Affinage

GLI3

Transcriptional activator GLI3 · UniProt P10071

Length
1580 aa
Mass
169.9 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLI3 is a sequence-specific zinc finger transcription factor that serves as a principal effector of the vertebrate Hedgehog pathway, translating SHH signaling into graded transcriptional programs that pattern the limb, neural tube, skeleton, and foregut (PMID:2118997, PMID:12198547, PMID:9006072, PMID:9731531). Its defining feature is bifunctionality: full-length GLI3 is a cytoplasmic activator (GLI3A) that drives target genes such as PTCH1, whereas proteolytic processing yields a nuclear C-terminal-truncated repressor (GLI3R) that silences targets in the absence of pathway activity (PMID:10077605). Processing is initiated by multisite PKA phosphorylation that primes sequential GSK3β and CK1 phosphorylation at βTrCP-binding motifs, driving SCFβTrCP-dependent ubiquitination (PMID:16705181); SUFU scaffolds this event by bridging GLI3 to GSK3β, and SHH stimulation dissociates the complex to block processing (PMID:19622347). The processing reaction itself requires a tripartite proteasomal signal—folded zinc fingers, a low-complexity linker, and a positioned degron—that distinguishes GLI3 from the non-processed GLI1 (PMID:21921029). Pathway activation is read out at the primary cilium, where ciliary PKA normally phosphorylates GLI3 (PMID:28673820) and the kinase DYRK2 phosphorylates GLI3 in response to SMO activity to trigger SUFU dissociation and nuclear entry of the activator (PMID:38968120); Set7-mediated methylation of full-length GLI3 at K436 and K595 further stabilizes the activator and enhances its DNA binding (PMID:27146893). As an activator, GLI3 engages the MED12 subunit of Mediator together with CBP to activate Hedgehog targets (PMID:17000779), and partners with context-specific cofactors including Hand2 at divergent Gli motifs in the mandible (PMID:34610962) and Trps1 to drive chondrocyte programs such as Wnt5a (PMID:19389374, PMID:31550480). As a repressor, GLI3R directly occupies promoters of Gli1, Gli2, and patterning genes to silence them when SHH-SMO signaling is off (PMID:16396903), represses Fgf8 independently of SHH (PMID:12435361), and cross-inhibits canonical Wnt signaling by binding β-catenin (PMID:17331723); GLI3 transcription is itself a Wnt/TCF target, integrating dorsal Wnt and ventral SHH inputs (PMID:18057099). Through these activities GLI3 controls cell-cycle exit and differentiation—restricting Cdk6 and cyclin D1 to limit progenitor proliferation (PMID:22465667, PMID:21976438) and maintaining muscle satellite cell dormancy by restraining mTORC1 (PMID:35803939). GLI3 protein levels are additionally regulated by SPOP-mediated proteasomal degradation, whose cancer-associated loss stabilizes GLI3 to cooperate with the androgen receptor in prostate cancer (PMID:34610962).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1990 High

    Established GLI3 as a sequence-specific DNA-binding protein, defining the molecular basis for its role as a transcription factor with similarity to Drosophila cubitus interruptus.

    Evidence cDNA cloning and in vitro DNA-binding assays with polyclonal antisera-identified protein

    PMID:2118997

    Open questions at the time
    • Did not identify physiological target genes
    • No link yet to Hedgehog signaling or in vivo function
  2. 1996 Medium

    Placed GLI3 downstream of SHH in the vertebrate Hedgehog pathway by showing SHH down-regulates its expression in the limb bud.

    Evidence In situ hybridization and misexpression in chick limb bud

    PMID:8948590

    Open questions at the time
    • Expression-level regulation only; did not address protein processing or activator/repressor switch
    • Single tissue context
  3. 1997 High

    Defined non-redundant and Gli2-redundant developmental functions of GLI3 in skeletal patterning, distinguishing it from paralogs in vivo.

    Evidence Mouse single and double knockout genetics across multiple tissues

    PMID:9006072 PMID:9731531

    Open questions at the time
    • Did not resolve whether phenotypes reflect activator vs repressor loss
    • Mechanism of target gene control unaddressed
  4. 1999 High

    Resolved the bifunctional model by showing full-length GLI3 is a cytoplasmic activator while a truncated form is a nuclear repressor, with transactivation domains mapped to the C-terminus.

    Evidence Subcellular localization, reporter assays with disease-mutant constructs, GAL4 transactivation domain mapping

    PMID:10077605 PMID:10441342

    Open questions at the time
    • Did not define how processing into the repressor is triggered or regulated
    • Cofactors mediating transactivation not identified
  5. 2002 High

    Demonstrated genetically that SHH controls digit identity and Fgf8 repression entirely through the GLI3 activator/repressor balance, including a SHH-independent repressor function.

    Evidence Shh;Gli3 double-knockout mouse epistasis with skeletal and in situ analysis

    PMID:12198547 PMID:12435361

    Open questions at the time
    • Did not identify the direct target promoters bound by GLI3R
    • Biochemical processing mechanism still open
  6. 2003 High

    Showed GLI3 acts as both activator and repressor of distinct Shh target subsets in somite induction, refining the dual-function model context by context.

    Evidence Mouse knockouts, somite explant rescue, adenoviral overexpression

    PMID:14602680

    Open questions at the time
    • Target gene specificity determinants not defined
    • No cofactor mapping
  7. 2006 High

    Reconstituted the biochemical processing cascade (PKA priming → GSK3β/CK1 → SCFβTrCP ubiquitination) and identified Mediator/MED12-CBP as the activation machinery, plus direct GLI3R promoter occupancy of patterning genes.

    Evidence Phosphorylation and ubiquitination assays with site mutagenesis; reciprocal Co-IP and dominant-negative for MED12; ChIP in embryonic kidney

    PMID:16396903 PMID:16705181 PMID:17000779

    Open questions at the time
    • Did not localize the cascade to the cilium
    • How SHH dissociates the kinase machinery from GLI3 unresolved
  8. 2007 Medium

    Established reciprocal crosstalk with Wnt signaling: GLI3R binds β-catenin to suppress Wnt transcription, while Wnt/TCF directly drives GLI3 transcription.

    Evidence Co-IP, reporter assays in cells and chick embryos, TCF-binding-site characterization

    PMID:17331723 PMID:18057099

    Open questions at the time
    • Single lab for each direction
    • Structural basis of GLI3R–β-catenin interaction not defined
  9. 2008 Medium

    Linked GLI3 nuclear localization and cyclin D1 output to PP2A and mTORC1 activity, connecting GLI3 to cell-proliferation control.

    Evidence Subcellular fractionation, pharmacological PP2A/mTORC1 modulation, reporter assays

    PMID:18559511

    Open questions at the time
    • Direct phosphosites targeted by PP2A not mapped
    • Single lab, pharmacological inference
  10. 2009 Medium

    Identified SUFU as a scaffold that recruits GSK3β to GLI3 for processing, and Trps1 as an activator-specific cofactor in chondrocytes.

    Evidence Co-IP, Sufu-null MEFs, siRNA; Trps1 domain mapping and double-mutant genetics

    PMID:19389374 PMID:19622347

    Open questions at the time
    • Single-lab Co-IP for the trimolecular complex
    • How SHH dissociates SUFU/GSK3β mechanistically unresolved at this stage
  11. 2010 Medium

    Extended GLI3 transcriptional control beyond canonical Hedgehog by showing direct VMP1 promoter binding with p300 to regulate autophagy downstream of KRAS.

    Evidence ChIP, RNAi, promoter-reporter and p300 knockdown

    PMID:22535956

    Open questions at the time
    • Single lab
    • Whether this involves GLI3A or GLI3R not fully resolved
  12. 2011 High

    Dissected the proteasomal processing signal into folded zinc fingers, a low-complexity linker, and a positioned degron, explaining why GLI3 but not GLI1 is processed.

    Evidence In vitro proteasome processing assays with domain mutagenesis and chimeric constructs

    PMID:21921029

    Open questions at the time
    • Identity of the proteasome stop signal not pinpointed
    • In vitro reconstitution; in vivo relevance assumed
  13. 2012 Medium

    Connected GLI3 directly to cell-cycle control in development by showing it restricts Cdk6 and cyclin D1 to limit progenitor S-phase entry in limb and cortex.

    Evidence Conditional and constitutive knockouts with cell-cycle and gene-expression readouts

    PMID:21976438 PMID:22465667

    Open questions at the time
    • Direct vs indirect repression of Cdk6 not distinguished by binding data
    • Single labs
  14. 2016 Medium

    Added post-translational and ciliary layers to activator regulation: Set7 methylation stabilizes and enhances DNA binding of full-length GLI3, and a Tbx3/Kif7/Sufu ciliary module governs GLI3 stability.

    Evidence In vitro methylation with site mutagenesis and functional assays; ciliary co-localization and Co-IP

    PMID:27046536 PMID:27146893

    Open questions at the time
    • Whether methylation and ciliary regulation intersect not tested
    • Single labs
  15. 2017 Medium

    Localized processing kinases to the cilium/centriole and identified SPOP as a proteasomal regulator of GLI3 protein levels in vivo.

    Evidence Ciliary-fraction phosphorylation assays, Talpid3 mutant analysis; Spop knockout mouse epistasis with Western blot

    PMID:28412462 PMID:28673820

    Open questions at the time
    • Direct SPOP–GLI3 binding not shown at this stage
    • Single labs
  16. 2019 High

    Showed cooperative, Hh-gradient-independent activation: GLI3A with Trps1 directly activates Wnt5a, and GLI3A with Hand2 co-occupies low-affinity divergent Gli motifs for mandibular patterning.

    Evidence ChIP/ChIP-seq, luciferase reporters with motif mutations, Co-IP, mouse double mutants

    PMID:31550480 PMID:33006313

    Open questions at the time
    • How cofactor choice is determined in different tissues unresolved
    • dGBM logic generality not established
  17. 2020 Medium

    Demonstrated GLI3A relays Hedgehog signals into specific differentiation programs, restoring steroidogenic identity in fetal Leydig cells.

    Evidence Gli3-mutant testis rescue with GLI3A reintroduction and gene-expression analysis

    PMID:32497091

    Open questions at the time
    • Direct target promoters in Leydig cells not mapped
    • Single lab
  18. 2021 Medium

    Implicated GLI3 in cancer through SPOP: SPOP degrades GLI3, and prostate-cancer SPOP mutations stabilize GLI3, which cooperates with the androgen receptor to drive tumor growth.

    Evidence Co-IP of GLI3 and AR, proteasomal degradation assay, SPOP-mutant overexpression, xenograft

    PMID:34610962

    Open questions at the time
    • Whether GLI3A or GLI3R mediates the AR cooperation not resolved
    • Single lab
  19. 2022 High

    Showed cilium-dependent GLI3 processing enforces stem-cell quiescence by restraining mTORC1 in muscle satellite cells.

    Evidence Conditional Gli3 knockout with cell-cycle, mTORC1 readouts and in vivo regeneration

    PMID:35803939

    Open questions at the time
    • Direct GLI3R target genes controlling GAlert entry not defined
    • Link between GLI3R and mTORC1 mechanistically indirect
  20. 2024 High

    Identified the ciliary kinase that activates GLI3: DYRK2 phosphorylates conserved serines at the ciliary base downstream of SMO to dissociate SUFU and drive nuclear translocation.

    Evidence In vitro kinase assay with site mapping, Co-IP for SUFU dissociation, localization, Dyrk2 knockout mouse

    PMID:38968120

    Open questions at the time
    • How DYRK2 activity is itself switched on by SMO not fully defined
    • Interplay with PKA-driven processing kinetics unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct post-translational marks (PKA/GSK3β/CK1 processing phosphorylation, DYRK2 activating phosphorylation, Set7 methylation) and cofactor choices (MED12, CBP/p300, Hand2, Trps1) are integrated to set the GLI3A:GLI3R ratio and target-gene specificity in each tissue remains unresolved.
  • No unified quantitative model of the activator/repressor switch
  • Determinants of context-specific cofactor recruitment unknown
  • Structural basis of GLI3 partner interactions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140110 transcription regulator activity 6
Localization
GO:0005929 cilium 4 GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3
Partners
CBPCTNNB1GSK3ΒHAND2MED12P300SUFUTRPS1
Complex memberships
Gli3/Sufu/GSK3β complexMediator complex (via MED12)SCFβTrCP (substrate)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 GLI3 encodes a 190-kDa protein (1,596 amino acids) with five zinc fingers that binds specifically to GLI-binding sites in genomic DNA, functioning as a sequence-specific DNA-binding protein; it shares seven regions of similarity with GLI (53–88% identity) and additional similarity with Drosophila cubitus interruptus beyond the zinc fingers. cDNA cloning, polyclonal antisera-based protein identification, in vitro DNA binding assay Molecular and cellular biology High 2118997
1996 Sonic hedgehog down-regulates GLI3 expression in limb bud mesenchymal cells (while up-regulating GLI1), placing GLI3 downstream of Shh signaling in the vertebrate hedgehog pathway. In situ hybridization and misexpression experiments in chick limb bud Developmental biology Medium 8948590
1997 Loss-of-function genetic analysis in mice shows Gli3 has specific, non-redundant roles in neural crest, somite, and lateral plate mesoderm derivatives during skeletal patterning, and also functions redundantly with Gli2; double mutants exhibit more severe skeletal defects than either single mutant. Mouse knockout genetics, double mutant analysis Development (Cambridge, England) High 9006072
1998 Gli2 and Gli3 together are essential for formation of the oesophagus, trachea, and lung downstream of Sonic hedgehog; Gli3 heterozygosity in a Gli2-null background exacerbates foregut defects, and complete loss of both genes eliminates these organs, demonstrating overlapping functions in Shh signal transduction. Mouse knockout genetics, double mutant analysis Nature genetics High 9731531
1999 Full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression (analogous to full-length Ci155); a PHS truncation mutant (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression (analogous to Ci75 repressor); GCPS mutant protein has no effect on PTCH1 transcription (consistent with haploinsufficiency). Subcellular localization assay (fluorescence microscopy), transcriptional reporter assays in transfected cells Proceedings of the National Academy of Sciences of the United States of America High 10077605
1999 Two independent transactivation domains (TA1 and TA2) located in the C-terminal third of GLI3 were identified by GAL4 fusion transfection assays; truncating mutations in GCPS that eliminate these domains cause functional haploinsufficiency. GAL4 fusion transactivation assays in transfected cells Human molecular genetics Medium 10441342
2002 Genetic epistasis in Shh−/−;Gli3−/− double-mutant mice shows that limb skeletal elements form without Shh or Gli3, but all wild-type digit identities are lost; the effects of Shh on skeletal patterning are necessarily mediated through Gli3, demonstrating that Shh controls digit identity by regulating the balance of Gli3 activator and repressor activities. Mouse double-knockout genetics, skeletal analysis Nature High 12198547
2002 GLI3 normally represses Fgf8 expression in the anterior neural ridge, isthmus, eye, facial primordia, and limb buds; this repression is independent of SHH, as Fgf8 is upregulated in Gli3−/−;Shh−/− double mutants even though Fgf8 is nearly absent in Shh−/− single mutants. Mouse knockout genetics, in situ hybridization, double-mutant analysis Developmental biology High 12435361
2003 Gli2 and Gli3 are required for Shh-dependent sclerotome induction; in the somite, Gli3 can function as both an activator and a repressor of Shh target genes, and each Gli preferentially activates a distinct subset of target genes. Mouse knockout genetics, in vitro somite explant assays, adenovirus-mediated overexpression Development (Cambridge, England) High 14602680
2004 Elevated Gli3 repressor (Gli3R) levels in the anterior limb bud, caused by absence of Shh signaling, correlate with increased Bmp4 expression and apoptosis; exogenous Noggin prevents this apoptosis, placing Bmp4 downstream of Gli3R in mediating cell death. Posterior wing-bud removal surgery, Noggin bead implantation, in situ hybridization, Western blot in chick and mouse mutants Developmental dynamics Medium 15305295
2006 Multisite PKA phosphorylation triggers a cascade of GSK3β and CK1 phosphorylation at multiple βTrCP-binding sites (DSGX2-4S-related motifs) in Gli3, leading to direct SCFβTrCP binding and ubiquitination, which is required for Gli3 proteolytic processing into the repressor form. Phosphorylation assays, mutagenesis of PKA/GSK3β/CK1 sites and βTrCP-binding motifs, co-immunoprecipitation, ubiquitination assay Molecular and cellular biology High 16705181
2006 GLI3 physically interacts with the MED12 subunit of the RNA Pol II Mediator complex through a Gli3 transactivation domain (MBD); this interaction, together with histone acetyltransferase CBP, is required for Gli3-dependent activation of Shh target genes. Dominant-negative disruption of Gli3-MED12 interaction inhibited transcriptional activation. Co-immunoprecipitation in vitro and in vivo, dominant-negative interference, RNAi knockdown, reporter assays Molecular and cellular biology High 17000779
2006 GLI3-dependent transcriptional repression directly controls expression of Gli1, Gli2, and kidney patterning genes (Pax2, Sall1, cyclin D1, MYCN); chromatin immunoprecipitation showed GLI3 repressor binds 5′ flanking regions of these target genes in embryonic kidney when SHH-SMO signaling is absent. Chromatin immunoprecipitation (ChIP), cyclopamine inhibition, mouse knockout rescue (Gli3−/−; Shh−/−) Development (Cambridge, England) High 16396903
2007 The Gli3 repressor form (Gli3R) inhibits canonical Wnt/β-catenin signaling by physically interacting with the C-terminal transactivation domain of β-catenin, thereby suppressing Wnt-mediated transcription in the neural tube. Co-immunoprecipitation, reporter assays in cells and chick embryos, Gli3R overexpression/loss-of-function Current biology : CB Medium 17331723
2007 Canonical Wnt/β-catenin signaling directly controls Gli3 transcription through conserved Tcf-binding sequences in the human GLI3 gene, linking dorsal Wnt activity to restriction of ventral Shh/Gli targets in the neural tube. Identification and functional characterization of conserved non-coding Tcf-binding regions, reporter assays, chick electroporation Development (Cambridge, England) Medium 18057099
2008 Protein phosphatase 2A (PP2A) and rapamycin (mTORC1 inhibitor) regulate the nuclear localization and transcriptional activity of GLI3; increased PP2A activity or rapamycin treatment causes cytosolic retention of GLI3 and reduces cyclin D1 expression, while PP2A inhibition increases cyclin D1. Subcellular fractionation, pharmacological modulation of PP2A and mTORC1, reporter assays, Western blot Cancer research Medium 18559511
2009 Sufu directly binds both Gli3 and GSK3β and mediates formation of a trimolecular Gli3/Sufu/GSK3β complex, thereby recruiting GSK3β to phosphorylate Gli3 for processing into the repressor form; Sonic Hh stimulation dissociates the Sufu/GSK3β complex from Gli3, blocking processing. Co-immunoprecipitation, Sufu−/− mouse embryonic fibroblasts, siRNA knockdown, biochemical complex analysis Biochemical and biophysical research communications Medium 19622347
2009 Trps1 specifically binds to the transactivation domain of the activator form of Gli3 (but not the repressor form) via a 185 aa domain containing three predicted zinc fingers; this interaction coordinates chondrocyte differentiation and proliferation in distal chondrocytes. Co-immunoprecipitation in vitro and in vivo, domain mapping, mouse double-mutant genetics Developmental biology Medium 19389374
2010 GLI3 binds directly to the VMP1 promoter and forms a complex with the histone acetyltransferase p300 to regulate VMP1 promoter activity and autophagy downstream of KRAS via the PI3K-AKT1 pathway, independently of canonical Hedgehog signaling. Chromatin immunoprecipitation, RNAi, promoter-reporter assay, p300 knockdown The Journal of biological chemistry Medium 22535956
2011 The proteasome processes Gli3 (but not Gli1) via a three-part signal comprising the zinc finger domain (required as a folded structure), an adjacent linker sequence with regions of low complexity, and a degron whose location (but not identity) is critical; Gli1 is not processed because both its linker and degron are ineffective. In vitro proteasome processing assays, domain mutagenesis, chimeric Gli1/Gli3 constructs The Journal of biological chemistry High 21921029
2012 GLI3 directly restricts expression of Cdk6 (a G1-S cell cycle regulator) to limit S-phase entry of digit progenitors in the anterior hand plate, and also promotes exit from proliferation toward BMP-dependent chondrogenic differentiation by restricting Gremlin1 expression. Conditional Gli3 knockout in mouse hand plate, cell cycle analysis, gene expression, conditional inactivation Developmental cell Medium 22465667
2012 Gli3 repressor activity (Gli3R), acting through primary cilia, regulates cell cycle kinetics in cortical progenitors; loss of Gli3 (or loss of Kif3a/cilia) shortens G1 via increased cyclin D1 and Fgf15 expression, causing cortical overgrowth. Conditional Kif3a knockout (cilia loss), Gli3 knockout, cell cycle analysis, gene expression in mouse cortex Developmental neurobiology Medium 21976438
2013 Gli3 repressor GLI3R is required for the therapeutic effect of SMO antagonists in AML; GLI3R represses AML growth by downregulating AKT expression; GLI3 locus is epigenetically silenced by aberrant methylation in most AML samples. Gene expression and methylation analysis, GLI3R restoration in AML cells, SMO antagonist treatment, Western blot Blood Medium 28487292
2016 Set7 methyltransferase methylates full-length Gli3 (but not the truncated repressor) at K436 and K595; methylation at K436 increases Gli3 protein stability, while methylation at K595 increases DNA-binding ability, both enhancing Shh signaling activation. In vitro methylation assay, mutagenesis of K436 and K595, stability assays, DNA-binding assays, in vivo functional experiments eLife High 27146893
2016 T-box3 is present in primary cilia where it co-localizes with Gli3 and interacts with Kif7, and is required for normal stoichiometry and function of a Kif7/Sufu complex that regulates Gli3 stability and processing. Live imaging/co-localization in primary cilia, Co-immunoprecipitation, mouse conditional genetics eLife Medium 27046536
2017 PKA phosphorylates Gli3 within primary cilia; Hh signaling inhibits this ciliary PKA-mediated phosphorylation; the Talpid3 mutation reduces Gli3 processing and phosphorylation due in part to failure of PKARIIβ to localize at centrioles. Phosphorylation assays in cilia fractions, Talpid3 mutant analysis, Co-IP of Talpid3 with PKARIIβ, centriolar localization assay Developmental biology Medium 28673820
2017 Spop E3 ubiquitin ligase negatively regulates Gli3 protein levels in the spinal cord; loss of Spop moderately increases Gli3 protein and activator activity, suppressing the floor plate/V3 interneuron deficit of Gli2 mutants, placing Spop as a negative regulator of Gli3 activity in Shh signaling. Mouse Spop knockout genetics, Western blot for Gli3 protein, genetic epistasis with Gli2 and Sufu mutants Developmental biology Medium 28412462
2019 Trps1 and activator Gli3 (Gli3A) bind to an upstream regulatory sequence (URS1) in the Wnt5a promoter (identified by ChIP and reporter assays) to activate Wnt5a transcription in chondrocytes; loss of both Trps1 and Gli3 decreases endogenous Wnt5a mRNA and protein during chondrocyte differentiation. Chromatin immunoprecipitation, luciferase reporter assay, mouse double mutant genetics, Western blot Developmental biology Medium 31550480
2020 GLI3 activator (GLI3A) reintroduction into Gli3XtJ testes restores Hedgehog pathway and steroidogenic gene expression in fetal Leydig cells, demonstrating that GLI3A translates Hedgehog signals to reinforce fetal Leydig cell identity and stimulate INSL3 and testosterone synthesis. Mouse Gli3 mutant rescue experiment, reintroduction of GLI3A via in vivo approach, gene expression analysis PLoS genetics Medium 32497091
2020 Gli3 and Hand2 physically interact and co-occupy regulatory elements at low-affinity divergent Gli-binding motifs (dGBMs) in the mandible, providing synergistic transcriptional activation of Gli3 target genes for mandibular patterning independently of a graded Hh signal. Co-immunoprecipitation, genomic (ChIP-seq) co-occupancy analysis, reporter gene assays with dGBM mutations, mouse genetic analysis eLife High 33006313
2021 GLI3 is a substrate of SPOP-mediated proteasomal degradation; prostate cancer driver mutations in SPOP abrogate GLI3 degradation, stabilizing GLI3; stabilized GLI3 physically interacts and functionally cooperates with androgen receptor (AR) to promote castration-resistant prostate cancer growth. Co-immunoprecipitation of GLI3 and AR, proteasomal degradation assay, SPOP mutant overexpression, xenograft tumor model Molecular cancer research : MCR Medium 34610962
2022 GLI3 processing by the primary cilium maintains satellite cells in a G0 dormant state; loss of GLI3 causes satellite cells to enter the GAlert state and activates mTORC1 signaling, resulting in increased proliferation and self-renewal. Conditional Gli3 knockout in satellite cells, cell-cycle analysis, mTORC1 signaling readout, in vivo muscle regeneration assay Nature communications High 35803939
2024 The ciliary kinase DYRK2 phosphorylates GLI3 (and GLI2) on evolutionarily conserved serine residues at the ciliary base in response to Hh pathway activation downstream of SMO; this phosphorylation induces dissociation of GLI3 from SUFU and nuclear translocation of GLI3. Transcriptome and interactome analysis, in vitro kinase assay, phosphorylation site mapping/mutagenesis, Co-IP, subcellular localization, mouse Dyrk2 knockout Proceedings of the National Academy of Sciences of the United States of America High 38968120

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development (Cambridge, England) 511 9006072
2002 Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 471 12198547
1998 Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nature genetics 439 9731531
1996 Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Developmental biology 327 8948590
1998 The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development (Cambridge, England) 299 9655803
1997 Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4. Developmental biology 243 9268572
2006 Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Molecular and cellular biology 208 16705181
2016 MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nature communications 184 27001906
2002 Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Developmental biology 167 12435361
2007 Wnt canonical pathway restricts graded Shh/Gli patterning activity through the regulation of Gli3 expression. Development (Cambridge, England) 162 18057099
1990 GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity. Molecular and cellular biology 158 2118997
2006 GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development (Cambridge, England) 149 16396903
1992 Expression of the zinc finger gene Gli3 is affected in the morphogenetic mouse mutant extra-toes (Xt). Development (Cambridge, England) 146 1289066
1999 GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proceedings of the National Academy of Sciences of the United States of America 142 10077605
1997 Point mutations in human GLI3 cause Greig syndrome. Human molecular genetics 141 9302279
1999 The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. American journal of human genetics 137 10441570
2004 Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation. Development (Cambridge, England) 128 15604102
2003 Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development (Cambridge, England) 123 14602680
1999 Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Human molecular genetics 118 10441342
2003 A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Developmental biology 107 12921747
2006 Mediator modulates Gli3-dependent Sonic hedgehog signaling. Molecular and cellular biology 106 17000779
2020 GLI3: a mediator of genetic diseases, development and cancer. Cell communication and signaling : CCS 105 32245491
2012 The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Human molecular genetics 94 23026747
2006 Gli3-mediated repression of Hedgehog targets is required for normal mammary development. Development (Cambridge, England) 94 16914490
2007 Inhibitory Gli3 activity negatively regulates Wnt/beta-catenin signaling. Current biology : CB 93 17331723
2003 Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Developmental biology 91 12812795
2012 GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Developmental cell 89 22465667
2000 Regulatory cross-talk between adhesin operons in Escherichia coli: inhibition of type 1 fimbriae expression by the PapB protein. The EMBO journal 89 10747013
2005 Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling. Developmental biology 88 15617692
2014 New insights into genotype-phenotype correlation for GLI3 mutations. European journal of human genetics : EJHG 85 24736735
2005 Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature 83 16015334
2009 Trps1, a regulator of chondrocyte proliferation and differentiation, interacts with the activator form of Gli3. Developmental biology 82 19389374
2009 Sufu recruits GSK3beta for efficient processing of Gli3. Biochemical and biophysical research communications 81 19622347
2012 Primary cilia and Gli3 activity regulate cerebral cortical size. Developmental neurobiology 69 21976438
2017 GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML. Blood 68 28487292
2006 What you can learn from one gene: GLI3. Journal of medical genetics 66 16740916
1993 PAP, a pancreatic secretory protein induced during acute pancreatitis, is expressed in rat intestine. The American journal of physiology 66 8238345
2011 Gli3 is required for maintenance and fate specification of cortical progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 21525285
2011 GLI3 repressor controls functional development of the mouse ureter. The Journal of clinical investigation 62 21339645
2012 Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. The Journal of biological chemistry 60 22535956
2016 Set7 mediated Gli3 methylation plays a positive role in the activation of Sonic Hedgehog pathway in mammals. eLife 57 27146893
2015 Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo. The EMBO journal 53 25908840
2001 PapB paralogues and their effect on the phase variation of type 1 fimbriae in Escherichia coli. Molecular microbiology 51 11703657
2005 The transcription factor Gli3 regulates differentiation of fetal CD4- CD8- double-negative thymocytes. Blood 50 15855276
2004 Levels of Gli3 repressor correlate with Bmp4 expression and apoptosis during limb development. Developmental dynamics : an official publication of the American Association of Anatomists 49 15305295
2009 The Hedgehog transcription factor Gli3 modulates angiogenesis. Circulation research 48 19729595
2008 A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Human molecular genetics 48 18397875
2008 Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3. Cancer research 48 18559511
2013 Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Developmental biology 47 23994639
2017 GLI3-related polydactyly: a review. Clinical genetics 46 28224613
2005 Gli3 is required for the specification and differentiation of preplate neurons. Developmental biology 44 16168404
2018 GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma. International journal of oncology 43 30272273
2009 A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud. Developmental biology 42 19248778
2007 Human GLI3 intragenic conserved non-coding sequences are tissue-specific enhancers. PloS one 40 17426814
2007 Hoxd and Gli3 interactions modulate digit number in the amniote limb. Developmental biology 37 17714700
2022 GLI3 regulates muscle stem cell entry into GAlert and self-renewal. Nature communications 36 35803939
2012 Haplotype distribution in the GLI3 gene and their associations with growth traits in cattle. Gene 36 23142388
2007 Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3. American journal of medical genetics. Part A 36 18000979
2019 Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 31767679
2018 Gli3 controls the onset of cortical neurogenesis by regulating the radial glial cell cycle through Cdk6 expression. Development (Cambridge, England) 32 30093555
2015 Sonic hedgehog through Gli2 and Gli3 is required for the proper development of placental labyrinth. Cell death & disease 32 25695606
1998 Oligomeric interaction of the PapB transcriptional regulator with the upstream activating region of pili adhesin gene promoters in Escherichia coli. Molecular microbiology 32 9822817
2011 A three-part signal governs differential processing of Gli1 and Gli3 proteins by the proteasome. The Journal of biological chemistry 31 21921029
2014 Signaling-State Formation Mechanism of a BLUF Protein PapB from the Purple Bacterium Rhodopseudomonas palustris Studied by Femtosecond Time-Resolved Absorption Spectroscopy. The journal of physical chemistry. B 30 25406769
2010 Gli3 mediates cell survival and sensitivity to cyclopamine in pancreatic cancer. Cancer biology & therapy 30 20814245
2018 Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of Shh. Development (Cambridge, England) 28 29361554
2017 Spop regulates Gli3 activity and Shh signaling in dorsoventral patterning of the mouse spinal cord. Developmental biology 28 28412462
2016 T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number. eLife 28 27046536
2014 Gli3 repressor controls cell fates and cell adhesion for proper establishment of neurogenic niche. Cell reports 28 25127137
2005 Genetic interaction of Gli3 and Alx4 during limb development. The International journal of developmental biology 28 15968591
2002 Postaxial polydactyly type A/B (PAP-A/B) is linked to chromosome 19p13.1-13.2 in a Chinese kindred. European journal of human genetics : EJHG 28 11973619
2017 PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. Developmental biology 27 28673820
2012 Gli3 controls corpus callosum formation by positioning midline guideposts during telencephalic patterning. Cerebral cortex (New York, N.Y. : 1991) 27 23042737
2021 GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen Receptor in Prostate Cancer. Molecular cancer research : MCR 24 34610962
2020 Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks. eLife 23 33006313
2018 Gli3 is a negative regulator of Tas1r3-expressing taste cells. PLoS genetics 23 29415007
2011 Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53. Experimental cell research 23 22227409
2020 GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. PLoS genetics 22 32497091
2019 Wnt5a is a transcriptional target of Gli3 and Trps1 at the onset of chondrocyte hypertrophy. Developmental biology 22 31550480
2016 Fins into limbs: Autopod acquisition and anterior elements reduction by modifying gene networks involving 5'Hox, Gli3, and Shh. Developmental biology 22 26992366
2021 The Shh/Gli3 gene regulatory network precedes the origin of paired fins and reveals the deep homology between distal fins and digits. Proceedings of the National Academy of Sciences of the United States of America 21 34750251
2015 Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Frontiers in neuroanatomy 21 25859185
2013 A de novo GLI3 mutation in a patient with acrocallosal syndrome. American journal of medical genetics. Part A 21 23633388
2010 Birth defects caused by mutations in human GLI3 and mouse Gli3 genes. Congenital anomalies 21 20201963
2007 A hypermorphic mouse Gli3 allele results in a polydactylous limb phenotype. Developmental dynamics : an official publication of the American Association of Anatomists 21 17266131
2004 Loss of Gli3 and Shh function disrupts olfactory axon trajectories. The Journal of comparative neurology 21 15065125
2019 Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice. Human molecular genetics 20 30445565
2006 Essential roles of Gli3 and sonic hedgehog in pattern formation and developmental anomalies caused by their dysfunction. Congenital anomalies 20 16922918
2017 The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh. The Journal of experimental medicine 19 28533268
1997 Gene structure and allelic expression assay of the human GLI3 gene. Human genetics 19 9402960
2020 Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia. International journal of molecular sciences 18 32708452
2014 A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex. BMC medical genetics 18 25267529
2011 Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain. Developmental biology 18 21925158
2008 Mutational analysis of SHH and GLI3 in anorectal malformations. Birth defects research. Part A, Clinical and molecular teratology 17 18655123
2019 aCLS cancers: Genomic and epigenetic changes transform the cell of origin of cancer into a tumorigenic pathogen of unicellular organization and lifestyle. Gene 16 31647999
2017 Direct Interactions Between Gli3, Wnt8b, and Fgfs Underlie Patterning of the Dorsal Telencephalon. Cerebral cortex (New York, N.Y. : 1991) 16 26656997
2016 Regulation of Expression of Uropathogenic Escherichia coli Nonfimbrial Adhesin TosA by PapB Homolog TosR in Conjunction with H-NS and Lrp. Infection and immunity 16 26755158
2015 GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth. EBioMedicine 16 26288817
2024 Positive regulation of Hedgehog signaling via phosphorylation of GLI2/GLI3 by DYRK2 kinase. Proceedings of the National Academy of Sciences of the United States of America 15 38968120
1999 Mutational analysis of the PapB transcriptional regulator in Escherichia coli. Regions important for DNA binding and oligomerization. The Journal of biological chemistry 15 10391913

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