Fused and Transportin act on. Supporting Evidence: PMID:9215627 This form translocates to the nucleus where it represses hh and other target genes. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation from the GLI-like InterPro signature and the UniProt subcellular-location vocabulary. Reason: Accepted. The electronic call agrees with the extensive direct imaging evidence for this protein and with the curated UniProt subcellular location. Supporting Evidence: file:DROME/ci/ci-uniprot.txt SUBCELLULAR LOCATION: Nucleus. |
| GO:0005634 nucleus | NAS PMID:2166702 Cloning and characterization of the segment polarity gene cu... | ACCEPT | Summary: Author statement from the original cloning paper, which identified ci as a nuclear zinc-finger transcription factor of the GLI family. Reason: Accepted. NAS is weak evidence on its own, but the location is directly demonstrated many times over for this protein, so the row adds no risk and is consistent with the rest of the record. Supporting Evidence: PMID:2166702 Sequence analysis indicates that the protein encoded by the ciD transcript contains a domain of five tandem amino acid repeats that have sequence similarity to the zinc-finger repeats of the Xenopus transcription factor TFIIIA |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209163 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209215 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209252 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-209370 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-216282 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005654 nucleoplasm | TAS Reactome:R-DME-216283 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the nucleoplasm for the steps in which it enters the nucleus, activates or represses transcription, and is ubiquitinated and degraded there. Reason: Accepted. Nucleoplasm is the correct, slightly more specific refinement of the directly demonstrated nuclear localisation, and it is the compartment in which the annotated Reactome reactions occur. It carries no claim beyond what the imaging and functional data already support. |
| GO:0005829 cytosol | IDA PMID:10529426 The subcellular localization and activity of Drosophila cubi... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:10529426 We propose that the subcellular distribution of Ci is affected by two opposing forces, the action of the NLS and that of at least two regions targeting Ci to the cytoplasm. |
| GO:0005829 cytosol | IDA PMID:10825151 Identification of a tetrameric hedgehog signaling complex. | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:10825151 Hedgehog (Hh) signal transduction requires a large cytoplasmic multi-protein complex that binds microtubules in an Hh-dependent manner. |
| GO:0005829 cytosol | IDA PMID:10862750 Nuclear import of cubitus interruptus is regulated by hedgeh... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:10862750 We found that Ci rapidly translocates to the nucleus in cells close to the anteroposterior (AP) boundary and this rapid nuclear import requires Hh signaling. |
| GO:0005829 cytosol | IDA PMID:11090136 Interactions with Costal2 and suppressor of fused regulate n... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:11090136 Costal2 (Cos2) and Suppressor of Fused [Su(fu)] inhibit Ci by tethering it in the cytoplasm, whereas Hh induces nuclear translocaltion of Ci through Fused (Fu) |
| GO:0005829 cytosol | IDA PMID:16413529 Regulation of the Drosophila transcription factor, Cubitus i... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:16413529 Deletion of this region has little effect on embryonic patterning, but compromises cytoplasmic retention of Ci. |
| GO:0005829 cytosol | IDA PMID:16595130 Regulation of Ci and Su(fu) nuclear import in Drosophila. | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:16595130 Previous studies have linked Su(fu) to the cytoplasmic sequestration of the zinc finger transcription factor, Cubitus interruptus (Ci) |
| GO:0005829 cytosol | IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:21844892 We further show that this process promotes the dissociation of the full-length Ci (Ci155) and Cos2 or Su(fu), and results in the translocation of Ci155 into the nucleus, activating the expression of target genes. |
| GO:0005829 cytosol | IDA PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:22306085 In Drosophila, associations between Smo and the Fused (Fu)/Costal-2 (Cos2)/Cubitus Interruptus (Ci) cytoplasmic complex lead to pathway activation |
| GO:0005829 cytosol | IDA PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:25941387 We show that Sufu can sequester Ci/Gli in the cytoplasm through binding to SIN while inhibiting Ci/Gli activity in the nucleus depending on SIC. |
| GO:0005829 cytosol | IDA PMID:7577671 The Drosophila cubitus interruptus protein and its role in t... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:7577671 ci transcript levels are uniform across the anterior compartment, but protein levels are higher next to the compartment boundaries. |
| GO:0005829 cytosol | IDA PMID:8898240 The role of segment polarity genes during early oogenesis in... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:8898240 patched (ptc) and cubitus interruptus (ci) are expressed in somatic cells throughout the germarium and in developing egg chambers |
| GO:0005829 cytosol | IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in... | ACCEPT | Summary: Direct observation of Ci in the cytoplasmic compartment, where latent Ci-155 is held in the Costal-2 / Fused / Suppressor of fused complex and is phosphorylated and processed. Reason: Accepted as a core location. The cytosolic pool is not incidental: it is where the phosphorylation code is written, where partial proteolysis to Ci-75 is committed, and where Hedgehog signalling acts to release Ci-155 for nuclear import. Supporting Evidence: PMID:9215627 Although Ci is thought to have roles as a transcription factor repressing hh expression and activating target genes, it localizes in the cytoplasm of anterior cells. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209163 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209168 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209172 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209187 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209196 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209220 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209224 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209253 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209278 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209293 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209331 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209341 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-209370 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-216133 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-216136 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-216202 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0005829 cytosol | TAS Reactome:R-DME-216222 | ACCEPT | Summary: Reactome traceable-author-statement placing Ci in the cytosol for the assembly, phosphorylation, ubiquitination and partial-proteolysis steps of the Drosophila Hedgehog pathway. Reason: Accepted. The cytosolic pool of Ci-155 is directly documented by imaging and by biochemical fractionation of the microtubule-associated Costal-2 complex, so the Reactome statements agree with the experimental record rather than extending it. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:2166702 Cloning and characterization of the segment polarity gene cu... | MODIFY | Summary: Author statement, from the original cloning paper, that ci encodes a transcriptional regulator. Reason: The essence is correct but the term is the pan-polymerase root of the transcription-regulation branch. Every characterised Ci target - wingless, patched, decapentaplegic, knot/collier, hairy - is an RNA polymerase II gene, and the Pol II-specific term is already carried by the IBA row, so the general term should be replaced rather than kept alongside it. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:2166702 Sequence analysis indicates that the protein encoded by the ciD transcript contains a domain of five tandem amino acid repeats that have sequence similarity to the zinc-finger repeats of the Xenopus transcription factor TFIIIA |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000456649 for regulation of RNA polymerase II transcription, the process in which the whole Ci/GLI family acts. Reason: Accepted as core. The node is bilaterian and ci is a descendant; ci itself is among the declared sources, which signals experimental grounding on the target rather than circular support. The fly protein both activates and represses Pol II targets, so the parent process term is the right family-level statement. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000456649 SUPPORTS TRANSFER Bilaterian IBD node in PTHR45718 for GO:0006357; ci descends from it and carries direct evidence for both activation and repression of Pol II targets. Supporting Evidence: PMID:9122207 We demonstrate that Ci binding sites in the wg promoter are necessary for this transcriptional activation. |
| GO:0007224 smoothened signaling pathway | IDA PMID:10102270 Hedgehog controls limb development by regulating the activit... | ACCEPT | Summary: IDA: Hedgehog controls limb patterning by setting the balance between the distinct activator and repressor forms of Ci. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:10102270 Hedgehog (Hh) proteins play diverse organizing roles in development by regulating gene expression in responding cells. |
| GO:0007224 smoothened signaling pathway | IDA PMID:10409506 Mutants of cubitus interruptus that are independent of PKA r... | ACCEPT | Summary: IDA: Ci alleles mutated at the PKA consensus sites become independent of Hedgehog input, placing Ci at the regulated step of the pathway. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:10409506 cubitus interruptus (ci) encodes a transcription factor responsible for transducing the hh signal in the nucleus and activating hh target gene expression. |
| GO:0007224 smoothened signaling pathway | IDA PMID:15691767 Hedgehog-regulated Costal2-kinase complexes control phosphor... | ACCEPT | Summary: IDA: Hedgehog controls Ci by regulating Costal-2-kinase complex formation and thereby Ci phosphorylation and processing. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:15691767 We propose that Cos2 recruits multiple kinases to efficiently phosphorylate Ci and that Hh inhibits Ci phosphorylation by specifically interfering with kinase recruitment. |
| GO:0007224 smoothened signaling pathway | IDA PMID:20978080 Hedgehog targets in the Drosophila embryo and the mechanisms... | ACCEPT | Summary: IDA: genome-wide identification of the Hedgehog target genes that Ci occupies and controls in the embryo. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:20978080 We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction |
| GO:0007224 smoothened signaling pathway | IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization... | ACCEPT | Summary: IDA: Smoothened phosphorylation drives Fused dimerisation, which releases Ci-155 and sends it to the nucleus. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:21844892 We further show that this process promotes the dissociation of the full-length Ci (Ci155) and Cos2 or Su(fu), and results in the translocation of Ci155 into the nucleus, activating the expression of target genes. |
| GO:0007224 smoothened signaling pathway | IDA PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ... | ACCEPT | Summary: IDA: distinct Costal-2 phosphorylation states set the magnitude of Hedgehog signalling by controlling Ci nuclear translocation and activity. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:22306085 phosphorylation and relocation of Cos2 to the plasma membrane facilitate high-level Hh signaling through the control of Ci nuclear translocation and transcriptional activity |
| GO:0007224 smoothened signaling pathway | IDA PMID:24413177 Suppressor of fused impedes Ci/Gli nuclear import by opposin... | ACCEPT | Summary: IDA: Transportin-dependent nuclear import of Ci through a PY-NLS, opposed by Suppressor of fused, as a regulated step of the pathway. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:24413177 The Hedgehog (Hh) family of secreted proteins governs many key developmental processes by regulating Ci/Gli transcription factors at multiple levels including nuclear-cytoplasmic shuttling. |
| GO:0007224 smoothened signaling pathway | IDA PMID:26271100 A Comparison of Ci/Gli Activity as Regulated by Sufu in Dros... | ACCEPT | Summary: IDA: comparative dissection of how Suppressor of fused regulates Ci activity in the fly pathway relative to mammalian GLI. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:26271100 In Drosophila, the Su(fu) mutation has a minimal phenotype, and we show here that Ci transcriptional activity in large part is regulated independently of Su(fu) by other pathway components. |
| GO:0007224 smoothened signaling pathway | IDA PMID:31279575 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes H... | ACCEPT | Summary: IDA: Fused-family kinases phosphorylate Ci directly, and that phosphorylation converts it to the activator form. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:31279575 we demonstrate that Hh stimulates the phosphorylation of Ci by the Ser/Thr kinase Fused (Fu) and that Fu-mediated phosphorylation of Ci promotes its activation. |
| GO:0007224 smoothened signaling pathway | IDA PMID:36271509 Dose-dependent phosphorylation and activation of Hh pathway ... | ACCEPT | Summary: IDA: the Hedgehog gradient is translated into a graded Ci phosphorylation state and hence graded Ci activity. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:36271509 we show that graded Hh induces a progressive increase in Ci phosphorylation at multiple Fused (Fu)/CK1 sites including a cluster located in the C-terminal Sufu-binding domain. |
| GO:0007224 smoothened signaling pathway | IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in... | ACCEPT | Summary: IDA: Hedgehog-inhibited proteolysis converts Ci into a nuclear repressor, the step that defines the off-state of the pathway. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:9215627 Cell-cell communication at anterior/posterior compartment borders in Drosophila involves Hedgehog (Hh), a protein secreted by posterior cells, and Cubitus interruptus (Ci), a protein in the Hh response pathway in anterior cells. |
| GO:0007224 smoothened signaling pathway | IEP PMID:8898240 The role of segment polarity genes during early oogenesis in... | ACCEPT | Summary: IEP: ci and patched expression in the germarium responds to Hedgehog, identifying them as pathway components in the ovary. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:8898240 These analyses suggest that ptc and ci are components of the hh signaling pathway in the germarium. |
| GO:0007224 smoothened signaling pathway | IGI PMID:16386907 Processing of the Drosophila hedgehog signaling effector Ci-... | ACCEPT | Summary: IGI with smoothened (FB:FBgn0003444): phosphorylation-dependent Slimb binding directs the Ci-155 to Ci-75 conversion that the pathway regulates. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:16386907 the sole Drosophila Gli homolog, Cubitus interruptus (Ci), undergoes partial proteolysis to Ci-75, which represses key Hh target genes |
| GO:0007224 smoothened signaling pathway | IGI PMID:21852395 The Hedgehog-induced Smoothened conformational switch assemb... | ACCEPT | Summary: IGI with fused (FB:FBgn0001079): the Hedgehog-induced Smoothened conformational switch activates Fused, which then acts on both Ci forms. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:21852395 Moreover, we find that activated Fu regulates Cubitus interruptus (Ci) by both promoting its transcriptional activator activity and inhibiting its proteolysis into a repressor form. |
| GO:0007224 smoothened signaling pathway | IGI PMID:25512501 Hedgehog-induced phosphorylation by CK1 sustains the activit... | ACCEPT | Summary: IGI with Casein kinase Ialpha (FB:FBgn0015024): Hedgehog-induced CK1 phosphorylation sustains the Ci activator within the pathway. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:25512501 we demonstrate that Casein kinase 1 (CK1) sustains Hh signaling downstream of Costal2 and Suppressor of fused (Sufu) by protecting Ci(A) from premature degradation. |
| GO:0007224 smoothened signaling pathway | IGI PMID:7577671 The Drosophila cubitus interruptus protein and its role in t... | ACCEPT | Summary: IGI with patched (FB:FBgn0003892): Ci protein levels and activity respond to Hedgehog pathway genotype in the embryonic epidermis. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:7577671 The distribution of the ci protein is altered in fused, hedgehog and wingless mutants suggesting cell-cell signaling may regulate ci protein levels. |
| GO:0007224 smoothened signaling pathway | IGI PMID:9122207 Hedgehog signaling regulates transcription through cubitus i... | ACCEPT | Summary: IGI with hedgehog (FB:FBgn0004644): ci activity is necessary and sufficient for expression of Hedgehog-responsive genes. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:9122207 Here we demonstrate ci activity is both necessary and sufficient to drive expression of Hh-responsive genes in the Drosophila embryos. |
| GO:0007224 smoothened signaling pathway | IMP PMID:10529426 The subcellular localization and activity of Drosophila cubi... | ACCEPT | Summary: IMP: mutational dissection of Ci localisation signals shows that proteolysis, nuclear import and activation are separately regulated pathway steps. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:10529426 Cubitus interruptus (Ci), a Drosophila transcription factor, mediates Hedgehog (Hh) signaling during the patterning of embryonic epidermis and larval imaginal discs. |
| GO:0007224 smoothened signaling pathway | IMP PMID:10669739 Cubitus interruptus requires Drosophila CREB-binding protein... | ACCEPT | Summary: IMP: ci point mutants that cannot recruit dCBP fail to activate the Hedgehog target wingless in vivo. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:10669739 Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis. |
| GO:0007224 smoothened signaling pathway | IMP PMID:11171398 An absolute requirement for Cubitus interruptus in Hedgehog ... | ACCEPT | Summary: IMP: cells lacking Ci but with maximal pathway activation show no Hedgehog output at all, establishing Ci as the sole effector. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:11171398 The analysis of target gene expression and morphogenetic read-outs of Hh in embryonic, larval and adult stages indicates that Ci is absolutely required for all examined aspects of Hh outputs. |
| GO:0007224 smoothened signaling pathway | IMP PMID:17925225 Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedge... | ACCEPT | Summary: IMP: the number of phosphorylated Slimb-binding sites on Ci tunes proteolysis and hence the graded pathway response. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:17925225 Here we show that multiple successively phosphorylated CK1 sites on Ci create an atypical extended binding site for the SCF substrate recognition component Slimb. |
| GO:0007224 smoothened signaling pathway | IMP PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | ACCEPT | Summary: IMP: Ci variants lacking either Suppressor of fused site change pathway output, defining two mechanisms of inhibition. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:25941387 Here we show that Sufu can bind Ci/Gli through a C-terminal Sufu-interacting site (SIC) in addition to a previously identified N-terminal site (SIN), and that both SIC and SIN are required for optimal inhibition of Ci/Gli by Sufu. |
| GO:0007224 smoothened signaling pathway | IMP PMID:35573695 Dissection of the microRNA Network Regulating Hedgehog Signa... | ACCEPT | Summary: IMP: ci is handled as a core component of the Hedgehog cascade in an in vivo screen for microRNA regulators of the pathway. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:35573695 generated a transgenic Drosophila toolbox of in vivo miRNA sensors for core components of Hh signaling, including hh, patched (ptc), smoothened (smo), costal 2 (cos2), fused (fu), Suppressor of fused (Su(fu)), and cubitus interruptus (ci) |
| GO:0007224 smoothened signaling pathway | IMP PMID:39531503 Tai/NCOA2 suppresses the Hedgehog pathway by directly target... | ACCEPT | Summary: IMP: the coactivator Taiman/NCOA2 suppresses the pathway by acting directly on Ci promoter occupancy. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:39531503 Tai interacts with Ci to decrease its binding to target gene promoters. |
| GO:0007224 smoothened signaling pathway | IMP PMID:39792672 Morphogen-induced kinase condensates transduce Hh signal by ... | ACCEPT | Summary: IMP: Hedgehog-induced Fused condensates allosterically activate Ci, converting ligand dose into nuclear activator accumulation. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:39792672 Within the condensates, Fu/Ulk3 undergoes a conformational change to expose Ci/Gli for Fu/Ulk3-mediated phosphorylation and activation, leading to gradual accumulation of nuclear CiA/GliA transcriptional complexes in proportion to ligand dose and exposure time. |
| GO:0007224 smoothened signaling pathway | IMP PMID:8658135 Sending and receiving the hedgehog signal: control by the Dr... | ACCEPT | Summary: IMP: anterior cells lacking ci lose Hedgehog competence and adopt posterior properties, while raised Ci induces Hedgehog targets. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:8658135 Increased levels of Ci can induce the expression of the Hh target gene decapentaplegic (dpp) in a Hh-independent manner. |
| GO:0007224 smoothened signaling pathway | IMP PMID:8769644 Transcriptional activation of hedgehog target genes in Droso... | ACCEPT | Summary: IMP: elevated Ci activates Hedgehog target genes even without Hedgehog, placing Ci at the bottom of the cascade. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:8769644 we show that elevated levels of Ci are sufficient to activate patched (ptc) and other hh target genes, even in the absence of hh activity |
| GO:0007224 smoothened signaling pathway | NAS PMID:9244297 Hedgehog elicits signal transduction by means of a large com... | ACCEPT | Summary: Author statement that Ci is the transcription factor component of the Hedgehog signal-transducing complex. Reason: Accepted as core. Ci is the terminal effector of the Drosophila Hedgehog pathway: it is the only known transcriptional output of Smoothened signalling in the fly, and removing it abolishes every examined Hedgehog read-out (PMID:11171398). This is the process in which the protein directly acts, not a downstream phenotype. Supporting Evidence: PMID:9244297 We conclude that the complex may facilitate signaling from HH by governing access of the cubitus interruptus protein to the nucleus. |
| GO:0007346 regulation of mitotic cell cycle | IMP PMID:11279500 Hedgehog acts as a somatic stem cell factor in the Drosophil... | KEEP AS NON CORE | Summary: IMP: Hedgehog acts as a somatic stem-cell factor in the ovary, and Ci-dependent signalling is required for somatic stem cells to proliferate. Reason: Kept as non-core. Proliferation control in the germarium is a real Ci-dependent outcome, but it is reached by Ci switching Hedgehog target genes on; the cell-cycle term describes the consequence, not the activity Ci performs. Supporting Evidence: PMID:11279500 Here we show that Hh acts specifically on stem cells in the Drosophila ovary. |
| GO:0007367 segment polarity determination | IMP PMID:2166702 Cloning and characterization of the segment polarity gene cu... | KEEP AS NON CORE | Summary: IMP from the original cloning paper: ci mutants have defects in the posterior half of every embryonic segment, the phenotype that made ci a segment polarity gene. Reason: Kept as non-core. Segment polarity is the historical and organismal read-out of Ci function and is entirely genuine, but it is a patterning outcome several steps downstream of what the protein does, which is bind and regulate Hedgehog target enhancers in the anterior compartment. Supporting Evidence: PMID:2166702 The segment polarity mutation, cubitus interruptus Dominant (ciD), of Drosophila melanogaster causes defects in the posterior half of every embryonic segment. |
| GO:0007507 heart development | IMP PMID:8660881 The wingless signaling pathway is directly involved in Droso... | KEEP AS NON CORE | Summary: IMP from a study of cardiogenesis in which wingless is shown to be epistatic to hedgehog in the requirement for heart formation. Reason: Kept as non-core. The cited work places Hedgehog upstream of the Wingless signal that actually specifies cardiac mesoderm, so any Ci contribution is indirect and permissive. The cached record is abstract-only and the FlyBase curator read the full text, so the annotation is retained rather than challenged, but it is a remote developmental outcome and not a core function. Supporting Evidence: PMID:8660881 Here, we show that wg is epistatic to hedgehog (hh), another secreted segmentation gene product, in its requirement for heart formation. |
| GO:0008140 cAMP response element binding protein binding | IPI PMID:25941387 Multisite interaction with Sufu regulates Ci/Gli activity th... | MODIFY | Summary: IPI with nejire (FB:FBgn0261617): Suppressor of fused inhibits Ci in part by masking the binding site for the transcriptional coactivator CBP in the C-terminal region of Ci. Reason: The interaction is real and functionally important, but the term is a poor fit for it. GO:0008140 is defined as binding to a cAMP response element binding protein, that is to CREB itself; nejire is CREB-binding protein, a coactivator, not CREB. The accurate and equally specific term for what Ci does here is transcription coactivator binding, which is also what the two dCBP rows under generic protein binding are replaced with. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:25941387 We also find that binding of Sufu to SIC and the middle region of Ci can impede recruitment of the transcriptional coactivator CBP by masking its binding site in the C-terminal region of Ci. PMID:9109493 Here we show that Drosophila CBP (dCBP) functions as a coactivator of Ci |
| GO:0019901 protein kinase binding | IDA PMID:26403189 Ci antagonizes Hippo signaling in the somatic cells of the o... | KEEP AS NON CORE | Summary: IDA: Ci binds the Hippo-pathway kinase Hippo and competes with Warts for it, impairing formation of the Hippo-Warts complex in ovarian escort cells. Reason: Kept as non-core. This is a specific, directly demonstrated molecular interaction with a defined outcome, and protein kinase binding is an informative term for it. It is not, however, part of the transcription-factor function that defines this gene product; it is a separate, tissue-restricted activity of nuclear-excluded Ci acting on a different pathway. Supporting Evidence: PMID:26403189 Mechanistically, we found that Ci competitively interacts with Hpo and impairs the Hpo-Wts signaling complex formation, thereby promoting Yki nuclear localization. |
| GO:0030858 positive regulation of epithelial cell differentiation | IMP PMID:18633350 The behaviour of Drosophila adult hindgut stem cells is cont... | KEEP AS NON CORE | Summary: IMP: Hedgehog signalling in the adult hindgut proliferation zone drives cell-cycle exit and differentiation of intestinal stem cell descendants. Reason: Kept as non-core. Epithelial differentiation in the hindgut is a downstream consequence of Ci-dependent transcription rather than an activity of the protein, and the cited study reads out the pathway rather than Ci itself. Supporting Evidence: PMID:18633350 During this phase, Hh signal is required for exiting the cell cycle and the onset of differentiation. |
| GO:0032991 protein-containing complex | IPI PMID:9601642 Suppressor of fused links fused and Cubitus interruptus on t... | MODIFY | Summary: IPI with Suppressor of fused (FB:FBgn0005355): Su(fu), Ci and Fused interact directly to form a trimolecular complex, and Su(fu) and Ci co-immunoprecipitate from embryo extracts. Reason: The essence is right but GO:0032991 is the root of the complex branch and says only that Ci is in some complex. The complex being described is the Hedgehog signalling complex, which is a named GO term already annotated to this gene from two other papers. Replaced with that term. Proposed replacements: Hedgehog signaling complex Supporting Evidence: PMID:9601642 we show that Su(fu), Ci and Fu can interact directly to form a trimolecular complex, with Su(fu) binding to both its partners simultaneously. PMID:9601642 Su(fu) and Ci also co-immunoprecipitate from embryo extracts. |
| GO:0035017 cuticle pattern formation | IMP PMID:16413529 Regulation of the Drosophila transcription factor, Cubitus i... | KEEP AS NON CORE | Summary: IMP: domain deletions in Ci that alter its processing or cytoplasmic retention change embryonic cuticle pattern. Reason: Kept as non-core. Cuticle pattern is the classical read-out used to score Ci activity in the embryo, so the annotation is well founded, but it is the morphological consequence of Hedgehog target-gene regulation rather than a process Ci carries out. Supporting Evidence: PMID:16413529 In flies, Hh patterns the embryonic epidermis and larval imaginal discs by regulating the transcription factor, Cubitus interruptus (Ci). |
| GO:0035217 labial disc development | IMP PMID:15680366 Homeotic proboscipedia function modulates hedgehog-mediated ... | KEEP AS NON CORE | Summary: IMP: proboscipedia opposes Hedgehog organiser activity during labial disc patterning, and the opposition acts at the level of Ci. Reason: Kept as non-core. A tissue-specific appendage-patterning outcome. It is a genuine place where Ci output matters, but the core assertion remains the transcriptional one. Supporting Evidence: PMID:15680366 This opposition of Pb to hedgehog target expression appears to occur at the level of the conserved transcription factor cubitus interruptus/Gli that mediates hedgehog signaling activity. |
| GO:0035224 genital disc anterior/posterior pattern formation | IEP PMID:8798147 Expression patterns of developmental genes reveal segment an... | MARK AS OVER ANNOTATED | Summary: IEP from a descriptive survey in which ci expression was used to mark the anterior compartment of each segment of the male and female genital discs. Reason: Marked as over-annotated rather than removed. The cited work uses ci as an anterior-compartment marker; it reports where ci protein is, not that ci function is required for genital disc anteroposterior patterning. Given that Ci is the sole Hedgehog effector in the fly, involvement is likely and the term is probably not wrong, but expression-pattern evidence does not establish it, and the annotation reaches beyond what this reference shows. Supporting Evidence: PMID:8798147 cubitus interrupts (ci) localized the anterior compartments for each segment |
| GO:0035277 spiracle morphogenesis, open tracheal system | IMP PMID:15930099 Hox-controlled reorganisation of intrasegmental patterning c... | KEEP AS NON CORE | Summary: IMP: the Hedgehog pathway provides one of the intrasegmental inputs that Abdominal-B reorganises to build the posterior spiracle. Reason: Kept as non-core. Another organ-level morphogenetic outcome downstream of Ci-dependent transcription, in a Hox-controlled context; it records where Ci output is used rather than what Ci does. Supporting Evidence: PMID:15930099 We show that the Hedgehog (Hh), Wingless (Wg) and Epidermal Growth Factor Receptor (Egfr) pathways provide specific inputs for posterior spiracle morphogenesis |
| GO:0035301 Hedgehog signaling complex | IPI PMID:10825151 Identification of a tetrameric hedgehog signaling complex. | ACCEPT | Summary: IPI with costa (FB:FBgn0000352): Costal-2, Fused and Ci bind one another directly to form a trimeric Hedgehog signalling complex. Reason: Accepted as a core complex. The Costal-2 / Fused / Ci assembly, with or without Suppressor of fused, is where latent Ci-155 is held, phosphorylated and committed to processing; Ci is a constitutive subunit of it, not an incidental co-purifying protein. Supporting Evidence: PMID:10825151 Here, we show that three members of this complex, Costal2 (Cos2), Fused (Fu), and Cubitus interruptus (Ci), bind each other directly to form a trimeric complex. |
| GO:0035301 Hedgehog signaling complex | IPI PMID:10825151 Identification of a tetrameric hedgehog signaling complex. | ACCEPT | Summary: IPI with fused (FB:FBgn0001079): the same study shows that Suppressor of fused joins Cos2, Fu and Ci to form a tetrameric version of the complex. Reason: Accepted as a core complex. The Costal-2 / Fused / Ci assembly, with or without Suppressor of fused, is where latent Ci-155 is held, phosphorylated and committed to processing; Ci is a constitutive subunit of it, not an incidental co-purifying protein. Supporting Evidence: PMID:10825151 However, we subsequently show that Su(fu), although not a requisite component of this complex, does form a tetrameric complex with Fu, Cos2, and Ci. |
| GO:0035301 Hedgehog signaling complex | IPI PMID:9244297 Hedgehog elicits signal transduction by means of a large com... | ACCEPT | Summary: IPI from the paper that first purified the large Hedgehog signal-transducing complex and identified Ci as its transcription factor component. Reason: Accepted as a core complex. The Costal-2 / Fused / Ci assembly, with or without Suppressor of fused, is where latent Ci-155 is held, phosphorylated and committed to processing; Ci is a constitutive subunit of it, not an incidental co-purifying protein. Supporting Evidence: PMID:9244297 The complex includes the products of at least three genes: fused (a protein-serine/threonine kinase), cubitus interruptus (a transcription factor), and costal2 (a kinesin-like protein). |
| GO:0035301 Hedgehog signaling complex | IPI PMID:9244297 Hedgehog elicits signal transduction by means of a large com... | ACCEPT | Summary: IPI with costa and fused (FB:FBgn0000352, FB:FBgn0001079) from the same purification, which also showed that the complex binds microtubules in a Hedgehog-reversible manner. Reason: Accepted as a core complex. The Costal-2 / Fused / Ci assembly, with or without Suppressor of fused, is where latent Ci-155 is held, phosphorylated and committed to processing; Ci is a constitutive subunit of it, not an incidental co-purifying protein. Supporting Evidence: PMID:9244297 The complex binds with great affinity to microtubules in the absence of HH, but binding is reversed by HH. |
| GO:0035331 negative regulation of hippo signaling | IGI PMID:26403189 Ci antagonizes Hippo signaling in the somatic cells of the o... | KEEP AS NON CORE | Summary: IGI with hippo and warts (FB:FBgn0261456, FB:FBgn0011739): Ci antagonises the Hippo kinase cascade in ovarian escort cells, promoting Yorkie nuclear localisation and germline stem cell differentiation. Reason: Kept as non-core. This is a well-supported, mechanistically specific activity, but it is a tissue-restricted side branch in which Ci acts by competing for Hippo rather than by regulating transcription, and it is not the function that defines this gene product. Supporting Evidence: PMID:26403189 Hedgehog (Hh) signals emanating primarily from cap cells support the function of ECs, where Cubitus interruptus (Ci), the Hh signaling effector, acts to inhibit Hippo kinase cascade activity. |
| GO:0042802 identical protein binding | IPI PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | KEEP AS NON CORE | Summary: IPI with itself (UniProtKB:P19538): Ci forms dimers or higher-order oligomers, which underlies the multivalent, cooperative engagement of its Ser/Thr-rich degrons by Roadkill/HIB. Reason: Kept as non-core. Self-association is a genuine and functionally relevant property of the protein, demonstrated in the same study that mapped the degrons, but it is a mechanism serving Ci turnover rather than one of the core transcriptional activities. Supporting Evidence: PMID:19955409 We provide evidence that both HIB and Ci form dimers/oligomers and engage in multivalent interactions |
| GO:0042803 protein homodimerization activity | IDA PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | KEEP AS NON CORE | Summary: IDA for homodimerisation, the more specific statement of the same self-association result. Reason: Kept as non-core for the same reason as the companion identical-protein-binding row: the oligomerisation is real and mechanistically informative for Cul3-HIB-mediated degradation, but it is not one of the defining activities of the gene product. Supporting Evidence: PMID:19955409 We provide evidence that both HIB and Ci form dimers/oligomers and engage in multivalent interactions |
| GO:0043565 sequence-specific DNA binding | IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in... | MODIFY | Summary: IDA for sequence-specific DNA binding, from the study that identified the cytoplasmic tethering domain and showed that the cleaved form enters the nucleus and represses targets. Reason: The essence is right but the term sits one level above what the evidence shows. Ci binds GLI consensus sites in the Pol II cis-regulatory regions of hedgehog, wingless and patched (PMID:9122207, PMID:8769644), so the Pol II-specific descendant is both supported and more informative; it is already carried by the IBA row. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:9215627 This form translocates to the nucleus where it represses hh and other target genes. PMID:9122207 We show that Ci is a sequence-specific DNA binding protein that drives transcription from the wg promoter in transiently transfected cells. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24413177 Suppressor of fused impedes Ci/Gli nuclear import by opposin... | ACCEPT | Summary: IDA: nuclear delivery of full-length Ci through its two nuclear localisation signals drives target-gene activation. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:24413177 We demonstrate that the PY-NLS functions in parallel with a previously identified bipartite NLS to promote nuclear localization and activity of full-length Ci. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:9122207 Hedgehog signaling regulates transcription through cubitus i... | ACCEPT | Summary: IDA: Ci drives transcription from the wingless promoter, and its binding sites there are required for the response. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:9122207 We demonstrate that Ci binding sites in the wg promoter are necessary for this transcriptional activation. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:10669739 Cubitus interruptus requires Drosophila CREB-binding protein... | ACCEPT | Summary: IGI with nejire (FB:FBgn0261617): Ci-mediated activation of wingless requires the coactivator dCBP. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:10669739 Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:10102270 Hedgehog controls limb development by regulating the activit... | ACCEPT | Summary: IMP: a distinct, separately regulated activator form of Ci drives a defined subset of Hedgehog target genes. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:10102270 We provide evidence for the existence of a distinct activator form of Ci, which does not arise by mere prevention of Ci proteolysis, but rather depends on a separate regulatory step subject to Hh control. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:10669739 Cubitus interruptus requires Drosophila CREB-binding protein... | ACCEPT | Summary: IMP: Ci point mutants defective in coactivator recruitment fail to activate endogenous wingless in embryos. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:10669739 When expressed exogenously in embryos, the CI point mutants cannot activate endogenous wg expression. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:8769644 Transcriptional activation of hedgehog target genes in Droso... | ACCEPT | Summary: IMP: raising Ci levels activates patched and other Hedgehog targets even without Hedgehog. Reason: Accepted as core. Activation of Hedgehog target genes by nuclear Ci-155 is one of the two defining outputs of this gene product, performed by the protein itself at Pol II promoters and enhancers. Supporting Evidence: PMID:8769644 we show that elevated levels of Ci are sufficient to activate patched (ptc) and other hh target genes, even in the absence of hh activity |
| GO:0048100 wing disc anterior/posterior pattern formation | IMP PMID:15708556 The role of Dpp signaling in maintaining the Drosophila ante... | KEEP AS NON CORE | Summary: IMP: clonal analysis of the wing anteroposterior compartment boundary, where Hedgehog transduction in anterior cells is required to maintain the boundary. Reason: Kept as non-core. Compartment boundary maintenance is among the best-studied outcomes of Ci activity, but it is a tissue-level patterning result produced by Ci-dependent transcription of decapentaplegic and other targets. Supporting Evidence: PMID:15708556 Finally, we provide evidence that Dpp signaling acts downstream of or in parallel with Hedgehog signaling to maintain the A/P boundary. |
| GO:0048813 dendrite morphogenesis | IMP PMID:23977298 Functional genomic analyses of two morphologically distinct ... | KEEP AS NON CORE | Summary: IMP: ci was among 37 transcription factors validated in a class-specific RNAi screen for regulators of dendrite morphology in Drosophila dendritic arborisation neurons. Reason: Kept as non-core. The screen gives genuine loss-of-function evidence, but a quantitative dendrite phenotype in one neuronal class is a distant read-out of Ci transcriptional output and is not a core function of the gene. Supporting Evidence: PMID:23977298 we have identified and validated the role of 37 transcription factors in regulating class specific dendrite development using in vivo class-specific RNAi knockdowns followed by rigorous and quantitative neurometric analysis. |
| GO:0140297 DNA-binding transcription factor binding | IEA GO_REF:0000117 | REMOVE | Summary: Electronic ARBA annotation asserting that Ci binds a DNA-binding transcription factor. Reason: Removed. No characterised Drosophila Ci partner is a DNA-binding transcription factor: the documented partners are Costal-2 (a kinesin-related protein), Fused (a kinase), Suppressor of fused, Slimb and Roadkill/HIB (ubiquitin ligase substrate receptors), nejire/CBP and Taiman/NCOA2 (coactivators), Hyrax (a PAF1 subunit) and Rbfox1 (an RNA-binding protein). The only partner of Ci that is itself a DNA-binding transcription factor is Ci, and that self-association is already stated precisely by GO:0042803. The electronic rule therefore adds no information about this protein and asserts a partner class that has not been demonstrated for it. Supporting Evidence: file:DROME/ci/ci-uniprot.txt Interacts with RDX (PubMed:16740475). Interacts with cos |
| GO:1900087 positive regulation of G1/S transition of mitotic cell cycle | IMP PMID:15809036 Extracellular signals responsible for spatially regulated pr... | KEEP AS NON CORE | Summary: IMP: Hedgehog and Decapentaplegic act redundantly to arrest retinal cells in G1 ahead of the morphogenetic furrow, and Hedgehog input is transduced by Ci. Reason: Kept as non-core. G1/S control in the differentiating eye is a downstream, tissue-specific consequence of Ci-dependent transcription, and the cited study assays the extracellular signals rather than Ci activity itself. Supporting Evidence: PMID:15809036 Arrest depends on Dpp and Hh, acting redundantly. |
| GO:2000495 regulation of cell proliferation involved in compound eye morphogenesis | IMP PMID:17559828 Suppression of Hedgehog signaling by Cul3 ligases in prolife... | KEEP AS NON CORE | Summary: IMP: loss of Cullin-3 raises Ci levels and expands the interommatidial cell population, a phenotype mimicked by Ci overexpression and suppressed by removing Ci. Reason: Kept as non-core. The epistasis is clean and shows that Ci dosage sets retinal precursor proliferation, but proliferation control here is the downstream effect of Ci-driven target-gene expression rather than an activity of the protein. Supporting Evidence: PMID:17559828 In Cul3 mutants, the population of interommatidial cells is increased, which can be mimicked by overexpression of Ci and suppressed by depleting endogenous Ci. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in... | NEW | Summary: Proposed addition. GOA records the repressor output of Ci only as a biological process (GO:0000122, five rows) and as the unsigned parent molecular function (GO:0000981), while the signed activator molecular function GO:0001228 is present. The repressor molecular function is missing, although Ci-75 is the best-characterised transcriptional repressor in the pathway. Reason: Participation test: the entity that performs the repression is Ci itself. Ci-155 is cleaved to a C-terminally truncated form that enters the nucleus and represses hedgehog and other Hedgehog target genes (PMID:9215627); this repressor form binds the same GLI/Ci consensus sites through the same five zinc fingers, and its cleavage is required for limb patterning in vivo (PMID:10102270). No other gene product does the repressing. Comparator test: the signed repressor term is applied to the Ci/GLI repressor-forming paralogue elsewhere in the family - mouse Gli3 carries GO:0001227 - and the term is in ordinary use in Drosophila, so its absence here is a gap rather than a convention. On redundancy: GO:0001227 is a child of GO:0000981, which ci already carries, but GOA already pairs GO:0000981 with the sibling GO:0001228 on this same gene product, so adding GO:0001227 completes the activator/repressor pair rather than merely refining an existing assertion. Proposed with IDA evidence from the paper that demonstrated the repressor form directly. Supporting Evidence: PMID:9215627 This form translocates to the nucleus where it represses hh and other target genes. PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. PMID:10102270 A repressor form of Ci arises in the absence of Hh signaling by proteolytic cleavage of intact Ci. PMID:16386907 the sole Drosophila Gli homolog, Cubitus interruptus (Ci), undergoes partial proteolysis to Ci-75, which represses key Hh target genes |
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Download this section (compressed HTML)Q: Where exactly is Ci-155 cleaved, and what determines that the proteasome stops at that point instead of degrading the protein completely? The processed product has never been mapped to a residue, and the UniProt repressor chain is annotated with an undefined C-terminal boundary.
Q: Does the Ci-75 repressor use a dedicated corepressor, or does it repress simply by occupying GLI sites and excluding Ci-155? Groucho and Atrophin have been proposed for Ci/GLI repressors, but no partner has been shown to be required for repression of hedgehog itself.
Q: Is the Hippo-antagonising activity of Ci in ovarian escort cells a property of Ci-155, of Ci-75, or of a form that never reaches the nucleus, and does it require DNA binding at all?
Q: Which Hedgehog targets are controlled principally by loss of Ci-75 and which by gain of Ci-155? Activator and repressor forms are known to control overlapping but distinct target subsets, but the split has not been resolved genome-wide.
Experiment: Generate endogenous ci alleles that produce only the truncated repressor (by installing a stop codon at the mapped processing site) and derivatives carrying point mutations across the N-terminal region, then score repression of hedgehog and of patched enhancer reporters alongside CUT&RUN occupancy in anterior compartment cells.
Hypothesis: Ci-75 represses hedgehog and other targets by direct occupancy of GLI sites, and a separable corepressor-recruiting region is required for repression but not for DNA binding.
Experiment: Perform form-specific chromatin profiling by tagging Ci at both the N and C termini, so that N-terminal signal reports both forms and C-terminal signal reports only Ci-155, in wing discs sorted by position relative to the anteroposterior boundary, and compare the site sets with matched transcriptomes.
Hypothesis: The activator and repressor forms occupy overlapping but non-identical sets of cis-regulatory elements in vivo.
Experiment: Test separation-of-function ci alleles that retain Hippo binding but carry disrupted zinc fingers, and the converse, for rescue of the escort-cell phenotype and for Yorkie nuclear localisation.
Hypothesis: Ci binding to Hippo, rather than Ci transcriptional output, is what drives germline stem cell differentiation in escort cells.
cubitus interruptus (ci) encodes a Zn-finger family of transcription factor. It contributes to Hedgehog (Hh) signaling pathway that is involved in pattern formation and growth control. The product of ci undergoes limited proteolysis to be converted into a truncated form that function as a transcription repressor in the absence of the ligand encoded by hh but is converted into a full-length transcription activator in the presence of the product of hh.
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