GLI3 is a C2H2 zinc-finger transcription factor that mediates Hedgehog-dependent gene regulation. The 1580-residue human protein recognizes GLI regulatory DNA sites and can act as a transcriptional activator. Regulated partial proteolysis produces an N-terminal repressor, GLI3R, that retains DNA recognition but lacks the C-terminal activation region. These are proteolytic products, not alternative splice isoforms. Full-length GLI3 undergoes regulated cytoplasmic, ciliary and nuclear trafficking; the repressor acts in the nucleus. SUFU, phosphorylation and ubiquitin-dependent processing control the balance of these activities. Nuclear GLI3 engages transcriptional regulatory complexes, with mechanisms depending on its product and cellular context. Its developmental roles include limb, craniofacial and nervous-system patterning. Pathogenic human variants cause disorders including Greig cephalopolysyndactyly and Pallister-Hall syndromes.
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
GLI3_REPRESSORPRO_0000406137| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:10693759 Hedgehog-regulated processing of Gli3 produces an anterior/p... | ACCEPT | Reason: Processing and human reporters support repression; full-length GLI3 is not uniformly repressive. Supporting Evidence: PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Reason: The verified GLI-like family mapping agrees with experimental GLI-site recognition; its label alone is insufficient. Supporting Evidence: PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:18298960 CD spectra show the relational style between Zic-, Gli-, Gli... | ACCEPT | Summary: Retain curated sequence-specific regulatory-DNA recognition. Reason: The accessible study compares Zic/Gli/Glis zinc-finger DNA recognition. Its abstract does not resolve every tested construct, so retain the curatorβs GLI3 IDA in the context of independently established GLI-site binding, without inventing target-specific assay details. Supporting Evidence: PMID:18298960 The addition of oligo DNA that included a Gli-binding sequence increased the alpha-helix content estimated by using circular dichroism spectroscopy. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Reason: AN0/PTN000456649 covers GLI3; target GLI-site experiments legitimately ground the self-donor, with no demonstrated loss of the retained zinc-finger function. Supporting Evidence: GO_REF:0000033 PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:2118997 GLI3 encodes a 190-kilodalton protein with multiple regions ... | ACCEPT | Reason: The primary abstract directly reports GLI3 binding to genomic GLI sites; complete scanned-paper inspection is not claimed. Supporting Evidence: PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Reason: AN0/PTN000456649 supports transcription-factor activity encompassing activation and repression. Preserve the extra incoming mouse donor despite the cached IBD discrepancy. Supporting Evidence: GO_REF:0000033 PMID:10075717 GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Chromatin association is compatible with regulatory-DNA occupancy. Reason: The actual mouse donor has experimental grounding; PMID:16396903 reports GLI3 chromatin immunoprecipitation in embryonic kidney tissue. Retain the orthology transfer without presenting that experiment as endogenous human tissue. Supporting Evidence: PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. |
| GO:0003690 double-stranded DNA binding | IEA GO_REF:0000117 | TOO GENERAL | Summary: Double-stranded DNA binding omits known sequence specificity. Reason: Existing GO:0000978 captures regulatory-site recognition and is a verified descendant of this term. Retain the source record while preferring the established specific DNA-binding assertion. Supporting Evidence: PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | TOO GENERAL | Summary: The known transcription-factor function is RNA polymerase II-specific. Reason: GO:0000981 is an existing, verified descendant and captures the relevant transcriptional machinery. The generic orthology assertion adds no separate molecular function. Supporting Evidence: PMID:10075717 GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. Reactome:R-HSA-5612508 GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10077605 GLI3 mutations in human disorders mimic Drosophila cubitus i... | MODIFY | Reason: Human full-length GLI3 activates a PTCH1 reporter; engineered PHS protein represses it. Refine to both Pol II activities without identifying that mutant as physiological GLI3R. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:10077605 Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. PMID:10077605 PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:17000779 Mediator modulates Gli3-dependent Sonic hedgehog signaling. | MODIFY | Reason: Human GLI3 activation-region/Mediator experiments support Pol II activator activity. Historical construct coordinates are not projected onto current P10071; MED12 depletion enhanced output in this study. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:17000779 We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. PMID:17000779 Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:17764085 Characterization of the interactions of human ZIC3 mutants w... | MODIFY | Reason: The primary abstract reports GLI3/ZIC3 coactivation of a GLI-site-containing TK reporter, supporting the more precise Pol II activator term. Complete methods were not inspected. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:17764085 Inclusion of GLIBS upstream of a basal TK promoter had no effect on the activation of the promoter by ZIC3 alone, but it enhanced the synergistic activation of ZIC3 and GLI3. PMID:17764085 Wild-type (WT) ZIC3 showed specific binding to GLI3 in GST-pull-down assays. |
| GO:0005515 protein binding | IPI PMID:10564661 Characterization of the human suppressor of fused, a negativ... | REMOVE | Summary: Remove an uninformative generic interaction annotation. Reason: The source explicitly includes physical SUFUβGLI3 interaction. Removal concerns the generic protein-binding label, not the truth of that interaction; binding and sequestration alone do not establish a more specific machinery-bridging molecular function. Supporting Evidence: PMID:10564661 HSu(fu) was found to repress activity of the zinc-finger transcription factor Gli, which mediates Hedgehog signaling in vertebrates, and to physically interact with Gli, Gli2 and Gli3 as well as with Slimb, an F-box containing protein |
| GO:0005515 protein binding | IPI PMID:11238441 Physical and functional interactions between Zic and Gli pro... | MODIFY | Reason: Human GLI3 associates with mouse Zic1 through zinc-finger regions. Specify DNA-binding transcription-factor binding; preserve this rowβs original context. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:11238441 We provide evidence that the Zic and Gli proteins physically and functionally interact through their zinc finger domains. PMID:11238441 Moreover, Gli proteins were translocated to cell nuclei by coexpressed Zic proteins, and both proteins regulated each other's transcriptional activity. |
| GO:0005515 protein binding | IPI PMID:11238441 Physical and functional interactions between Zic and Gli pro... | MODIFY | Reason: Human GLI3 associates with mouse Zic1. Specify DNA-binding transcription-factor binding and preserve the nuclear extension and distinct curator context. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11238441 Physical and functional interactions between Zic and Gli pro... | MODIFY | Reason: Human GLI3 associates with mouse Zic2. Specify DNA-binding transcription-factor binding and preserve the nuclear extension. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:11238441 We provide evidence that the Zic and Gli proteins physically and functionally interact through their zinc finger domains. PMID:11238441 Moreover, Gli proteins were translocated to cell nuclei by coexpressed Zic proteins, and both proteins regulated each other's transcriptional activity. |
| GO:0005515 protein binding | IPI PMID:12435627 Ski is involved in transcriptional regulation by the repress... | MODIFY | Summary: Human GLI3 binds SKI. Reason: Direct interaction and reporter assays support transcription-corepressor binding; retain SKIβs demonstrated repressor role. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:12435627 Here we report that the Ski corepressor binds to Gli3 and recruits the histone deacetylase complex. PMID:12435627 The Gli3-mediated repression was impaired by anti-Ski antibody and in Ski-deficient fibroblasts |
| GO:0005515 protein binding | IPI PMID:16371461 Evidence for the direct involvement of {beta}TrCP in Gli3 pr... | MODIFY | Summary: Specify binding to the ubiquitin-ligase recognition machinery. Reason: Phosphorylated human GLI3 binds the beta-TrCP component of an SCF E3 ligase; this row records mouse Btrc. GLI3 is the substrate in the subsequent processing reaction, not the enzyme carrying out ubiquitination. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16371461 Our gain- and loss-of-function analyses in cultured cells further reveal that betaTrCP, the vertebrate homolog of Slimb, is required for Gli3 processing, and we demonstrate that betaTrCP can bind phosphorylated Gli3 both in vitro and in vivo. |
| GO:0005515 protein binding | IPI PMID:16371461 Evidence for the direct involvement of {beta}TrCP in Gli3 pr... | MODIFY | Summary: Specify binding to the ubiquitin-ligase recognition machinery. Reason: Phosphorylated human GLI3 binds the beta-TrCP component of an SCF E3 ligase; this row records human BTRC. GLI3 is the substrate in the subsequent processing reaction, not the enzyme carrying out ubiquitination. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:16371461 Our gain- and loss-of-function analyses in cultured cells further reveal that betaTrCP, the vertebrate homolog of Slimb, is required for Gli3 processing, and we demonstrate that betaTrCP can bind phosphorylated Gli3 both in vitro and in vivo. |
| GO:0005515 protein binding | IPI PMID:17000779 Mediator modulates Gli3-dependent Sonic hedgehog signaling. | MODIFY | Reason: GLI3 binds MED12 and intact Mediator, with additional Mediator contacts. Specify complex binding; MED12 depletion enhances activation in this study. Proposed replacements: mediator complex binding Supporting Evidence: PMID:17000779 We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. PMID:17000779 Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. |
| GO:0005515 protein binding | IPI PMID:17764085 Characterization of the interactions of human ZIC3 mutants w... | MODIFY | Summary: Specify GLI3 binding to the DNA-binding transcription factor ZIC3. Reason: The primary abstract reports direct wild-type ZIC3βGLI3 binding by GST pull-down and reporter coactivation. Preserve this physical regulatory interaction without turning patient phenotypes into additional process annotations. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:17764085 Wild-type (WT) ZIC3 showed specific binding to GLI3 in GST-pull-down assays. PMID:17764085 Inclusion of GLIBS upstream of a basal TK promoter had no effect on the activation of the promoter by ZIC3 alone, but it enhanced the synergistic activation of ZIC3 and GLI3. |
| GO:0005515 protein binding | IPI PMID:19389374 Trps1, a regulator of chondrocyte proliferation and differen... | MODIFY | Summary: Specify binding to the DNA-binding transcription factor TRPS1. Reason: The primary abstract explicitly reports TRPS1 binding to the GLI3 transactivation domain, with no interaction for the repressor product. This supports transcription-factor binding. Detailed construct species were not independently recovered and are not inferred from the mouse phenotypes. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:19389374 We demonstrate that Trps1 specifically binds to the transactivation domain of Gli3 in vitro and in vivo, whereas the repressor form of Gli3 does not interact with Trps1. |
| GO:0005515 protein binding | IPI PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | MODIFY | Summary: Specify GLI3 binding to the kinesin-family protein KIF7. Reason: Coimmunoprecipitation recovered GLI3 with human KIF7-GFP in NIH3T3 cells; human GLI3 fragments mapped the association to its N-terminal region. Independent human GLI3 AP-MS also recovered KIF7. This supports kinesin binding without assigning motor or proteolytic activity to GLI3. Proposed replacements: kinesin binding Supporting Evidence: PMID:19592253 We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. |
| GO:0005515 protein binding | IPI PMID:19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/... | MODIFY | Summary: Specify binding to ubiquitin-ligase recognition machinery. Reason: GLI3 associates with the Cul3-associated substrate receptor SPOP, and mutating its recognition motifs affects that binding. Preserve the recorded mouse Spop partner. The specific binding term describes substrate recognition; GLI3 does not thereby acquire ubiquitin-ligase activity. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:19955409 We find that similar S/T-rich motifs are present in Gli proteins as well as in numerous HIB-interacting proteins and mediate Gli degradation by SPOP. |
| GO:0005515 protein binding | IPI PMID:23955340 Centrosomal protein DZIP1 regulates Hedgehog signaling by pr... | REMOVE | Summary: Remove an uninformative generic binding annotation while preserving DZIP1 association. Reason: The primary study demonstrates human DZIP1βGLI3 association and maps interacting regions. DZIP1 retains GLI3 in the cytoplasm and connects to transport machinery. These observations do not establish GLI3 as the transport adaptor; removal concerns the generic label, not the association. Supporting Evidence: PMID:23955340 First, DZIP1 interacts with GLI3, a transcriptional regulator for Hedgehog signaling, and prevents GLI3 from entering the nucleus. |
| GO:0005515 protein binding | IPI PMID:24311597 Structural basis of SUFU-GLI interaction in human Hedgehog s... | REMOVE | Reason: Human GLI3 peptideβSUFU structure and solution assays establish interaction. Remove the uninformative generic label; GLI1 reporters do not establish GLI3-specific reporter activity. Supporting Evidence: PMID:24311597 Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. PMID:24311597 SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. |
| GO:0005515 protein binding | IPI PMID:28965847 Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedg... | REMOVE | Reason: SUFU coimmunoprecipitation recovers GLI3 in IMCD3 cells; patient fibroblasts show processing changes. Remove the generic label while preserving association and distinct experimental contexts. Supporting Evidence: PMID:28965847 Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. |
| GO:0005515 protein binding | IPI PMID:29263200 WDR11-mediated Hedgehog signalling defects underlie a new ci... | REMOVE | Summary: Remove the generic label without converting a ternary complex into binary transcription-factor binding. Reason: WDR11 bridges GLI3 and EMX1; EMX1 does not bind GLI3 without WDR11 in the tested system. Preserve the combined partner group. The complex and transcriptional effects are informative evidence, but do not justify assigning GLI3 direct EMX1 binding or WDR11βs bridging role. Supporting Evidence: PMID:29263200 We also found that EMX1 was a part of this complex, suggesting the formation of a tertiary complex of WDR11/GLI3/EMX1. PMID:29263200 WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. |
| GO:0005515 protein binding | IPI PMID:35140242 Human transcription factor protein interaction networks. | REMOVE | Summary: Remove an uninformative generic label while retaining the verified SUFU interaction. Reason: The original Supplementary Data 1 records GLI3βSUFU in both AP-MS and BioID, using human GLI3 bait in inducible 293 cells. Both entries pass the reported confidence threshold. This supports association and proximity; removal concerns the generic functional label, not a failed or absent interaction. Supporting Evidence: PMID:35140242 Here, we identify 6703 and 1536 protein-protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. |
| GO:0008013 beta-catenin binding | IPI PMID:17331723 Inhibitory Gli3 activity negatively regulates Wnt/beta-caten... | KEEP AS NON CORE | Summary: Retain beta-catenin binding as a supported cross-pathway interaction. Reason: The primary abstract reports Gli3R interaction with the beta-catenin carboxy-terminal region and inhibition of Wnt output. Preserve the recorded mouse partner and curated IPI; the accessible abstract does not resolve all constructs or establish an endogenous-human assay. Supporting Evidence: PMID:17331723 Consistent with this, Gli3R appears to physically interact with the carboxy-terminal domain of beta-catenin, a region that includes the transactivation domain. PMID:17331723 Assays in embryos and cell lines indicate that repressor forms of the Hh-regulated transcription factor, Gli3 (Gli3R), which are generated in the absence of Hh signaling, inhibit canonical Wnt signaling. |
| GO:0035035 histone acetyltransferase binding | IPI PMID:10075717 Sonic Hedgehog-induced activation of the Gli1 promoter is me... | ACCEPT | Reason: Retain CREBBP coactivator binding: assays support association and activation; recorded P45481 is mouse Crebbp, not GLI3 acetyltransferase activity. Supporting Evidence: PMID:10075717 Transcriptional co-activator CBP binds to GLI3, but not to GLI1. PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. |
| GO:0036033 mediator complex binding | IDA PMID:17000779 Mediator modulates Gli3-dependent Sonic hedgehog signaling. | ACCEPT | Reason: Human GLI3 binds intact Mediator; MED12 is one interface. This supports complex binding without making MED12 uniformly activating. Supporting Evidence: PMID:17000779 We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. PMID:17000779 Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. |
| GO:0042826 histone deacetylase binding | IDA PMID:12435627 Ski is involved in transcriptional regulation by the repress... | ACCEPT | Summary: GLI3R associates with HDAC1. Reason: Co-immunoprecipitation supports a SKI-containing complex, not purified binary binding or GLI3 deacetylase activity. Supporting Evidence: PMID:12435627 Gli3 Rep was efficiently coprecipitated with HDAC1, indicating that HDAC1 and GLI3 Rep associate with one another. PMID:12435627 The Gli3-mediated repression was impaired by anti-Ski antibody and in Ski-deficient fibroblasts |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | TOO GENERAL | Summary: Regulatory-site binding is more informative than generic sequence specificity. Reason: The existing GO:0000978 is a verified descendant. Its regulatory-region context captures the established GLI3 DNA-recognition function without adding another activity. Supporting Evidence: PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | TOO GENERAL | Summary: Sequence-specific DNA binding is valid but less informative than regulatory-site binding. Reason: Existing GO:0000978 is a verified descendant and captures GLI3 regulatory-site recognition. The inspected HT-SELEX main text does not resolve the GLI3 supplementary experiment; no methylation preference or miscitation is inferred. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. PMID:2118997 Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12435627 Ski is involved in transcriptional regulation by the repress... | ACCEPT | Summary: GLI3R supports SKI-dependent repression. Reason: Human engineered repressor constructs inhibit transcription in reporter assays; their boundaries do not establish native processing sites. Supporting Evidence: PMID:12435627 The Gli3-mediated repression was impaired by anti-Ski antibody and in Ski-deficient fibroblasts PMID:12435627 Gli3 Rep was efficiently coprecipitated with HDAC1, indicating that HDAC1 and GLI3 Rep associate with one another. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:19084012 Identification of the gene transcription repressor domain of... | ACCEPT | Summary: Human GLI3 constructs directly repress transcriptional reporters. Reason: The study tests human full-length, PHS and deletion constructs and maps an N-terminal repression domain. Its isolated domain represses without detectable HDAC dependence, so SKI/HDAC recruitment is not asserted as the only GLI3 repression mechanism. Supporting Evidence: PMID:19084012 Overexpression studies confirm that the N-terminal parts harbor gene repression activity and we mapped the minimal repressor to residues 106 till 236 in Gli3. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:24311597 Structural basis of SUFU-GLI interaction in human Hedgehog s... | UNDECIDED | Reason: Human GLI3 peptide binding is directly demonstrated, but the inspected functional reporter uses GLI1. The exact GLI3 transcription IDA remains unresolved without claiming miscitation. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Reason: GLI3 descends from AN0/PTN000456649; direction-neutral transcriptional regulation accommodates both activator and repressor contexts. Supporting Evidence: GO_REF:0000033 PMID:10075717 GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. |
| GO:0007224 smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Reason: Human GLI3 descends from Deuterostomia AN105/PTN001836086 and executes downstream transcriptional control; processing-substrate status does not preclude pathway participation. Supporting Evidence: GO_REF:0000033 PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0007224 smoothened signaling pathway | IEA GO_REF:0000120 | ACCEPT | Reason: GLI3 executes Hedgehog transcriptional output, beyond being an upstream-processing substrate. Supporting Evidence: PMID:20154143 We also confirmed that phosphorylation and betaTrCP/Cul1 are required for endogenous Gli3 processing and that this is inhibited by Hh. |
| GO:0007224 smoothened signaling pathway | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | ACCEPT | Reason: The reviewβs Hedgehog assignment agrees with independent GLI3 transcription experiments. |
| GO:0007224 smoothened signaling pathway | IDA PMID:20154143 Kinetics of hedgehog-dependent full-length Gli3 accumulation... | ACCEPT | Summary: GLI3 is a regulated downstream effector of Smoothened signaling. Reason: The study examines signal-dependent full-length Gli3 trafficking and processing, principally in mouse cells, with human constructs used in antibody validation. Retain the curated pathway annotation without converting every endogenous-mouse experiment into a human assay. Supporting Evidence: PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. PMID:20154143 We also confirmed that phosphorylation and betaTrCP/Cul1 are required for endogenous Gli3 processing and that this is inhibited by Hh. |
| GO:0007224 smoothened signaling pathway | IDA PMID:31279575 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes H... | ACCEPT | Summary: The source directly examines Gli3 regulation within Hedgehog signaling. Reason: Beyond Ci/Gli2, the full text reports Shh-induced phosphorylation of endogenous knock-in Gli3 in mouse fibroblasts and kinase perturbations affecting that response. Retain pathway participation, with no claim that GLI3 catalyzes its own phosphorylation or that these are endogenous-human experiments. Supporting Evidence: PMID:31279575 Hedgehog (Hh) signaling culminates in the conversion of the latent transcription factor Cubitus interruptus (Ci)/Gli into its activator form (CiA/GliA), but the underlying mechanism remains poorly understood. |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | TOO GENERAL | Summary: The morphogenesis term is broader than supported contexts. Reason: Limb morphogenesis already provides a more informative existing annotation and is an is_a/part_of descendant of this term. The broad electronic assertion adds no distinct functional resolution. Supporting Evidence: PMID:18478223 However, additional features, including characteristic radiographic findings of the hands and a large hypothalamic tumour, presumably a hamartoma, favoured the diagnosis of Pallister-Hall syndrome (PHS), which was then genetically confirmed by detection of a GLI3 mutation (Q717X). |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | TOO GENERAL | Summary: Gene-expression regulation is broader than the established transcriptional role. Reason: GO:0006357 is an existing, verified descendant specifying regulation of RNA polymerase II transcription. The broad electronic term adds no distinct activity or cellular mechanism. Supporting Evidence: PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. |
| GO:0033077 T cell differentiation in thymus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the fetal thymic differentiation context. Reason: Mouse Gli3 mutants impair fetal thymocyte differentiation. Preserve this orthology-based context without presenting it as an experiment in human cells or as a general adult thymocyte function. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0033077 T cell differentiation in thymus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the fetal thymic differentiation context. Reason: Mouse Gli3 mutants impair fetal thymocyte differentiation. Preserve this orthology-based context without presenting it as an experiment in human cells or as a general adult thymocyte function. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0035108 limb morphogenesis | IMP PMID:18478223 Hydrometrocolpos, postaxial polydactyly, and hypothalamic ha... | KEEP AS NON CORE | Summary: Human variant evidence supports a limb-development context. Reason: The human Q717X case includes bilateral hand polydactyly. Retain the curatorβs IMP limb-morphogenesis assignment as a developmental phenotype context; the case does not identify direct transcriptional targets. Supporting Evidence: PMID:18478223 However, additional features, including characteristic radiographic findings of the hands and a large hypothalamic tumour, presumably a hamartoma, favoured the diagnosis of Pallister-Hall syndrome (PHS), which was then genetically confirmed by detection of a GLI3 mutation (Q717X). |
| GO:0035108 limb morphogenesis | IMP PMID:9354785 Mutation in GLI3 in postaxial polydactyly type A. | UNDECIDED | Summary: The source-specific limb evidence remains incompletely accessible. Reason: The original letter has no PubMed abstract, and the publisher exposes only a subscription preview. Preserve the experimental annotation pending source inspection; the established developmental role does not justify inventing its methods. Supporting Evidence: |
| GO:0042733 embryonic digit morphogenesis | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | KEEP AS NON CORE | Summary: Retain the reviewed human digit-development association. Reason: The recovered review explicitly links human GLI3 variants with multiple polydactyly phenotypes. Retain this TAS developmental context, without representing the review as a primary morphogenesis experiment. |
| GO:0043585 nose morphogenesis | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | KEEP AS NON CORE | Summary: Retain the reviewed nasal-development phenotype context. Reason: The recovered GLI3 section describes anteverted nares in Pallister-Hall syndrome. This supports the existing TAS context; it does not establish a direct nasal target-gene mechanism. Supporting Evidence: |
| GO:0045060 negative thymic T cell selection | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain stromal negative selection. Reason: Mouse stromal Gli3 supports thymocyte deletion; preserve the orthology transfer without implying human thymocyte-intrinsic activity. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0045060 negative thymic T cell selection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain stromal negative selection. Reason: Mouse stromal Gli3 supports thymocyte deletion; preserve the orthology transfer without implying human thymocyte-intrinsic activity. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0045879 negative regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Reason: Orthology supports processed-GLI3 repression, without assigning inhibition to every full-length product. Supporting Evidence: PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0045879 negative regulation of smoothened signaling pathway | IEA GO_REF:0000107 | ACCEPT | Reason: Orthology supports processed-GLI3 repression, without assigning inhibition to every full-length product. Supporting Evidence: PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12435627 Ski is involved in transcriptional regulation by the repress... | TOO GENERAL | Summary: Prefer the existing polymerase-II refinement. Reason: The same source supports GO:0000122, a verified descendant; retain both original evidence contexts. Supporting Evidence: PMID:12435627 The Gli3-mediated repression was impaired by anti-Ski antibody and in Ski-deficient fibroblasts PMID:12435627 Gli3 Rep was efficiently coprecipitated with HDAC1, indicating that HDAC1 and GLI3 Rep associate with one another. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:16254602 Gli2 and Gli3 localize to cilia and require the intraflagell... | TOO GENERAL | Reason: Engineered Gli3 repressor inhibits Gli1-driven Ptch1 in mouse IFT-defective limb cells; prefer the existing polymerase-II descendant without inferring native-human cleavage. Supporting Evidence: PMID:16254602 Our data show that loss of Tg737 results in altered Gli3 processing that abrogates Gli3-mediated repression of Gli1 transcriptional activity. PMID:16254602 As seen in previous studies, infection of cells with the full-length form of Gli3 was able to repress Gli1-mediated transcription when coexpressed in wild-type cells |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:19084012 Identification of the gene transcription repressor domain of... | TOO GENERAL | Summary: The reporter repression is already captured at polymerase-II resolution. Reason: The same source supports an existing GO:0000122 annotation, a verified descendant. No additional mechanism is established by retaining the broader transcription term. Supporting Evidence: PMID:19084012 Overexpression studies confirm that the N-terminal parts harbor gene repression activity and we mapped the minimal repressor to residues 106 till 236 in Gli3. |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | TOO GENERAL | Summary: The activation role is more precisely represented by the existing polymerase-II process. Reason: Actual mouse donor annotations support positive transcriptional regulation. Existing GO:0045944 is a verified descendant of this term and specifies the relevant machinery; no additional process is proposed. Supporting Evidence: PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. PMID:10077605 Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Reason: Experimental mouse donors and human reporter/Mediator evidence support conserved activation; preserve the orthology and product boundaries. Supporting Evidence: PMID:10075717 GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:17000779 Mediator modulates Gli3-dependent Sonic hedgehog signaling. | ACCEPT | Reason: Human reporter and mouse endogenous target experiments support activation. MED12-dependent effects are context-sensitive, including enhancement after MED12 depletion. Supporting Evidence: PMID:17000779 Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. PMID:17000779 We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:18559511 Protein phosphatase 2A and rapamycin regulate the nuclear lo... | ACCEPT | Summary: GLI3 can positively regulate transcription of a pathway target. Reason: The primary abstract links altered GLI3 nuclear localization to cyclin D1 transcription. This supports the curated activation process; the abstract-only inspection does not establish every assay, construct, or direct promoter-occupancy detail. Supporting Evidence: PMID:18559511 An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. PMID:18559511 Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. |
| GO:0046638 positive regulation of alpha-beta T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the positive fetal differentiation context. Reason: Mouse Gli3 deficiency impairs fetal DN-to-DP differentiation with proliferation and survival controls. Preserve the transfer without extending this result to adult human thymocytes. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0046638 positive regulation of alpha-beta T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the positive fetal differentiation context. Reason: Mouse Gli3 deficiency impairs fetal DN-to-DP differentiation with proliferation and survival controls. Preserve the transfer without extending this result to adult human thymocytes. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0046639 negative regulation of alpha-beta T cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: Negative differentiation remains unresolved. Reason: A genuine mouse IMP donor exists, but its abstract emphasizes selection; precise differentiation regulation remains unresolved without full methods. Supporting Evidence: |
| GO:0046639 negative regulation of alpha-beta T cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: Negative differentiation remains unresolved. Reason: A genuine mouse IMP donor exists, but its abstract emphasizes selection; precise differentiation regulation remains unresolved without full methods. Supporting Evidence: |
| GO:0048566 embryonic digestive tract development | TAS PMID:11001584 The sonic hedgehog-patched-gli pathway in human development ... | KEEP AS NON CORE | Summary: Retain the reviewed digestive-development phenotype context. Reason: The recovered GLI3 section includes imperforate anus among human Pallister-Hall phenotypes. Retain the TAS gut-development context without inferring direct regulation of a particular developmental target. Supporting Evidence: PMID:18478223 However, additional features, including characteristic radiographic findings of the hands and a large hypothalamic tumour, presumably a hamartoma, favoured the diagnosis of Pallister-Hall syndrome (PHS), which was then genetically confirmed by detection of a GLI3 mutation (Q717X). file:human/GLI3/GLI3-source-guide.md imperforate anus, anteverted nares |
| GO:0060173 limb development | IEA GO_REF:0000107 | TOO GENERAL | Summary: Existing limb morphogenesis provides greater specificity. Reason: The mouse donor studies processed and full-length Gli3 in digit patterning. Limb morphogenesis is already annotated and is part_of limb development, so this broad electronic row adds little resolution. Supporting Evidence: PMID:18478223 However, additional features, including characteristic radiographic findings of the hands and a large hypothalamic tumour, presumably a hamartoma, favoured the diagnosis of Pallister-Hall syndrome (PHS), which was then genetically confirmed by detection of a GLI3 mutation (Q717X). PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. |
| GO:0070242 thymocyte apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain stromal thymocyte apoptosis. Reason: Mouse Gli3-mutant stroma reduces thymocyte apoptosis during selection; preserve transfer without assigning an apoptosis-executing activity. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0070242 thymocyte apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain stromal thymocyte apoptosis. Reason: Mouse Gli3-mutant stroma reduces thymocyte apoptosis during selection; preserve transfer without assigning an apoptosis-executing activity. Supporting Evidence: PMID:10693759 The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IDA PMID:17331723 Inhibitory Gli3 activity negatively regulates Wnt/beta-caten... | KEEP AS NON CORE | Summary: Retain the demonstrated Wnt-antagonism context as non-core. Reason: The primary abstract explicitly reports that Gli3R antagonizes beta-catenin-dependent transcription in embryos and cell lines. This is a supported cross-pathway function, distinct from GLI3βs central Hedgehog transcriptional role; precise experimental species and constructs are not invented. Supporting Evidence: PMID:17331723 Assays in embryos and cell lines indicate that repressor forms of the Hh-regulated transcription factor, Gli3 (Gli3R), which are generated in the absence of Hh signaling, inhibit canonical Wnt signaling. PMID:17331723 Consistent with this, Gli3R appears to physically interact with the carboxy-terminal domain of beta-catenin, a region that includes the transactivation domain. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization of transcriptionally active GLI3 products. Reason: The actual nuclear assertion lies at AN0/PTN000456649 and includes target experimental grounding. Nuclear GLI3 products are compatible with regulated cytoplasmic and ciliary pools. This cellular-component assertion does not imply constitutive or exclusive nuclear localization. Supporting Evidence: GO_REF:0000033 PMID:10077605 PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75. Reactome:R-HSA-5610752 After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Reason: Human construct imaging corroborates the combined nuclear mapping; localization remains product-dependent. Supporting Evidence: Reactome:R-HSA-5610752 After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes |
| GO:0005634 nucleus | IDA PMID:10693759 Hedgehog-regulated processing of Gli3 produces an anterior/p... | ACCEPT | Reason: Retain curated nuclear localization; human constructs corroborate it without resolving the original assay. Supporting Evidence: PMID:10693759 We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. Reactome:R-HSA-5610752 After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes |
| GO:0005634 nucleus | IDA PMID:11238441 Physical and functional interactions between Zic and Gli pro... | ACCEPT | Reason: Retain nuclear localization: the Zic/Gli study reports regulated translocation; the accessible abstract does not resolve every imaging detail. Supporting Evidence: PMID:11238441 Moreover, Gli proteins were translocated to cell nuclei by coexpressed Zic proteins, and both proteins regulated each other's transcriptional activity. |
| GO:0005634 nucleus | IDA PMID:12435627 Ski is involved in transcriptional regulation by the repress... | ACCEPT | Summary: GLI3 constructs occupy nuclei. Reason: Human full-length and engineered repressor constructs have nuclear pools; the repressor is predominantly nuclear. Supporting Evidence: PMID:12435627 FL-Gli3 was localized to dot-like structures in both cytoplasm and nucleus, whereas Gli3ΞC staining only displayed a punctate pattern in the nucleus. |
| GO:0005634 nucleus | IDA PMID:16254602 Gli2 and Gli3 localize to cilia and require the intraflagell... | ACCEPT | Reason: Nuclear Gli3 constructs, including engineered repressor, were observed in mouse limb cells; preserve that organism boundary. Supporting Evidence: PMID:16254602 Most importantly, the data indicate that all three full-length Gli proteins along with Sufu colocalize to the distal tips of cilia in primary limb bud cells. |
| GO:0005634 nucleus | IDA PMID:18559511 Protein phosphatase 2A and rapamycin regulate the nuclear lo... | ACCEPT | Summary: The source supports regulated nuclear localization of GLI3. Reason: Its abstract directly links GLI3 nuclear localization with transcriptional activity and PP2A regulation. Retain the curated IDA; complete imaging and construct details were not independently recovered. Supporting Evidence: PMID:18559511 Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5610752 | ACCEPT | Summary: Processed GLI3R enters the nucleoplasm. Reason: The actual P10071 repressor participant is the nuclear output of this transport event; Reactome leaves its precise C-terminal boundary unspecified. Supporting Evidence: Reactome:R-HSA-5610752 Reactome:R-HSA-5610752 After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5612508 | ACCEPT | Summary: GLI3R binds the PTCH1 regulatory region in the nucleoplasm. Reason: Both free and promoter-bound repressor participants resolve to P10071 in this compartment. This event concerns the processed product. Supporting Evidence: Reactome:R-HSA-5612508 Reactome:R-HSA-5612508 GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5617408 | ACCEPT | Summary: GLI3R occupies the GLI1 regulatory region in the nucleoplasm. Reason: The actual repressor participant, including its DNA-bound complex, has the asserted compartment; no exact cleavage endpoint is assigned. Supporting Evidence: Reactome:R-HSA-5617408 Reactome:R-HSA-5612508 GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5617410 | ACCEPT | Summary: GLI3R occupies the GLI2 regulatory region in the nucleoplasm. Reason: The P10071 repressor participant is explicitly nucleoplasmic. This product-specific record does not describe full-length activation. Supporting Evidence: Reactome:R-HSA-5617410 Reactome:R-HSA-5612508 GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635841 | ACCEPT | Summary: Full-length phosphorylated GLI3 is modeled in the nucleoplasm. Reason: P10071 participants support the location. The event leaves the relevant kinase, phosphorylation location and ordering unsettled; the compartment annotation does not resolve those mechanisms. Supporting Evidence: Reactome:R-HSA-5635841 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635843 | ACCEPT | Summary: Phosphorylated full-length GLI3 enters the nucleoplasm. Reason: The actual P10071 output of the transport event is nucleoplasmic. Retain the location for this product rather than borrowing the repressor transport rationale. Supporting Evidence: Reactome:R-HSA-5635843 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635845 | ACCEPT | Summary: Full-length GLI3 associates with CDC73 in the nucleoplasm. Reason: The phosphorylated P10071 participant is present in both the free and CDC73-associated forms. This supports location, not a new catalytic activity. Supporting Evidence: Reactome:R-HSA-5635845 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635846 | ACCEPT | Summary: Phosphorylated full-length GLI3 occupies GLI1 regulatory DNA. Reason: The free and DNA-bound P10071 participants are nucleoplasmic. Preserve this activation-associated product context separately from GLI3R. Supporting Evidence: Reactome:R-HSA-5635846 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635848 | ACCEPT | Summary: Phosphorylated full-length GLI3 occupies PTCH1 regulatory DNA. Reason: Actual P10071 leaf participants have the nucleoplasmic location. This is distinct from the repressor productβs PTCH1-binding event. Supporting Evidence: Reactome:R-HSA-5635848 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635854 | ACCEPT | Summary: Ubiquitinated full-length GLI3 is a nucleoplasmic degradation substrate. Reason: The actual P10071 input supports the location. GLI3 is acted on by the proteasome; this record assigns neither protease activity nor a new proteolysis process. Supporting Evidence: Reactome:R-HSA-5635854 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635855 | ACCEPT | Summary: Phosphorylated full-length GLI3 binds the nuclear SPOP ligase complex. Reason: Free and complex-associated P10071 participants are nucleoplasmic. The location does not assign ligase activity to GLI3. Supporting Evidence: Reactome:R-HSA-5635855 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5635856 | ACCEPT | Summary: Full-length GLI3 is ubiquitinated within a nucleoplasmic complex. Reason: Both the unmodified and ubiquitinated P10071 participants carry this compartment. Preserve the substrate role and product-specific location. Supporting Evidence: Reactome:R-HSA-5635856 |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Reason: Human full-length imaging corroborates the mouse cytoplasm transfer; localization is not exclusive. Supporting Evidence: PMID:10077605 Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Reason: Human full-length imaging corroborates the mouse cytoplasm transfer; localization is not exclusive. Supporting Evidence: PMID:12435627 FL-Gli3 was localized to dot-like structures in both cytoplasm and nucleus, whereas Gli3ΞC staining only displayed a punctate pattern in the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:10077605 GLI3 mutations in human disorders mimic Drosophila cubitus i... | ACCEPT | Reason: Transfected human full-length GLI3 is predominantly cytoplasmic; engineered PHS products preferentially occupy nuclei. Supporting Evidence: PMID:10077605 Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. PMID:23955340 First, DZIP1 interacts with GLI3, a transcriptional regulator for Hedgehog signaling, and prevents GLI3 from entering the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:11238441 Physical and functional interactions between Zic and Gli pro... | ACCEPT | Reason: Zic-associated translocation and human full-length imaging support cytoplasmic pools; uninspected imaging details remain unresolved. Supporting Evidence: PMID:11238441 Moreover, Gli proteins were translocated to cell nuclei by coexpressed Zic proteins, and both proteins regulated each other's transcriptional activity. |
| GO:0005737 cytoplasm | IDA PMID:12435627 Ski is involved in transcriptional regulation by the repress... | ACCEPT | Summary: Full-length GLI3 also occupies cytoplasm. Reason: The human full-length construct has mixed nuclear/cytoplasmic distribution, unlike the predominantly nuclear engineered repressor. Supporting Evidence: PMID:12435627 FL-Gli3 was localized to dot-like structures in both cytoplasm and nucleus, whereas Gli3ΞC staining only displayed a punctate pattern in the nucleus. |
| GO:0005829 cytosol | IDA PMID:18559511 Protein phosphatase 2A and rapamycin regulate the nuclear lo... | ACCEPT | Summary: The source directly reports cytosolic retention of GLI3. Reason: PP2A activation or rapamycin treatment retains GLI3 in the cytosol and reduces target-gene transcription in the accessible abstract. This is a condition-dependent pool, not exclusion from the nucleus. Supporting Evidence: PMID:18559511 An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5610723 | ACCEPT | Summary: Full-length GLI3 binds SUFU in the cytosol. Reason: The free and SUFU-associated participants resolve to P10071 with this compartment; the location is directly modeled for GLI3 itself. Supporting Evidence: Reactome:R-HSA-5610723 PMID:18559511 An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5610752 | ACCEPT | Summary: Processed GLI3R starts this transport event in the cytosol. Reason: The actual repressor input has this compartment. Do not substitute a full-length processing rationale or invent a precise repressor endpoint. Supporting Evidence: Reactome:R-HSA-5610752 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5610754 | ACCEPT | Summary: Processing yields cytosolic GLI3R. Reason: The output participant is the P10071 repressor with an unspecified C-terminal boundary. The source specifically supports this productβs location. Supporting Evidence: Reactome:R-HSA-5610754 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5610767 | ACCEPT | Summary: Full-length GLI3βSUFU begins ciliary transport from the cytosol. Reason: The GLI3 leaf within the input complex is P10071 in the asserted compartment. GLI3 is transport cargo, not an IFT motor. Supporting Evidence: Reactome:R-HSA-5610767 PMID:18559511 An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5635860 | ACCEPT | Summary: Full-length GLI3βSUFU has a cytosolic input pool. Reason: The signal-dependent transport event explicitly contains P10071 in its cytosolic input complex, supporting the compartment without assigning transport activity. Supporting Evidence: Reactome:R-HSA-5635860 PMID:18559511 An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. |
| GO:0005929 cilium | IEA GO_REF:0000120 | ACCEPT | Reason: Endogenous mouse Gli3 supports ciliary localization; retain the orthology/location mapping without claiming direct endogenous-human imaging. Supporting Evidence: PMID:19592253 We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. |
| GO:0005929 cilium | IDA PMID:16254602 Gli2 and Gli3 localize to cilia and require the intraflagell... | ACCEPT | Reason: Tagged constructs and endogenous Gli3 staining in mouse cells support ciliary tips; preserve donor and engineered-repressor boundaries. Supporting Evidence: PMID:16254602 Most importantly, the data indicate that all three full-length Gli proteins along with Sufu colocalize to the distal tips of cilia in primary limb bud cells. PMID:16254602 Since the Gli3 antiserum recognizes the N-terminus of Gli3, and GFP is fused to the C-terminus in Gli3::GFP virus, the data suggest that it is the full-length form of Gli3 that localizes to the cilium tip. |
| GO:0005929 cilium | IDA PMID:19592253 The mammalian Cos2 homolog Kif7 plays an essential role in m... | ACCEPT | Summary: The cited study explicitly places Gli3 in primary cilia. Reason: The abstract reports Kif7-dependent Gli3 ciliary localization and processing in mouse experiments. Retain the curated location while distinguishing Gli3 from Kif7βs transport/regulatory role. Supporting Evidence: PMID:19592253 We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. |
| GO:0016607 nuclear speck | IEA GO_REF:0000107 | UNDECIDED | Summary: SPOP-associated nuclear foci do not yet resolve the specific speck compartment. Reason: The traced mouse source studies Flag-human GLI3 recruited to SPOP-positive nuclear foci. GO:0016607 specifies splicing-factor domains; the inspected passages do not establish that marker identity. Preserve the real foci observation while leaving the precise compartment unresolved, without a miscitation or exclusion claim. Supporting Evidence: |
| GO:0097542 ciliary tip | IEA GO_REF:0000117 | ACCEPT | Reason: Endogenous mouse tip staining and curated P10071 participants support the location; this does not assign cilium-assembly activity. Supporting Evidence: PMID:16254602 Most importantly, the data indicate that all three full-length Gli proteins along with Sufu colocalize to the distal tips of cilia in primary limb bud cells. PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5610766 | ACCEPT | Summary: Full-length GLI3βSUFU is present at the ciliary tip before transport. Reason: The actual P10071 input participant has this location. Retain the full-length cargo context, separately from nuclear GLI3R. Supporting Evidence: Reactome:R-HSA-5610766 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5610767 | ACCEPT | Summary: Full-length GLI3βSUFU reaches the ciliary tip. Reason: The IFT-associated eventβs output complex includes a P10071 leaf at the tip. The annotation concerns GLI3 location, not motor function. Supporting Evidence: Reactome:R-HSA-5610767 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5635842 | ACCEPT | Summary: Full-length GLI3 is modeled at the ciliary tip during phosphorylation. Reason: Both unphosphorylated and phosphorylated P10071 participants carry the tip compartment. No kinase activity is assigned to GLI3. Supporting Evidence: Reactome:R-HSA-5635842 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5635843 | ACCEPT | Summary: Phosphorylated full-length GLI3 leaves the ciliary tip for the nucleus. Reason: The P10071 input participant supplies direct source-specific support for the tip location, distinct from the nucleoplasmic output. Supporting Evidence: Reactome:R-HSA-5635843 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5635859 | ACCEPT | Summary: Full-length GLI3 remains at the ciliary tip during modeled SUFU release. Reason: Both complex-associated and free P10071 participants have the tip compartment. This does not generalize ciliary trafficking to the processed repressor. Supporting Evidence: Reactome:R-HSA-5635859 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5635860 | ACCEPT | Summary: Full-length GLI3βSUFU concentrates at the ciliary tip. Reason: The actual P10071 output of the Hedgehog-responsive transport event has this location. Retain the specific participant and product context. Supporting Evidence: Reactome:R-HSA-5635860 Reactome:R-HSA-5635860 Activation of the Hh pathway causes the GLI:SUFU complex to concentrate in the primary cilium PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097546 ciliary base | IEA GO_REF:0000117 | ACCEPT | Summary: Retain the source-specific ciliary-base localization. Reason: Independently inspected Reactome events resolve actual P10071 participants at the ciliary base. The broader ARBA location agrees with those participants; it does not specify a narrower basal-body substructure or infer localization from the reaction compartment alone. Supporting Evidence: Reactome:R-HSA-5610720 Reactome:R-HSA-5610722 Reactome:R-HSA-5610732 Reactome:R-HSA-5610746 Reactome:R-HSA-5610766 Although GLI and SUFU proteins are not concentrated in the cilium in the absence of Hh signaling, processing and/or degradation of the transcription factors requires transit through the cilium and basal levels of these proteins can be detected there |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610720 | ACCEPT | Summary: Full-length GLI3 is modeled at the ciliary base during PKA phosphorylation. Reason: The actual P10071 participant has the base compartment even where event metadata is broader. GLI3 is the kinase substrate, not the catalyst. Supporting Evidence: Reactome:R-HSA-5610720 |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610722 | ACCEPT | Summary: Phosphorylated full-length GLI3 is modeled at the ciliary base. Reason: The CK1 eventβs P10071 input and output leaves have this compartment. Retain participant location without inferring it solely from the event compartment. Supporting Evidence: Reactome:R-HSA-5610722 |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610732 | ACCEPT | Summary: The modeled GSK3 substrate GLI3 occupies the ciliary base. Reason: Actual P10071 phosphoprotein leaves support the location. The annotation neither identifies a narrower basal-body structure nor assigns kinase activity. Supporting Evidence: Reactome:R-HSA-5610732 |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610746 | ACCEPT | Summary: GLI3 ubiquitination is modeled with its participant at the ciliary base. Reason: The P10071 leaves before and after ubiquitination carry this compartment. GLI3 remains the substrate of SCF(beta-TrCP). Supporting Evidence: Reactome:R-HSA-5610746 |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610754 | ACCEPT | Summary: Full-length GLI3 enters processing from the ciliary-base compartment. Reason: The ubiquitinated P10071 input is explicitly assigned to the base; the processed cytosolic output is a separate product and location. Supporting Evidence: Reactome:R-HSA-5610754 |
| GO:0097546 ciliary base | TAS Reactome:R-HSA-5610766 | ACCEPT | Summary: Full-length GLI3βSUFU reaches the modeled ciliary-base compartment. Reason: The IFT-A eventβs output complex contains P10071 at the base. This source-specific location does not imply that GLI3 is an IFT component. Supporting Evidence: Reactome:R-HSA-5610766 |
| GO:0097730 non-motile cilium | IEA GO_REF:0000107 | ACCEPT | Summary: The orthology donor provides direct primary-cilium localization. Reason: PMID:20956384 examines endogenous mouse Gli3 in NIH-3T3 cells and fibroblasts, with signal-dependent ciliary enrichment and antibody specificity controls. Retain the non-motile-cilium transfer while preserving the mouse donor boundary. Supporting Evidence: PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. |
| GO:0097730 non-motile cilium | IDA PMID:20154143 Kinetics of hedgehog-dependent full-length Gli3 accumulation... | ACCEPT | Summary: Retain the curated primary-cilium location with experimental boundaries. Reason: The study observes endogenous Gli3 at ciliary tips, principally in mouse cells, and validates antibodies using historical human constructs. This supports the compartment and curated IDA without claiming an independently verified endogenous-human ciliary experiment. Supporting Evidence: PMID:20154143 We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. PMID:20154143 We also confirmed that phosphorylation and betaTrCP/Cul1 are required for endogenous Gli3 processing and that this is inhibited by Hh. |
| GO:0005930 axoneme | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact part_of-axoneme assertion remains unresolved. Reason: The traced mouse experiment positively localizes Gli3 to ciliary tips, while this row asserts part_of axoneme. A term-only replacement cannot correct that relation. Preserve the source record and seek curator clarification; located_in ciliary tip is already retained elsewhere, without excluding axonemal association. Supporting Evidence: |
| GO:0017053 transcription repressor complex | IEA GO_REF:0000107 | ACCEPT | Summary: GLI3 participates in repressor complexes. Reason: SKI/HDAC association supports the transferred complex term; GLI3 is not a deacetylase, and other repression mechanisms remain possible. Supporting Evidence: PMID:12435627 Gli3 Rep was efficiently coprecipitated with HDAC1, indicating that HDAC1 and GLI3 Rep associate with one another. PMID:12435627 Here we report that the Ski corepressor binds to Gli3 and recruits the histone deacetylase complex. |
| GO:1990788 GLI-SUFU complex | IPI PMID:24311597 Structural basis of SUFU-GLI interaction in human Hedgehog s... | ACCEPT | Reason: Human GLI3 peptideβSUFU structural and solution evidence supports complex membership, without mapping every property of the full-length cellular complex. Supporting Evidence: PMID:24311597 Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. PMID:24311597 SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. |
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Download this section (compressed HTML)Q: How should routine gene-level annotations represent the distinct full-length activator and processed repressor products already distinguished in curated human GO-CAM activities, without treating them as splice isoforms?
Q: For the transferred part_of axoneme assertion, should the relation and compartment be revised to located_in ciliary tip? The donor experiment localizes Gli3 to tips but does not resolve the exact axonemal association.
Q: Do the SPOP-associated GLI3 nuclear foci have the splicing-factor markers required for the nuclear-speck annotation?
Q: Which target-specific experiment supports the transcriptional-regulation IDA from PMID:24311597, beyond the demonstrated human GLI3 peptide interaction and inspected GLI1 reporter assay?
Q: What evidence supports the precise negative thymocyte-differentiation transfers and digit-morphogenesis assertion whose primary details remain inaccessible or unresolved? Preserve stromal versus thymocyte-intrinsic effects and mouse versus human scope.
Experiment: Combine validated product-specific immunoprecipitation with endogenous N- and C-terminal tagging, protein measurements and matched transcriptional profiling. Calibrate enrichment and avoid treating simple subtraction of two ChIP signals as a quantitative repressor-specific profile.
Hypothesis: Full-length and processed GLI3 occupy partially overlapping regulatory sites with different transcriptional outputs.
Type: Chromatin profiling with product-specific controls
Experiment: Image endogenous GLI3 with validated base, tip and axoneme markers during Hedgehog stimulation, resolving molecular proximity and product identity alongside residence time.
Hypothesis: The GLI3 ciliary-base and tip pools have distinct trafficking kinetics.
Type: Endogenous imaging
Experiment: Test colocalization with independent splicing-speck markers at endogenous expression levels and quantify recruitment after controlled SPOP perturbation.
Hypothesis: SPOP-associated GLI3 nuclear foci correspond to a defined nuclear compartment.
Type: Compartment-specific imaging
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