Affinage

GLI2

Zinc finger protein GLI2 · UniProt P10070

Length
1586 aa
Mass
167.8 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLI2 is a zinc-finger transcription factor that serves as the principal transcriptional activator of the Hedgehog (Hh) signaling pathway, essential for ventral neural patterning, foregut organogenesis, skeletal development, and stem cell maintenance (PMID:12361967, PMID:9731531, PMID:18927476). Upon Smoothened activation, DYRK2 phosphorylates GLI2 at the ciliary base to dissociate it from the cytoplasmic sequestration complex with SUFU, enabling ciliary tip accumulation through a dedicated ciliary localization domain and subsequent nuclear translocation to activate target genes including GLI1, PTCH, Sox2, Runx2, cyclins D/E, and cFlip (PMID:38968120, PMID:24463817, PMID:23034632, PMID:18927476, PMID:18264131). GLI2 protein stability is controlled by opposing ubiquitin-dependent degradation via β-TrCP and SPOP E3 ligases and stabilization by OTUB2 deubiquitination and MEK1-RSK2 inhibition of GSK-3β-mediated phosphorylation, while PRMT7-mediated arginine methylation near the SUFU-binding site and cAMP/PKA-dependent phosphorylation within cilia provide additional layers of post-translational regulation (PMID:16651270, PMID:36252002, PMID:30241937, PMID:23208494, PMID:31000813, PMID:28673820). GLI2 mRNA levels are regulated transcriptionally by BMAL1 and post-transcriptionally by METTL3-mediated m6A methylation, and GLI2 functions as a co-activator of the androgen receptor through direct physical interaction (PMID:33813752, PMID:36288719, PMID:25132524).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Establishing that GLI2 is a non-redundant transcriptional mediator of Shh signaling in organogenesis resolved whether individual Gli family members have distinct developmental requirements.

    Evidence Gli2/Gli3 single and compound knockout mice with foregut phenotyping

    PMID:9731531

    Open questions at the time
    • Activator vs. repressor function of Gli2 not yet distinguished
    • Target gene specificity not defined
  2. 2001 High

    Demonstrating that Gli1 knocked into the Gli2 locus rescues Gli2-null defects established that Gli2 functions primarily as a transcriptional activator (not repressor) in Shh signaling, and that Gli2's essential role is to initiate pathway activation upstream of Gli1.

    Evidence Knock-in of Gli1 cDNA into endogenous Gli2 locus in mice with phenotypic rescue analysis

    PMID:11748151 PMID:12361967

    Open questions at the time
    • Mechanism by which Gli2 is activated at the protein level was unknown
    • Whether Gli2 has context-dependent repressor activity in non-neural tissues
  3. 2003 High

    Compound mutant analyses in neural tube and somite showed that Gli2 specifies ventral cell fates (floor plate, V3 interneurons) and activates distinct target gene sets from Gli3, clarifying the division of labor among Gli proteins along the rostral-caudal axis.

    Evidence Gli2/Gli3/Ptc1 single and compound null mice with neural and somite cell-fate marker analysis

    PMID:12812795 PMID:14602680 PMID:15604102

    Open questions at the time
    • Post-translational regulation of Gli2 activity not yet addressed
    • Ciliary trafficking of Gli2 not yet discovered
  4. 2006 High

    Identification of β-TrCP2 as a direct E3 ubiquitin ligase for Gli2 revealed the first mechanism controlling Gli2 protein turnover, showing that ubiquitin-dependent proteasomal degradation limits Gli2 transcriptional potency.

    Evidence Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of β-TrCP binding site on Gli2

    PMID:16651270

    Open questions at the time
    • Kinases priming Gli2 for β-TrCP recognition not fully mapped
    • Whether deubiquitinases counteract this degradation was unknown
  5. 2007 High

    Showing that Gli2 physically interacts with Runx2 and upregulates its expression in osteoblasts established Gli2 as a direct transcriptional and protein-interaction partner linking Ihh signaling to bone differentiation.

    Evidence Co-immunoprecipitation of Gli2-Runx2, epistasis in Runx2-null cells, ALP activity assays

    PMID:17442891

    Open questions at the time
    • Whether this interaction is direct or scaffolded was not resolved
    • Structural basis of Gli2-Runx2 interaction unknown
  6. 2009 High

    ChIP demonstration that Gli2 directly binds the Sox2 enhancer in neural progenitors established a transcriptional cascade (Gli2→Sox2→Hes5) maintaining neural stem cell identity, connecting Hh signaling to stemness.

    Evidence Chromatin immunoprecipitation, shRNA knockdown, dominant-negative Gli2, Gli2-null mouse analysis

    PMID:18927476

    Open questions at the time
    • Whether Gli2 regulation of Sox2 operates in non-neural stem cells
    • Epigenetic co-regulators at the Sox2 enhancer not identified
  7. 2010 High

    Demonstrating that arsenic blocks Hh-induced ciliary accumulation of Gli2 provided the first evidence that Gli2 translocation to the primary cilium is a regulated and pharmacologically targetable step in pathway activation.

    Evidence Ciliary localization assay, protein level measurement, medulloblastoma allograft model

    PMID:20624968

    Open questions at the time
    • The ciliary domain on Gli2 required for this translocation was not yet mapped
    • Mechanism of arsenic action on ciliary trafficking not fully defined
  8. 2012 High

    Two studies resolved opposing regulatory inputs on Gli2: Sufu sequesters Gli2 in the cytoplasm while Kif7 promotes Sufu-Gli2 dissociation, and MEK1-RSK2 stabilizes Gli2 by blocking GSK-3β-mediated phosphorylation and ubiquitination, establishing convergent kinase-scaffolding control of Gli2 activity.

    Evidence Conditional Sufu/Kif7 knockout mice with Gli2 localization; protein half-life, ubiquitination, and phosphosite mutagenesis experiments

    PMID:23034632 PMID:23208494

    Open questions at the time
    • Identity of the kinase that phosphorylates Gli2 to release it from Sufu was still unknown
    • Whether MEK1-RSK2 regulation of Gli2 operates in non-cancer contexts
  9. 2014 High

    Systematic domain deletions identified a central region of Gli2 (distinct from zinc fingers and activation domain) required for ciliary tip accumulation and transcriptional activation, establishing ciliary localization as a prerequisite for Gli2 function.

    Evidence Domain-deletion knock-in alleles in ESCs, live imaging, transcriptional reporter assays

    PMID:24463817

    Open questions at the time
    • Binding partners recognizing this ciliary localization domain not identified
    • Structural basis of ciliary targeting unknown
  10. 2014 High

    Multiple studies expanded the Gli2 target gene repertoire: Gli2 directly activates ARHGEF16, RPS3, and co-activates androgen receptor through a C-terminal domain–tau5/AF5 interaction, revealing context-dependent transcriptional partnerships beyond canonical Hh targets.

    Evidence ChIP, reporter assays, GST pull-down domain mapping for AR interaction, functional rescue experiments

    PMID:25132524 PMID:25449781 PMID:30305138

    Open questions at the time
    • Global ChIP-seq map of Gli2 binding across tissues not available from these studies
    • Whether AR co-activation is Hh ligand-dependent
  11. 2017 High

    Demonstrating that Hh signaling inhibits PKA-mediated phosphorylation of Gli2 within primary cilia, and that Talpid3 anchors PKA regulatory subunits at the centriole, established cilia as the compartment where Gli2 phosphorylation state is set.

    Evidence Biochemical phosphorylation assays, co-IP of Talpid3 with PKARIIβ, Talpid3 mutant analysis

    PMID:28673820

    Open questions at the time
    • The activating kinase counteracting PKA on Gli2 was not yet identified
    • Stoichiometry of PKA-Gli2 interaction in cilia unknown
  12. 2018 High

    OTUB2 was identified as the deubiquitinase stabilizing Gli2, directly removing ubiquitin chains, while METTL3-mediated m6A methylation of GLI2 mRNA was shown to regulate its stability and translation, revealing both protein- and RNA-level post-translational/transcriptional control.

    Evidence In vitro deubiquitination assay with catalytic mutant control; m6A-seq identifying GLI2 mRNA as methylated target with functional RNA stability assays

    PMID:30241937 PMID:36288719

    Open questions at the time
    • Whether OTUB2 is recruited by Hh signaling or constitutively acts on Gli2
    • m6A reader proteins mediating GLI2 mRNA fate not identified
  13. 2019 High

    PRMT7-mediated arginine methylation of Gli2 at R225/R227 near the SUFU binding site disrupts GLI2-SUFU interaction and promotes GLI2 nuclear accumulation, adding arginine methylation as a regulatory modification controlling Hh pathway activation.

    Evidence In vitro methylation assay, arginine mutagenesis, SUFU binding assay, nuclear localization in PRMT7-deficient MEFs

    PMID:31000813

    Open questions at the time
    • Whether PRMT7 is itself regulated by Hh signaling
    • Interplay between PRMT7 methylation and DYRK2 phosphorylation on SUFU release not examined
  14. 2020 High

    PGE1/EP4 receptor signaling was shown to inhibit Gli2 ciliary accumulation via cAMP-PKA-dependent phosphorylation and ubiquitination, and FHL2-GLI2 fusion genes were identified as drivers of SHH pathway activation in sclerosing stromal tumors, establishing pharmacological and oncogenic modalities of Gli2 regulation.

    Evidence High-content screening of GLI2 ciliary translocation, EP4 cilia localization, cAMP-PKA assays; whole-exome/RNA sequencing with in vitro functional validation of FHL2-GLI2 fusion

    PMID:31896750 PMID:32371475

    Open questions at the time
    • Whether EP4-PKA regulation of Gli2 is tissue-specific
    • In vivo oncogenic potential of FHL2-GLI2 fusion not tested in animal models
  15. 2024 High

    Identification of DYRK2 as the ciliary kinase that phosphorylates GLI2 on conserved serines at the ciliary base upon Smoothened activation, triggering SUFU dissociation and nuclear translocation, resolved the long-standing question of how positive Hh signaling converts Gli2 from a SUFU-sequestered to an active state.

    Evidence In vitro kinase assay, phosphosite mapping, Dyrk2 knockout mice, nuclear translocation assays

    PMID:38968120

    Open questions at the time
    • Whether DYRK2 and PRMT7 act sequentially or independently on SUFU dissociation
    • Structural basis of phosphorylated Gli2 release from SUFU not determined
    • Whether DYRK2 activity is itself regulated by other Hh pathway components

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational modifications (DYRK2 phosphorylation, PRMT7 methylation, PKA phosphorylation, GSK-3β phosphorylation, ubiquitination) are coordinated temporally and spatially within the cilium-to-nucleus transit of Gli2 remains unresolved.
  • No integrated temporal model of Gli2 modification cascade
  • Structural basis of Gli2 ciliary localization domain interactions unknown
  • Comprehensive tissue-resolved ChIP-seq of Gli2 not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 4 GO:0005929 cilium 4 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 5
Partners
ARDYRK2FOXC1OTUB2PRMT7RUNX2SPOPSUFU
Complex memberships
SUFU-GLI2 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Gli2, but not Gli1, is required for initial Shh signaling in the mouse nervous system and limbs; Gli2 also mediates inappropriate Shh pathway activation caused by loss of the negative regulator Patched (Ptc), as demonstrated in Gli2;Ptc double mutants. Genetic null alleles and double-mutant analysis in mice (Gli1 lacZ knock-in, Gli1;Ptc double mutants) Development High 12361967
2001 Gli2's activator function, but not its repressor function, is required for Shh signaling in vivo; Gli1 expressed from the Gli2 locus can fully rescue Gli2 null defects in the presence of wild-type Shh, demonstrating that Gli2 primarily acts as a transcriptional activator in Shh signaling. Knock-in of Gli1 into the endogenous Gli2 locus in mice, phenotypic rescue analysis Development High 11748151
1998 Gli2 and Gli3 have specific and overlapping functions as transcriptional mediators of Shh signaling during foregut development; Gli2 loss causes foregut defects and Gli2/Gli3 double mutants fail to form esophagus, trachea, and lung. Knockout mouse analysis (Gli2−/−, Gli3−/−, double mutants) with phenotypic characterization Nature Genetics High 9731531
2006 β-TrCP2 E3 ubiquitin ligase directly binds Gli2 and promotes its ubiquitination and proteasomal degradation; a single amino acid substitution in the β-TrCP binding site on Gli2 inhibits this interaction and stabilizes Gli2 protein, increasing its transcriptional potency. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, protein stability assay Journal of Biological Chemistry High 16651270
2010 Arsenic antagonizes the Hedgehog pathway by blocking Hh-induced ciliary accumulation of Gli2 (the primary Hh pathway activator) and, with prolonged treatment, reducing steady-state Gli2 protein levels. Ciliary localization assay, protein level measurement, medulloblastoma allograft model PNAS High 20624968
2007 Ihh signaling promotes osteoblast differentiation through Gli2, which upregulates Runx2 expression and transcriptional activity; Gli2 physically interacts with Runx2, and Gli2 overexpression cannot increase ALP activity in Runx2-deficient cells. Co-immunoprecipitation, overexpression of Gli2/dominant-negative Gli2, Runx2-deficient cell assays, ALP activity and osteocalcin expression Molecular Biology of the Cell High 17442891
2014 A central region of Gli2 (distinct from previously characterized domains including zinc fingers, activation domain, repressor domain, and Sufu binding motif) is required for ciliary localization of Gli2; Gli2 lacking this domain cannot accumulate at the ciliary tip and cannot activate Hh target genes. Systematic domain-deletion knock-in alleles in ESCs using the Floxin system, live imaging of ciliary localization, transcriptional reporter assays Journal of Cell Science High 24463817
2012 Sufu restrains Gli2 activity through cytoplasmic sequestration, while Kif7 promotes Hh pathway activity through dissociation of the Sufu–Gli2 complex; Kif7 also has a Sufu-independent repressive function. Both proteins regulate Gli2 localization in keratinocytes. Conditional knockout mice (Sufu, Kif7, double KO) in skin, genetic epistasis, immunofluorescence of Gli2 localization Development High 23034632
2012 MEK1-RSK2 signaling stabilizes Gli2 by inhibiting GSK-3β-mediated phosphorylation and ubiquitination of Gli2; constitutively active MEK1 prolongs Gli2 half-life, increases nuclear translocation, and reduces ubiquitination; RSK2 mimics these effects, and they are lost on Gli2 lacking GSK-3β phosphorylation sites. Protein half-life measurement, nuclear fractionation, ubiquitination assay, dominant-active and phosphosite-mutant Gli2 constructs Oncogene High 23208494
2017 Hedgehog signaling inhibits PKA-mediated phosphorylation of Gli2 and Gli3 within primary cilia; the cilia-related gene Talpid3 interacts with PKA regulatory subunit PKARIIβ at centrioles and is required for proper Gli2/Gli3 phosphorylation and processing. Biochemical phosphorylation assays, co-immunoprecipitation of Talpid3 with PKARIIβ, centriolar localization by immunofluorescence, Talpid3 mutant analysis Developmental Biology High 28673820
2024 The ciliary kinase DYRK2 phosphorylates GLI2 and GLI3 on evolutionarily conserved serine residues at the ciliary base in response to Smoothened activation; this phosphorylation induces dissociation of GLI2/GLI3 from SUFU and their nuclear translocation to activate Hh target genes. Transcriptome and interactome analyses, in vitro phosphorylation assay, phosphosite mapping, Dyrk2 knockout mice, nuclear translocation assays PNAS High 38968120
2019 PRMT7 interacts with and methylates GLI2 on arginine residues 225 and 227 near the SUFU binding region; this methylation interferes with GLI2-SUFU binding, promoting GLI2 nuclear accumulation and Shh signaling, and preventing cellular senescence. Co-immunoprecipitation, in vitro methylation assay, arginine-specific mutagenesis, SUFU binding assay, Gli2 nuclear localization measurement in PRMT7-deficient MEFs Cell Death and Differentiation High 31000813
2016 NEK2A phosphorylates and stabilizes SuFu, and phosphorylated SuFu inhibits nuclear localization and transcriptional activity of Gli2; NEK2A was identified as a SuFu-interacting protein, confirmed by GST pull-down and co-immunoprecipitation. Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, kinase assay, Gli2 nuclear localization assay, transcriptional reporter assay Cellular Signalling High 27297360
2003 Gli2 and Gli3 are required for Shh-dependent sclerotome induction; Gli2 possesses both activator and repressor functions in the developing somite, and each Gli protein preferentially activates a distinct set of Shh target genes. Gli2/Gli3 mutant analysis, in vitro somite explant assays, adenoviral overexpression of individual Gli proteins in presomitic mesoderm Development High 14602680
2003 Gli2 is essential for ventral neural cell fate specification (floor plate and V3 interneurons) in the mouse neural tube, particularly in the caudal neural tube; Gli2 and Gli3 have overlapping but distinct contributions along the rostral-caudal axis of Shh signaling. Compound mutant analysis (Gli2, Gli3, Ptc1 single/double/triple null mice) with neural cell fate marker analysis Developmental Biology High 12812795
2004 Gli2 and Gli3 are required for Gli1 expression in the somite, establishing them as primary and Gli1 as a secondary mediator of Shh signaling; Gli3 (but not Gli2) represses Myf5 transcription in a dose-dependent manner in the absence of Shh. Compound mutant mouse analysis (Gli2−/−, Gli3−/−, Shh−/−) with Myf5 ES enhancer reporter transgenic line, in situ hybridization Development High 15604102
2009 Gli2 binds to an enhancer required for Sox2 expression in telencephalic neuroepithelial cells; Gli2 activity maintains neural stem cell markers (Sox2, Hes1, Hes5, Notch1, CD133, Bmi1) and prevents premature neuronal differentiation through a Gli2→Sox2→Hes5 transcriptional cascade. Chromatin immunoprecipitation (ChIP) of Gli2 at Sox2 enhancer, shRNA knockdown, dominant-negative Gli2 overexpression in vivo and in vitro, Gli2-null mouse analysis Stem Cells High 18927476
2015 Gli2 drives myofibroblast cell-cycle progression; myofibroblast-specific deletion of Gli2 (but not Gli1) limits kidney fibrosis by inducing cell-cycle arrest. Darinaparsin (an arsenical) reduces fibrosis through reduction of GLI2 protein levels, and its anti-fibrotic effect is abolished in Gli2-conditional KO mice, confirming GLI2 as its direct target. Conditional Gli2/Gli1 knockout in GLI1+ progenitors, darinaparsin drug treatment, GLI2 overexpression rescue, cell-cycle analysis, fibrosis quantification Journal of Clinical Investigation High 26193634
2008 FKBP8 antagonizes Shh signaling cell-autonomously at a step independent of Smoothened but dependent on the Gli2 transcription factor; this activation also requires the kinesin-2 subunit Kif3a, a component of intraflagellar transport machinery for cilia. Genetic analysis of Fkbp8 mutants combined with Gli2 and Kif3a epistasis, neural patterning marker analysis Developmental Biology Medium 18590716
2015 Foxc1 is a transcriptional partner of Gli2 in Ihh signaling; Foxc1 physically interacts with Gli2 and stimulates expression of Ihh target genes (PTHrP, Col10a1); a pathological Foxc1 missense mutation (Axenfeld-Rieger syndrome) impairs Gli2-Foxc1 association. In vivo microarray, co-immunoprecipitation of Gli2 and Foxc1, dominant-negative Foxc1 experiments, Foxc1ch/ch mouse analysis, reporter assays Nature Communications High 25808752
2002 GLI2 activates transcription of GLI1 in human keratinocytes, forming a positive feedback loop; both GLI2alpha and GLI2beta isoforms increase DNA synthesis and are upregulated in basal cell carcinoma. GLI1 overexpression in human keratinocytes, time-course transcriptional analysis, BCC patient tissue analysis Oncogene Medium 12165851
2006 GLI2 (constitutively active GLI2DeltaN) regulates both overlapping and distinct transcriptional target genes compared with GLI1, and preferentially mediates repression of target genes (potentially via activation of negative regulators) in human keratinocytes; no processed GLI2 repressor was detected. Inducible HaCaT keratinocyte expression system, global expression profiling (microarray), comparison of GLI1 vs GLI2DeltaN transcriptomes Genomics Medium 16434164
2004 FOXE1 is a direct transcriptional target of GLI2 in human epidermis; a 2.5 kb FOXE1 upstream fragment containing five GLI-binding sites activates transcription in reporter assays with kinetics similar to the direct GLI target PTCH. Reporter assay with GLI-binding sites in FOXE1 promoter, expression analysis in BCC and normal skin, in situ hybridization Journal of Investigative Dermatology Medium 15140221
2008 Gli2 directly binds to the cFlip promoter and activates its transcription, thereby conferring resistance to death-ligand-mediated (TRAIL) apoptosis in basal cell carcinoma; Gli2 silencing reduces cFlip expression and restores TRAIL sensitivity. Gli2 promoter binding site identification and confirmation in cFlip promoter, RNA interference, TRAIL apoptosis assay in BCC cells and tissue Oncogene Medium 18264131
2014 GLI2 directly binds to the ARHGEF16 promoter and activates its transcription in glioblastoma cells; ARHGEF16 in turn interacts with CKAP5, and this GLI2/ARHGEF16/CKAP5 axis promotes glioma cell migration and proliferation. Chromatin immunoprecipitation, dual-luciferase reporter assay, yeast two-hybrid, co-immunoprecipitation, GST pull-down, xenograft model Journal of Experimental & Clinical Cancer Research High 30305138
2014 Gli2 transcriptionally activates RPS3 (ribosomal protein S3), and GLI2-mediated upregulation of RPS3 is required for osteosarcoma cell migration and invasion; knockdown of RPS3 reduces the pro-migratory effect of constitutively active GLI2. Microarray analysis, GLI2 knockdown/overexpression, RPS3 knockdown rescue experiments, migration and invasion assays Cancer Letters Medium 25449781
2014 Gli2 co-activates androgen receptor (AR) through a direct protein-protein interaction; the Gli2 C-terminal domain (aa628-897) binds the tau5/AF5 ligand-independent activation domain of AR (mediated by the WxxLF motif), and this interaction is sufficient for AR co-activation including truncated AR splice variants. Co-immunoprecipitation, GST pull-down, androgen-responsive promoter reporter assays, chromatin immunoprecipitation (ChIP) in LNCaP cells The Prostate High 25132524
2018 METTL3 methylates PTCH1 and GLI2 RNAs (m6A modification), regulating their RNA stability and translation in SHH-medulloblastoma; inhibition of METTL3 suppresses tumor progression by reducing GLI2 RNA methylation and downstream Sonic hedgehog signaling. m6A-seq, METTL3 depletion, METTL3 inhibitor (STM2457) treatment, RNA stability and translation assays Cell Reports High 36288719
2018 OTUB2 (deubiquitinating enzyme) stabilizes Gli2 protein by removing ubiquitin modifications; OTUB2 co-immunoprecipitates with Gli2, its knockdown decreases Gli2 protein levels (rescued by proteasome inhibitor), and in vitro deubiquitination assay shows OTUB2 directly removes ubiquitin from Gli2. Co-immunoprecipitation, in vitro deubiquitination assay, OTUB2 overexpression/knockdown, protein half-life measurement Biochemical and Biophysical Research Communications High 30241937
2020 FHL2-GLI2 fusion genes (identified in 65% of sclerosing stromal tumors) result in transcriptomic activation of the Sonic Hedgehog pathway; expression of the FHL2-GLI2 fusion in vitro leads to increased proliferation, migration, colony formation, and SHH pathway activation, which are reversed by targeted SHH pathway inhibition. Whole-exome, targeted capture, RNA sequencing; in vitro FHL2-GLI2 fusion expression; SHH pathway inhibition functional assays Nature Communications High 31896750
2022 Sufu (negative regulator) controls Gli2 mRNA expression, and Spop promotes Gli2 protein degradation; removal of Sufu leads to elevated Gli2 activity inhibiting cochlear hair cell differentiation by maintaining Sox2 expression in progenitors; deletion of both Sufu and Spop exacerbates Gli2 activation and HC differentiation defects. Conditional knockout mice (Sufu, Spop, double KO), Gli2 mRNA/protein measurement, Sox2 expression analysis, hair cell differentiation markers PNAS High 36252002
2009 Gli2 overexpression in lung mesenchyme increases expression of cyclin D1, D2, and E1, correlating with increased cell proliferation; Gli3 does not affect cyclin expression, establishing Gli2 as the primary Gli transcription factor mediating Shh-regulated fetal lung growth through cyclin regulation. Gli2 overexpression transgenic mice, Gli3-null and Gli3-repressor mice, real-time PCR, immunoblotting, phospho-histone H3 immunohistochemistry American Journal of Respiratory Cell and Molecular Biology Medium 19574535
2018 HER2 overexpression stabilizes GLI2 by inhibiting GSK3β-mediated proteasomal degradation; this stabilization promotes anoikis resistance and metastasis of breast cancer cells, and silencing GLI2 reduces migration and invasion of HER2-overexpressing cells. GLI2 protein stability assay, HER2/GSK3β/GLI2 pathway knockdown experiments, anoikis resistance assay, migration/invasion assay, in vivo metastasis model Cancer Letters Medium 30409762
2021 BMAL1 (core circadian clock component) directly binds the Gli2 promoter and activates Gli2 transcription (but not Gli1); TGF-β increases Bmal1 in tubular cells, and Bmal1 knockdown abolishes while overexpression increases Gli2 and fibrosis markers. ChIP assay, luciferase reporter assay, conditional Bmal1 knockout mice, siRNA knockdown and overexpression in proximal tubular cells FASEB Journal Medium 33813752
2020 PGE1 inhibits Hh signaling by blocking GLI2 accumulation in the primary cilium through EP4 receptor-mediated enhancement of cAMP-PKA activity, which promotes GLI2 phosphorylation and ubiquitination-dependent degradation. High-content screening of GLI2 ciliary translocation, EP4 receptor localization to cilia, cAMP-PKA activity assay, GLI2 phosphorylation and ubiquitination measurement, xenograft model Cancer Research High 32371475
2016 Notch signaling converges on Gli2 to prime postnatal retinal progenitor cells and Müller glia to proliferate in response to Hh; disrupting Notch signaling rapidly downregulates all three Gli proteins and inhibits Hh-induced proliferation, while ectopic Notch activation increases Gli2 protein. Fluorescent pathway reporter transgenes, genetic Notch disruption, pharmacological Notch inhibition, Gli2 protein measurement Developmental Biology Medium 26795056
2020 Gli2 transcriptionally activates circ-STAT3 (circ_0043800), which in turn sequesters miR-29a/b/c-3p to upregulate both Gli2 and STAT3, forming a feedforward regulatory loop in hepatoblastoma. ChIP assay demonstrating Gli2 binding at circ-STAT3 promoter, RNA pull-down, RIP assay, luciferase reporter, rescue experiments Journal of Experimental & Clinical Cancer Research Medium 32493490
2022 SPOP (E3 ubiquitin ligase adaptor) accelerates Gli2 degradation and reduces cytoplasmic Gli2; co-immunoprecipitation confirms SPOP-Gli2 interaction; increased SPOP reduces Gli2-dependent Hh signaling in gastric cancer cells. Co-immunoprecipitation, immunofluorescence of Gli2 localization, Gli2 degradation assay, luciferase reporter, SPOP overexpression/depletion Journal of Experimental & Clinical Cancer Research Medium 25204354
2023 circ-FIRRE interacts with HNRNPC to stabilize GLI2 mRNA by directly binding to its 3'-UTR in the cytoplasm, thereby elevating GLI2 protein expression and subsequent transcription of MYC, CCNE1, and CCNE2 in esophageal squamous cell carcinoma. RNA pull-down, RIP-qPCR, RNA sequencing, HNRNPC overexpression rescue in circ-FIRRE KD cells, in vitro and in vivo functional assays Cancer Science Medium 37417427

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development (Cambridge, England) 603 12361967
2007 Optimized THP-1 differentiation is required for the detection of responses to weak stimuli. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 461 17334670
1998 Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nature genetics 439 9731531
1998 The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development (Cambridge, England) 294 9655803
2010 Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proceedings of the National Academy of Sciences of the United States of America 262 20624968
2001 Gli1 can rescue the in vivo function of Gli2. Development (Cambridge, England) 249 11748151
2018 Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America 240 29891662
2002 Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene 174 12165851
2011 TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer research 162 21862631
2007 Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Molecular biology of the cell 144 17442891
2010 GLI2-mediated melanoma invasion and metastasis. Journal of the National Cancer Institute 137 20660365
2015 Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. The Journal of clinical investigation 136 26193634
2004 Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation. Development (Cambridge, England) 128 15604102
2013 The THO complex component Thp2 counteracts telomeric R-loops and telomere shortening. The EMBO journal 123 24084588
2003 Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development (Cambridge, England) 123 14602680
2006 Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. The Journal of biological chemistry 121 16651270
2003 Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Developmental biology 91 12812795
2010 Antiinflammatory effects in THP-1 cells treated with verbascoside. Phytotherapy research : PTR 90 20812283
2006 Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics 88 16434164
2009 Gli2 is a novel regulator of sox2 expression in telencephalic neuroepithelial cells. Stem cells (Dayton, Ohio) 87 18927476
2016 Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene 86 27748762
2004 FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. The Journal of investigative dermatology 78 15140221
2015 GLI2 inhibition abrogates human leukemia stem cell dormancy. Journal of translational medicine 76 25889765
2007 Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells. Cancer research 72 18006803
2002 The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells. Journal of leukocyte biology 65 12429726
2022 METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma. Cell reports 64 36288719
2015 The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification. Nature communications 64 25808752
2014 SPOP suppresses tumorigenesis by regulating Hedgehog/Gli2 signaling pathway in gastric cancer. Journal of experimental & clinical cancer research : CR 63 25204354
2012 Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis. Development (Cambridge, England) 62 23034632
2016 Long noncoding RNA BCAR4 promotes osteosarcoma progression through activating GLI2-dependent gene transcription. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 59 27460090
2011 Role of GLI2 in the growth of human osteosarcoma. The Journal of pathology 59 21506130
2023 Optimization of differentiation and transcriptomic profile of THP-1 cells into macrophage by PMA. PloS one 58 37459313
2008 FKBP8 cell-autonomously controls neural tube patterning through a Gli2- and Kif3a-dependent mechanism. Developmental biology 58 18590716
2001 A new hyperrecombination mutation identifies a novel yeast gene, THP1, connecting transcription elongation with mitotic recombination. Genetics 57 11139493
2015 Differentiation of THP1 Cells into Macrophages for Transwell Co-culture Assay with Melanoma Cells. Bio-protocol 56 27034969
2015 Role of GLI2 in hypopituitarism phenotype. Journal of molecular endocrinology 55 25878059
2004 Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. Journal of lipid research 55 15314095
2011 Redundant and differential roles of transcription factors Gli1 and Gli2 in the development of mouse fetal Leydig cells. Biology of reproduction 52 21209421
2020 Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature communications 51 31896750
2015 Hedgehog signaling through GLI1 and GLI2 is required for epithelial-mesenchymal transition in human trophoblasts. Biochimica et biophysica acta 48 25888497
2019 Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation. The Journal of clinical investigation 47 31264977
2018 GLI2 promotes cell proliferation and migration through transcriptional activation of ARHGEF16 in human glioma cells. Journal of experimental & clinical cancer research : CR 47 30305138
2014 A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity. Journal of cell science 47 24463817
2008 Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene 45 18264131
2014 Highly efficient transfection of human THP-1 macrophages by nucleofection. Journal of visualized experiments : JoVE 43 25226503
2015 Hydrogen sulphide induces HIF-1α and Nrf2 in THP-1 macrophages. Biochimie 42 25795259
2014 Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion. Cancer letters 42 25449781
2014 miR-202 suppresses proliferation and induces apoptosis of osteosarcoma cells by downregulating Gli2. Molecular and cellular biochemistry 41 25156120
2020 Transcription activation of circ-STAT3 induced by Gli2 promotes the progression of hepatoblastoma via acting as a sponge for miR-29a/b/c-3p to upregulate STAT3/Gli2. Journal of experimental & clinical cancer research : CR 40 32493490
2017 The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. Journal of genetics and genomics = Yi chuan xue bao 40 28847472
2015 Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis. Tuberculosis (Edinburgh, Scotland) 36 26099547
2008 Sonic Hedgehog mediator Gli2 regulates bladder mesenchymal patterning. The Journal of urology 36 18710724
2018 HER2-mediated GLI2 stabilization promotes anoikis resistance and metastasis of breast cancer cells. Cancer letters 35 30409762
2012 Hesperetin upregulates ABCA1 expression and promotes cholesterol efflux from THP-1 macrophages. Journal of natural products 34 22429094
2021 MiR-144-3p inhibits gastric cancer progression and stemness via directly targeting GLI2 involved in hedgehog pathway. Journal of translational medicine 33 34657624
2020 Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts. Arthritis research & therapy 33 33303026
2019 Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production. Cell death & disease 33 31427566
2014 Modulation of IL-37 expression by triptolide and triptonide in THP-1 cells. Cellular & molecular immunology 33 25308753
2015 Sonic hedgehog through Gli2 and Gli3 is required for the proper development of placental labyrinth. Cell death & disease 32 25695606
2021 Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells. Frontiers in pharmacology 31 34621174
2018 lncRNA BCAR4 Increases Viability, Invasion, and Migration of Non-Small Cell Lung Cancer Cells by Targeting Glioma-Associated Oncogene 2 (GLI2). Oncology research 31 29615150
2016 A Notch-Gli2 axis sustains Hedgehog responsiveness of neural progenitors and Müller glia. Developmental biology 31 26795056
2012 MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination. Oncogene 30 23208494
2009 Gli2 influences proliferation in the developing lung through regulation of cyclin expression. American journal of respiratory cell and molecular biology 30 19574535
2017 miR-141-3p suppresses proliferation and promotes apoptosis by targeting GLI2 in osteosarcoma cells. Oncology reports 29 29251328
2023 Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA. Cancer science 28 37417427
2023 Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth. Pharmacological research 27 37473878
2017 PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. Developmental biology 27 28673820
1997 Cloning and sequencing of the mouse Gli2 gene: localization to the Dominant hemimelia critical region. Genomics 27 9027508
2015 Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages. Toxicology in vitro : an international journal published in association with BIBRA 26 26119525
2021 Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 33813752
2019 PRMT7 methylates and suppresses GLI2 binding to SUFU thereby promoting its activation. Cell death and differentiation 25 31000813
2019 Organophosphorus Pesticides Induce Cytokine Release from Differentiated Human THP1 Cells. American journal of respiratory cell and molecular biology 24 30978295
2016 Designer Nuclease-Mediated Generation of Knockout THP1 Cells. Methods in molecular biology (Clifton, N.J.) 24 26443227
2018 BCAR4 activates GLI2 signaling in prostate cancer to contribute to castration resistance. Aging 23 30513511
2014 Lycopene modulates THP1 and Caco2 cells inflammatory state through transcriptional and nontranscriptional processes. Mediators of inflammation 22 24891766
2011 shRNA-mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL-induced apoptosis. Journal of cellular biochemistry 22 21695716
2021 Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model. Cancer gene therapy 21 33414520
2021 Gli2-regulated activation of hepatic stellate cells and liver fibrosis by TGF-β signaling. American journal of physiology. Gastrointestinal and liver physiology 21 33728992
2019 Unique and overlapping GLI1 and GLI2 transcriptional targets in neoplastic chondrocytes. PloS one 21 30695055
2015 Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Frontiers in neuroanatomy 21 25859185
2022 Icariin Treatment Rescues Diabetes Induced Bone Loss via Scavenging ROS and Activating Primary Cilia/Gli2/Osteocalcin Signaling Pathway. Cells 20 36552853
2019 FOXE1 supports the tumor promotion of Gli2 on papillary thyroid carcinoma by the Wnt/β-catenin pathway. Journal of cellular physiology 20 30793770
2022 The transcript ENST00000444125 of lncRNA LINC01503 promotes cancer stem cell properties of glioblastoma cells via reducing FBXW1 mediated GLI2 degradation. Experimental cell research 19 34990616
2022 Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling. Oncogene 19 35418691
2009 Transcription at the proximity of the nuclear pore: a role for the THP1-SAC3-SUS1-CDC31 (THSC) complex. RNA biology 19 19229139
2017 Chromium contributes to human bronchial epithelial cell carcinogenesis by activating Gli2 and inhibiting autophagy. Toxicology research 18 30090501
2014 Determinants of Gli2 co-activation of wildtype and naturally truncated androgen receptors. The Prostate 18 25132524
2022 Selective cleavage of ncRNA and antiviral activity by RNase2/EDN in THP1-induced macrophages. Cellular and molecular life sciences : CMLS 17 35347428
2020 Relative Levels of Gli1 and Gli2 Determine the Response of Ventral Neural Stem Cells to Demyelination. Stem cell reports 17 33125874
2020 Prostaglandin E1 Inhibits GLI2 Amplification-Associated Activation of the Hedgehog Pathway and Drug Refractory Tumor Growth. Cancer research 16 32371475
2018 Regulation of Gli2 stability by deubiquitinase OTUB2. Biochemical and biophysical research communications 16 30241937
2016 Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism. Cellular signalling 16 27297360
2013 RACK1 promotes the proliferation of THP1 acute myeloid leukemia cells. Molecular and cellular biochemistry 16 24000012
2014 Divergent signalling pathways regulate lipopolysaccharide-induced eRNA expression in human monocytic THP1 cells. FEBS letters 15 25554418
2008 Gene silencing of transcription factor Gli2 inhibits basal cell carcinomalike tumor growth in vivo. International journal of cancer 15 17721996
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 14 38968120
2022 Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes. Open life sciences 14 35415237
2022 Sufu- and Spop-mediated regulation of Gli2 is essential for the control of mammalian cochlear hair cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 14 36252002
2017 α-Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP-1 Monocytes. Journal of cellular biochemistry 14 28059487