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Showing GLI2 — THP2 is a alias.

GLI2

Zinc finger protein GLI2 · UniProt P10070

Length
1586 aa
Mass
167.8 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLI2 is the principal transcriptional effector of Sonic/Indian Hedgehog signaling, controlling skeletal patterning, foregut and lung formation, neural and somite development, and—when dysregulated—tumorigenesis and fibrosis (PMID:9006072, PMID:9731531, PMID:15604102). It is a bipartite transcription factor whose N-terminal repression domain restrains a C-terminal activation domain; removal of the repression domain converts GLI2 into a constitutive activator that can ectopically induce Hedgehog target genes in vivo, while truncation of the activation domain yields a repressor (PMID:10433919). In the absence of ligand, GLI2 activity is held in check by SUFU-mediated cytoplasmic sequestration and by PKA phosphorylation at the ciliary base, with GLI2 protein levels limited by E3 ligase–driven proteasomal degradation (PMID:23034632, PMID:28673820, PMID:16651270). Pathway activation reverses these constraints: the ciliary kinase DYRK2 phosphorylates GLI2 on conserved serines to dissociate it from SUFU and drive nuclear translocation, and PRMT7-mediated arginine methylation near the SUFU-binding region similarly promotes nuclear accumulation (PMID:38968120, PMID:31000813). GLI2 abundance is set by competing ubiquitin machinery—β-TrCP2 and WWP2 promote its degradation while the deubiquitinase OTUB2 stabilizes it—and by upstream kinase inputs through mTORC2/GSK3β (PMID:16651270, PMID:34546340, PMID:30241937, PMID:28703798). Once nuclear, GLI2 binds promoters and enhancers to activate or repress targets including Sox2, Runx2, ARHGEF16, MDR1, cFlip, and CDH1, and it partners combinatorially with Runx2, Foxc1, MEF2C, the androgen receptor, and phospho-SMAD3 to direct context-specific transcriptional programs (PMID:18927476, PMID:17442891, PMID:25808752, PMID:22199256, PMID:25132524, PMID:38453045). Dose-dependent GLI2 dysfunction causes holoprosencephaly in mice, and constitutive GLI2 activation via recurrent FHL2-GLI2 fusions drives sclerosing stromal tumors of the ovary (PMID:27585885, PMID:31896750).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Established GLI2 as a required, partly non-redundant effector of Hedgehog signaling in vertebrate skeletal patterning, defining its developmental role through loss-of-function genetics.

    Evidence Mouse knockout and Gli2/Gli3 double-mutant epistasis with defined skeletal phenotypes

    PMID:9006072

    Open questions at the time
    • Did not define the molecular activity (activator vs repressor) of GLI2
    • Did not separate cell-autonomous from tissue-level effects
  2. 1998 High

    Extended GLI2's essential role to foregut, trachea and lung organogenesis, showing overlapping and gene-specific functions with GLI3 downstream of Shh.

    Evidence Mouse single- and compound-mutant genetic analysis with organ-formation phenotypes

    PMID:9731531

    Open questions at the time
    • No direct transcriptional targets identified
    • Mechanism of GLI2/GLI3 functional partitioning unresolved
  3. 1999 High

    Resolved GLI2's molecular architecture, showing it is a bipartite factor whose N-terminal repression domain gates a C-terminal activation domain, explaining how a single protein can act as activator or repressor.

    Evidence Domain truncation analysis in cells and transgenic embryos with reporter and in vivo target readouts

    PMID:10433919

    Open questions at the time
    • How the repression domain is relieved physiologically not defined
    • Did not address post-translational control of the switch
  4. 2004 High

    Defined a GLI hierarchy (Gli2/Gli3 → Gli1) and target-gene preference in somite myogenesis, refining how distinct GLI factors apportion Shh outputs.

    Evidence Mouse knockouts, transgenic enhancer reporter, and explant gain-of-function assays

    PMID:14602680 PMID:15604102

    Open questions at the time
    • Direct GLI2 binding sites on somite targets not mapped
    • Basis of GLI2 vs GLI3 target selectivity unknown
  5. 2006 High

    Identified the first ubiquitin-mediated control of GLI2 abundance, showing β-TrCP2 directly binds and targets GLI2 for proteasomal degradation to limit pathway output.

    Evidence Co-IP, in vitro ubiquitination, and binding-site mutagenesis with reporter assays

    PMID:16651270

    Open questions at the time
    • Upstream signals controlling β-TrCP2 recruitment not defined
    • Relationship to GLI2 processing into a repressor unclear
  6. 2007 High

    Connected Ihh-GLI2 signaling to osteoblast differentiation by establishing a physical and functional GLI2-Runx2 complex, showing GLI2 acts partly through a transcriptional partner.

    Evidence Reciprocal Co-IP, dominant-negative constructs, and Runx2-deficient rescue with differentiation assays

    PMID:17442891

    Open questions at the time
    • Direct GLI2 target genes in osteoblasts not mapped
    • Structural basis of GLI2-Runx2 interaction unknown
  7. 2008 High

    Identified direct GLI2 transcriptional targets in neural and tumor contexts (Sox2 enhancer; cFlip promoter) and placed GLI2 downstream of primary cilia, linking it to stemness, survival, and Hedgehog signal transduction architecture.

    Evidence ChIP/promoter mapping, shRNA and KO mice, epistasis rescue, and Fkbp8/Kif3a genetic epistasis

    PMID:18264131 PMID:18590716 PMID:18927476

    Open questions at the time
    • How ciliary localization is mechanistically coupled to GLI2 activation not yet resolved
    • cFlip regulation shown in BCC only (Medium confidence)
  8. 2011 High

    Demonstrated combinatorial GLI2 transcription through a reciprocal GLI2-MEF2C feed-forward complex that synergistically activates shared promoters, expanding GLI2's partner repertoire into cardiomyogenesis.

    Evidence Reciprocal Co-IP, ChIP on both genes, dominant-negative and reporter assays in P19 cells

    PMID:22199256

    Open questions at the time
    • In vivo requirement for the GLI2-MEF2C complex not established
    • Interaction interface not mapped
  9. 2014 High

    Showed GLI2 functions as a co-activator beyond canonical GLI sites by binding and transactivating the androgen receptor, including ligand-independent AR splice variants, linking Hedgehog effector function to AR-driven transcription.

    Evidence Co-IP, GST-pulldown, domain mutagenesis, ChIP at androgen response elements in LNCaP cells

    PMID:25132524

    Open questions at the time
    • Physiological relevance in prostate tissue not tested
    • Whether AR co-activation requires GLI2 DNA binding unclear
  10. 2015 High

    Established GLI2 as a selective driver of myofibroblast proliferation and fibrosis and identified a new transcriptional partner Foxc1, expanding GLI2 functions into kidney fibrosis and endochondral ossification with disease-relevant readouts.

    Evidence Conditional Gli2 (not Gli1) KO, pharmacologic epistasis, Foxc1 Co-IP and disease-allele mutagenesis, EMT/CDH1 ChIP

    PMID:25808752 PMID:25888497 PMID:26193634

    Open questions at the time
    • GLI2 transcriptional targets driving cell-cycle progression not fully defined
    • CDH1 repression mechanism (cofactors) unresolved
  11. 2017 Medium

    Resolved key post-translational control nodes: PKA phosphorylates GLI2 in cilia (regulated via Talpid3-PKARIIβ), and mTORC2/GSK3β controls GLI2 ubiquitination and stability, integrating ciliary and metabolic kinase inputs into GLI2 regulation.

    Evidence Ciliary phosphorylation assays, Co-IP, Talpid3 mutants; mTORC2 inhibition, ubiquitination and fractionation assays

    PMID:28673820 PMID:28703798

    Open questions at the time
    • Phosphatase that dephosphorylates ciliary GLI2 not identified
    • mTORC2→GSK3β→GLI2 axis from single lab with limited orthogonal validation
  12. 2018 High

    Identified OTUB2 as a deubiquitinase that stabilizes GLI2, establishing a counterbalance to ubiquitin-mediated degradation and tuning Hedgehog-dependent osteogenesis.

    Evidence Co-IP, in vitro/in vivo deubiquitination with catalytic-dead mutants, half-life and osteogenesis assays

    PMID:30241937

    Open questions at the time
    • How OTUB2 activity toward GLI2 is regulated unknown
    • Competition with E3 ligases not directly tested
  13. 2019 High

    Defined activating modifications and direct genomic targets: PRMT7 methylation near the SUFU-binding region promotes GLI2 nuclear accumulation, and ChIP-seq mapped direct GLI2 enhancer targets (including Wnt ligands) and a new target ARHGEF16 driving glioma migration.

    Evidence In vitro methylation and site mutagenesis, SUFU-binding interference; ChIP-seq and ChIP, interaction assays, xenografts

    PMID:30305138 PMID:31000813 PMID:31167144

    Open questions at the time
    • Whether PRMT7 methylation is dynamically regulated by Hh signal unknown
    • ARHGEF16 axis (Medium) validated in single lab
  14. 2019 Medium

    Linked GLI2 to primary cilia length and cell-cycle re-entry via autophagy-mediated Ofd1 control, suggesting GLI2 feeds back on the ciliary machinery that governs its own pathway.

    Evidence CRISPR Gli2 KO in NIH3T3, Kif3a-knockdown epistasis, cilia measurement, cell-cycle and autophagy analysis

    PMID:30463852

    Open questions at the time
    • Whether cilia-length control depends on GLI2 transcriptional activity unclear
    • Single lab, fibroblast-restricted
  15. 2020 Medium

    Showed GLI2 activation can be pharmacologically blocked at the ciliary translocation step (PGE1/EP4/cAMP-PKA), and that constitutive GLI2 activation via FHL2-GLI2 fusion drives ovarian sclerosing stromal tumors, establishing GLI2 as a therapeutic target.

    Evidence High-content ciliary-translocation screen, cAMP-PKA and ubiquitination assays, xenograft; fusion detection by sequencing with in vitro gain-of-function rescue

    PMID:31896750 PMID:32371475

    Open questions at the time
    • Durability/specificity of PGE1-EP4 targeting in vivo unresolved
    • FHL2-GLI2 mechanism characterized in vitro only
  16. 2021 Medium

    Identified WWP2 as an additional GLI2 E3 ligase, regulated by Wnt/β-catenin via DKK1, linking Wnt input to GLI2 stability and chemoresistance.

    Evidence Ubiquitination and Co-IP, WWP2 over/knockdown, DKK1-Wnt epistasis, in vitro/in vivo studies

    PMID:34546340

    Open questions at the time
    • Relative contribution of WWP2 vs β-TrCP2 to GLI2 turnover unclear
    • Degron recognized by WWP2 not mapped
  17. 2022 High

    Resolved layered negative regulation of GLI2 (SUFU and SPOP acting at the mRNA and protein levels) controlling differentiation timing, and identified direct GLI2 target MDR1 driving chemoresistance.

    Evidence Sufu/Spop conditional and compound KO mice with HC differentiation/Sox2 readouts; MDR1 promoter reporter, shRNA and xenograft

    PMID:35059317 PMID:36252002

    Open questions at the time
    • Mechanism by which SUFU loss elevates Gli2 mRNA unknown
    • MDR1 axis lacks ChIP confirmation (Medium)
  18. 2024 High

    Defined the activating ciliary kinase DYRK2 that drives SUFU dissociation and GLI2 nuclear translocation, and established non-canonical GLI2 activation by phospho-SMAD3 (TGF-β) including new transactivating isoforms in cancer.

    Evidence Kinase/phosphorylation assays with site mutagenesis, SUFU-binding and translocation assays, Dyrk2 KO mice; SMAD3-GLI2 Co-IP, isoform cloning, HCC models

    PMID:38453045 PMID:38968120

    Open questions at the time
    • How DYRK2 activity is gated by upstream Hh signal not fully defined
    • SMAD3-GLI2 crosstalk (Medium) characterized in single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing post-translational inputs (PKA/DYRK2 phosphorylation, PRMT7 methylation, β-TrCP2/WWP2/OTUB2/SPOP, SUFU sequestration) are quantitatively integrated to set GLI2 activator-versus-repressor output in a given cell remains unresolved.
  • No structural model of full-length GLI2 with its modifications
  • Stoichiometry and ordering of modifications during signal transduction unknown
  • Genome-wide GLI2 occupancy across tissues incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005929 cilium 4 GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
ARBTRCFOXC1MEF2COTUB2RUNX2SMAD3SUFU

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 GLI2 is a composite of positive and negative regulatory domains: the N-terminal region contains a repression domain that suppresses its activation potential, while the C-terminal half contains a transcriptional activation domain. Truncation of the activation domain yields a repressor; removal of the N-terminal repression domain converts GLI2 into a strong transcriptional activator. In transgenic mouse embryos, N-terminally truncated GLI2 activates the Shh target gene HNF3beta in the dorsal neural tube, mimicking Shh signaling. Domain truncation analysis in cultured cells and transgenic mouse embryos; reporter assays and in vivo target gene expression Development High 10433919
1997 GLI2 loss-of-function in mice causes severe skeletal abnormalities (cleft palate, tooth defects, absent vertebral body and intervertebral discs, shortened limbs and sternum). Double mutant analysis with Gli3 reveals both specific and redundant functions for GLI2 and GLI3 in skeletal patterning downstream of Hedgehog signaling. Mouse knockout and double-mutant genetic epistasis analysis Development High 9006072
1998 GLI2 and GLI3 are essential downstream mediators of Sonic hedgehog signaling in foregut development. Gli2 single mutants show stenosis of the oesophagus and trachea and lung hypoplasia; Gli2/Gli3 double mutants completely fail to form oesophagus, trachea and lung, establishing overlapping and specific functions. Mouse knockout and compound mutant genetic analysis Nature Genetics High 9731531
2004 GLI2 and GLI3 are primary mediators of Shh signaling in somite myogenesis: Gli2 and Gli3 are required for Gli1 expression in somites, establishing a hierarchy (Gli2/Gli3 → Gli1). Gli2 or Gli3 is required for Myf5 activation in epaxial muscle progenitors; Gli3 (but not Gli2) represses Myf5 in a dose-dependent manner in the absence of Shh. Each Gli preferentially activates a distinct set of Shh target genes in presomitic mesoderm. Mouse knockout genetics, transgenic reporter line (Myf5 epaxial somite enhancer), adenoviral overexpression in explant assays, in vivo target gene expression Development High 15604102
2003 GLI2 and GLI3 are required for Shh-dependent sclerotome induction. Gli2−/−Gli3−/− embryos show severe loss of sclerotomal gene expression, and somitic mesoderm from these embryos cannot activate sclerotomal genes in response to exogenous Shh. One copy of either Gli2 or Gli3 suffices to mediate Shh induction of Pax1 and Pax9. Gli2 can also act as a repressor, and Gli3 can act as an activator, in the developing somite. Mutant mouse analysis, in vitro explant assays with exogenous Shh, adenoviral overexpression of Gli proteins Development High 14602680
2006 β-TrCP2 (beta-transducin repeat-containing protein) E3 ubiquitin ligase directly binds GLI2 and promotes its ubiquitination and proteasomal degradation. A single amino acid substitution in the GLI2 β-TrCP binding site abolishes interaction, ubiquitination, and stabilizes the protein, resulting in higher GLI2 levels and enhanced Gli-dependent transcription. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, reporter assays Journal of Biological Chemistry High 16651270
2007 Indian hedgehog (Ihh) signaling promotes osteoblast differentiation through GLI2. Overexpression of Gli2 (but not Gli3) induced alkaline phosphatase activity, osteocalcin expression, and calcification. Gli2 up-regulates Runx2 expression and enhances Runx2 transcriptional activity. Physical interaction between Gli2 and Runx2 was demonstrated by co-immunoprecipitation. Ihh/Gli2-induced osteoblast differentiation was abolished in Runx2-deficient cells. Overexpression, dominant-negative constructs, co-immunoprecipitation, loss-of-function in Runx2-deficient cells, ALP and osteocalcin assays Molecular Biology of the Cell High 17442891
2009 GLI2 binds a Sox2 enhancer that is essential for Sox2 expression in telencephalic neuroepithelial cells. Overexpression of truncated Gli2 (Gli2ΔC) or Gli2 shRNA in vivo and in vitro inhibits cell proliferation, decreases Sox2 and other NSC markers (Hes1, Hes5, Notch1, CD133, Bmi1), and induces premature neuronal differentiation. Sox2 expression is significantly decreased in Gli2-deficient mouse neuroepithelium. Epistasis: coexpression of Gli2ΔC and Sox2 rescues Hes5 expression and prevents premature differentiation but not proliferation, defining a cascade Gli2→Sox2→Hes5. In vivo and in vitro shRNA knockdown, overexpression, genetic Gli2 knockout mice, ChIP (Gli2 binding to Sox2 enhancer), epistasis rescue experiments Stem Cells High 18927476
2008 Sufu (Suppressor of Fused) restricts GLI2 activity through cytoplasmic sequestration in keratinocytes. Kif7 promotes Hedgehog pathway activity by dissociating the Sufu-Gli2 complex, and also contributes to repression of Hh target genes independently of Sufu. Simultaneous deletion of both Sufu and Kif7 in adult epidermis induces basal cell carcinoma, establishing their overlapping tumor suppressor functions through Gli2 regulation. Conditional knockout mouse genetics (skin-specific deletion), immunolocalization of Gli2, genetic epistasis with compound mutants Development High 23034632
2017 PKA phosphorylates GLI2 and GLI3 in cilia; Hedgehog signaling inhibits this PKA-mediated phosphorylation. The cilia-associated protein Talpid3 (Ta3) interacts with PKA regulatory subunit PKARIIβ at centrioles; Ta3 mutation reduces Gli2 and Gli3 phosphorylation and processing. This provides direct evidence that Gli2 is dephosphorylated and activated within cilia. Phosphorylation assays in cilia, co-immunoprecipitation (Ta3-PKARIIβ), immunolocalization, Talpid3 mutant analysis Developmental Biology Medium 28673820
2019 PRMT7 methylates GLI2 on arginine residues R225 and R227, which are near the SUFU binding region. This methylation interferes with GLI2-SUFU binding, leading to facilitated GLI2 nuclear accumulation and enhanced Shh signaling. PRMT7-deficient MEFs show premature cellular senescence and reduced Shh signaling activity. Co-immunoprecipitation (PRMT7-GLI2), in vitro methylation assay, site-directed mutagenesis of R225/R227, GLI2-SUFU binding assay, reporter assay, nuclear localization analysis, PRMT7 KO MEFs Cell Death and Differentiation High 31000813
2017 mTORC2 inhibits GSK3β, thereby preventing GLI2 ubiquitination and promoting GLI2 protein stability and nuclear translocation. Inhibition of mTORC2 formation decreases GLI2 protein levels through enhanced ubiquitination, attenuating Hedgehog pathway activity and downstream oncogenic processes in glioblastoma. mTORC2 inhibition, ubiquitination assay, GSK3β activity analysis, nuclear fractionation, Hedgehog reporter assays Cell Death & Disease Medium 28703798
2015 GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. Myofibroblast-specific deletion of Gli2 (but not Gli1) in mice limits kidney fibrosis by inducing cell-cycle arrest. Darinaparsin reduces GLI2 protein levels and causes cell-cycle arrest; Gli2 overexpression rescues this effect. Darinaparsin was ineffective in conditional Gli2-KO mice, identifying GLI2 as its direct target. Conditional knockout mouse genetics, pharmacologic inhibition (darinaparsin, GANT61), cell-cycle analysis, Gli2 overexpression rescue, in vivo fibrosis model (UUO) Journal of Clinical Investigation High 26193634
2014 GLI2 co-activates the androgen receptor (AR). The GLI2 C-terminal domain (CTD) is sufficient for AR co-activation, requiring both an AR binding domain (aa628-897) and the GLI2 transactivation domain. GLI2 binds the tau5/AF5 ligand-independent activation domain of AR N-terminus; mutations in the WxxLF motif of tau5/AF5 diminish GLI2 binding. GLI2 also co-activates truncated AR splice variants (AR-V7, ARV567es). ChIP confirmed GLI2 associates with androgen response elements in LNCaP cells. Co-immunoprecipitation, GST-pulldown, domain deletion/mutagenesis, androgen-responsive promoter reporter assays, ChIP The Prostate High 25132524
2015 Foxc1 is a transcriptional partner of Gli2 during endochondral ossification downstream of Ihh. Foxc1 physically interacts with Gli2 and stimulates Ihh target gene expression (PTHrP, Col10a1) through this interaction. A pathological Foxc1 missense mutation (in Axenfeld-Rieger syndrome) impairs Gli2-Foxc1 association and Ihh function. Co-immunoprecipitation (Gli2-Foxc1 interaction), in vivo microarray, Foxc1 loss-of-function mouse (Foxc1ch/ch), dominant-negative Foxc1, reporter assays Nature Communications High 25808752
2011 Gli2 and MEF2C form a protein complex, bind each other's regulatory genomic elements (Gli2 binds Mef2c gene; MEF2C binds Gli2 gene), and activate each other's expression. The Gli2-MEF2C complex synergistically activates transcription from promoters containing both Gli- and MEF2-binding elements, enhancing cardiomyogenesis. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), dominant-negative constructs, reporter assays in P19 EC cells Nucleic Acids Research High 22199256
2008 FKBP8 antagonizes the Shh pathway cell-autonomously at a step independent of Smoothened but dependent on the Gli2 transcription factor, and also requires Kif3a (a component of intraflagellar transport/ciliogenesis machinery), placing GLI2 downstream of primary cilia in Shh signal transduction. Genetic epistasis analysis using Fkbp8, Gli2, Smo, and Kif3a mutant mouse combinations Developmental Biology Medium 18590716
2000 Gli2 functions downstream of FGF signaling in anteroposterior patterning in Xenopus: Gli2 directly induces brachyury (a mesodermal gene), is induced by FGF signaling, and directly regulates the homeobox gene Xhox3. This places GLI2 in the FGF-brachyury regulatory loop, distinct from its known role in Hedgehog signaling. Gain-of-function overexpression in Xenopus embryos, epistasis with FGF signaling, target gene induction assays Development Medium 11003839
2008 GLI2 directly regulates cFlip expression by binding to identified sites in the cFlip promoter, thereby preventing death-ligand-mediated apoptosis. Gli2 silencing in BCC cells and tissue downregulates cFlip (and Bcl-2) and sensitizes tumor cells to TRAIL-mediated apoptosis. Promoter analysis identifying GLI2 binding sites, RNAi knockdown, apoptosis assays, functional validation in BCC tissue Oncogene Medium 18264131
2019 GLI2 transcriptionally activates ARHGEF16 (a Rho guanine nucleotide exchange factor): GLI2 binds the ARHGEF16 promoter and activates its transcription. ARHGEF16 interacts with CKAP5, and this signaling axis mediates GLI2-driven glioma cell migration and proliferation. GLI2 inhibition and ARHGEF16 knockdown both retard tumor growth in vivo. Microarray, ChIP, dual-luciferase assay, yeast two-hybrid, Co-IP, GST-pulldown, in vivo xenograft Journal of Experimental & Clinical Cancer Research Medium 30305138
2018 The deubiquitinase OTUB2 co-immunoprecipitates with GLI2, deubiquitinates GLI2 in vivo and in vitro (wild-type OTUB2 but not catalytic mutants), stabilizes GLI2 protein, and extends its half-life. OTUB2 knockdown decreases GLI2 protein and reduces Hedgehog signaling-dependent osteogenic differentiation. Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, OTUB2 catalytic mutant analysis, half-life analysis, osteogenesis assays Biochemical and Biophysical Research Communications High 30241937
2021 WWP2 E3 ubiquitin ligase mediates the ubiquitination and proteasomal degradation of GLI2. DKK1 suppresses WWP2 expression via canonical Wnt/β-catenin signaling, thereby stabilizing GLI2 and activating the Hedgehog pathway, contributing to bortezomib resistance in multiple myeloma. Ubiquitination assays, co-immunoprecipitation, WWP2 overexpression/knockdown, in vitro and in vivo functional studies Carcinogenesis Medium 34546340
2024 The ciliary kinase DYRK2 phosphorylates GLI2 (and GLI3) on evolutionarily conserved serine residues at the ciliary base in response to Hedgehog pathway activation. This phosphorylation induces dissociation of GLI2/GLI3 from SUFU and their nuclear translocation. DYRK2 loss in mice causes skeletal malformation. DYRK2 also promotes cilia formation, placing it as a positive regulator of the Hh-GLI2 axis downstream of SMO. Transcriptome analysis, interactome/co-immunoprecipitation, phosphorylation assays, site-specific mutagenesis of serine residues, Dyrk2 knockout mice, nuclear translocation assays Proceedings of the National Academy of Sciences USA High 38968120
2020 PGE1 (prostaglandin E1) inhibits GLI2 by blocking its ciliary translocation, a key activation step. Mechanistically, PGE1 acts through the EP4 receptor (which localizes to the primary cilium), enhancing cAMP-PKA activity, which promotes GLI2 phosphorylation and subsequent ubiquitin-proteasome degradation. PGE1 overcomes resistance caused by GLI2 amplification or SMO mutation. High-content screening of ciliary GLI2 translocation, cAMP-PKA assays, ubiquitination assays, EP4 receptor localization, in vivo xenograft Cancer Research Medium 32371475
2019 GLI2 modulates cell cycle re-entry through regulation of primary cilia length. Gli2-knockout NIH3T3 fibroblasts have longer primary cilia due to enhanced autophagy-mediated degradation of Ofd1. These cells show delayed cell cycle re-entry after serum stimulation; ablation of cilia by Kif3a knockdown rescues this delay, placing GLI2 upstream of cilia length control and cell cycle re-entry. CRISPR/Cas9 Gli2 knockout, RNAi, ciliary length measurements, flow cytometry cell cycle analysis, autophagy inhibition (pharmacological and genetic) Journal of Cell Science Medium 30463852
2022 Sufu is essential for controlling cochlear hair cell (HC) differentiation timing through Gli2: Sufu removal leads to elevated Gli2 mRNA expression and severe delay in HC differentiation. Later, Spop promotes Gli2 protein degradation to restore differentiation. Deletion of both Sufu and Spop causes robust Gli2 activation and exacerbated HC differentiation defects. GLI2 inhibits HC differentiation by maintaining Sox2+ prosensory progenitor state; Shh signaling controls Sox2 levels along the basal-apical cochlear axis through Gli2. Conditional knockout mouse genetics (Sufu, Spop, compound mutants), immunohistochemistry, RNA in situ hybridization, Gli2 mRNA/protein expression analysis Proceedings of the National Academy of Sciences USA High 36252002
2019 SUFU and SPOP are dosage-dependent negative regulators of GLI2 in gut mesenchyme. In mice lacking Sufu and/or Spop in the gut mesenchyme, abnormal mesenchymal growth occurs; these defects are partially rescued by Gli2 heterozygosity (epistasis). ChIP-seq and chromatin analysis reveal GLI2 directly regulates intestinal stem cell niche signal genes (including Wnt ligands) through enhancer binding. Conditional knockout mouse genetics (Sufu, Spop, Gli2 heterozygosity), ChIP-seq, chromatin analysis, intestinal tumorigenesis model Cell Reports High 31167144
2020 FHL2-GLI2 fusion genes are recurrently found in sclerosing stromal tumors of the ovary (65% of SSTs). Expression of the FHL2-GLI2 fusion in vitro leads to increased proliferation, migration, and colony formation, and activates SHH pathway transcription. Targeted inhibition of the SHH pathway reverses these oncogenic properties, demonstrating that constitutive GLI2 activation drives SST pathogenesis. Whole-exome, targeted capture, and RNA-sequencing to detect fusions; in vitro expression of fusion construct; SHH pathway inhibition rescue experiments Nature Communications Medium 31896750
2021 Gli2 regulates hepatic stellate cell (HSC) activation and liver fibrosis by upregulating TGF-β signaling. Conditional Gli2 knockout in HSCs decreases liver fibrosis and HSC activation/proliferation by reducing cyclin D1/D2 expression. Overexpression of Gli2 in HSCs rescues proliferation and activation through upregulation of TGF-β signaling. Conditional knockout mice (GFAP-CreERT;Gli2flox/flox), in vitro Gli2 KO HSCs, RNA-seq, CCl4 fibrosis model, Western blot and qRT-PCR American Journal of Physiology: Gastrointestinal and Liver Physiology Medium 33728992
2015 HH signaling through GLI1 and GLI2 (but not GLI3) is required for epithelial-mesenchymal transition (EMT) in human trophoblasts. Both GLI1 and GLI2 act directly as transcriptional repressors of the CDH1 gene encoding E-cadherin, as demonstrated by chromatin immunoprecipitation and reporter assays. Lentiviral shRNA knockdown, reporter assays, chromatin immunoprecipitation, EMT marker analysis, migration and invasion assays Biochimica et Biophysica Acta Medium 25888497
2024 TGF-β1/SMAD3 drives non-canonical GLI2 activation in HCC: Phospho-SMAD3 interacts with active GLI2 isoforms (including two newly identified isoforms with transactivating activity) to transactivate downstream genes modulating stemness, EMT, chemoresistance, and metastasis in poorly differentiated hepatoma cells. Co-immunoprecipitation (SMAD3-GLI2 interaction), isoform cloning and functional characterization, reporter assays, transgenic HBV-HCC mouse model, in situ xenograft model Cancer Letters Medium 38453045
2022 GLI2 directly transcriptionally activates MDR1 (multidrug resistance gene), as confirmed by dual-luciferase reporter gene assays with the MDR1 promoter. This GLI2/MDR1 axis promotes cisplatin resistance in ovarian cancer cells. GLI2 knockdown reduces MDR1 expression and sensitizes cells to cisplatin. Dual-luciferase reporter assay (GLI2 binding to MDR1 promoter), shRNA knockdown, MDR1 inhibitor (verapamil), xenograft model Frontiers in Oncology Medium 35059317
2016 Gli2 mutations cause or predispose to holoprosencephaly (HPE) in a dose-dependent manner in mice. Mice with single-allele Gli2 mutations show increased HPE penetrance and severity upon low-dose teratogen exposure, mechanistically linked to a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. Mouse knockout genetics, teratogen exposure (gene-environment interaction), cellular Hh responsiveness assays Disease Models & Mechanisms Medium 27585885

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development (Cambridge, England) 590 10433919
1997 Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development (Cambridge, England) 511 9006072
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.] 464 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) 299 9655803
2000 A protein complex containing Tho2, Hpr1, Mft1 and a novel protein, Thp2, connects transcription elongation with mitotic recombination in Saccharomyces cerevisiae. The EMBO journal 257 11060033
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 164 21862631
2007 Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Molecular biology of the cell 145 17442891
2015 Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. The Journal of clinical investigation 137 26193634
2010 GLI2-mediated melanoma invasion and metastasis. Journal of the National Cancer Institute 137 20660365
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 122 16651270
2003 Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Developmental biology 91 12812795
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
2015 GLI2 inhibition abrogates human leukemia stem cell dormancy. Journal of translational medicine 76 25889765
2000 Gli2 functions in FGF signaling during antero-posterior patterning. Development (Cambridge, England) 74 11003839
2007 Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells. Cancer research 72 18006803
2023 Optimization of differentiation and transcriptomic profile of THP-1 cells into macrophage by PMA. PloS one 69 37459313
2015 The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification. Nature communications 64 25808752
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
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 Role of GLI2 in hypopituitarism phenotype. Journal of molecular endocrinology 56 25878059
2020 HOTAIR and androgen receptor synergistically increase GLI2 transcription to promote tumor angiogenesis and cancer stemness in renal cell carcinoma. Cancer letters 54 33157157
2009 Efficient non-viral transfection of THP-1 cells. Journal of immunological methods 54 19345690
2020 Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature communications 52 31896750
2015 Hedgehog signaling through GLI1 and GLI2 is required for epithelial-mesenchymal transition in human trophoblasts. Biochimica et biophysica acta 49 25888497
2019 Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation. The Journal of clinical investigation 48 31264977
2018 GLI2 promotes cell proliferation and migration through transcriptional activation of ARHGEF16 in human glioma cells. Journal of experimental & clinical cancer research : CR 48 30305138
2019 YAP Promotes VEGFA Expression and Tumor Angiogenesis Though Gli2 in Human Renal Cell Carcinoma. Archives of medical research 46 31518897
2008 Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene 45 18264131
2014 miR-326 is downstream of Sonic hedgehog signaling and regulates the expression of Gli2 and smoothened. American journal of respiratory cell and molecular biology 43 24617895
2014 Highly efficient transfection of human THP-1 macrophages by nucleofection. Journal of visualized experiments : JoVE 43 25226503
2016 Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model. Disease models & mechanisms 42 27585885
2014 Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion. Cancer letters 42 25449781
2017 Circular RNA GLI2 promotes osteosarcoma cell proliferation, migration, and invasion by targeting miR-125b-5p. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 41 28695772
2015 The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity. Journal of cell science 41 25908851
2011 Gli2 and MEF2C activate each other's expression and function synergistically during cardiomyogenesis in vitro. Nucleic acids research 38 22199256
2017 mTORC2 regulates hedgehog pathway activity by promoting stability to Gli2 protein and its nuclear translocation. Cell death & disease 37 28703798
2018 HER2-mediated GLI2 stabilization promotes anoikis resistance and metastasis of breast cancer cells. Cancer letters 36 30409762
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
2020 Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts. Arthritis research & therapy 35 33303026
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
2014 Modulation of IL-37 expression by triptolide and triptonide in THP-1 cells. Cellular & molecular immunology 33 25308753
2019 GLI2 Modulated by SUFU and SPOP Induces Intestinal Stem Cell Niche Signals in Development and Tumorigenesis. Cell reports 32 31167144
2019 Gli2 Rescues Delays in Brain Development Induced by Kif3a Dysfunction. Cerebral cortex (New York, N.Y. : 1991) 31 29342244
2016 A Notch-Gli2 axis sustains Hedgehog responsiveness of neural progenitors and Müller glia. Developmental biology 31 26795056
2017 GLI2 induces PDGFRB expression and modulates cancer stem cell properties of gastric cancer. European review for medical and pharmacological sciences 29 28975979
2017 miR-141-3p suppresses proliferation and promotes apoptosis by targeting GLI2 in osteosarcoma cells. Oncology reports 29 29251328
2010 Gli2 expression and human bladder transitional carcinoma cell invasiveness. The Journal of urology 29 20488474
2003 Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma. The British journal of dermatology 29 12786818
2023 Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA. Cancer science 28 37417427
2021 GPR126 regulates colorectal cancer cell proliferation by mediating HDAC2 and GLI2 expression. Cancer science 28 33629464
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
2019 Organophosphorus Pesticides Induce Cytokine Release from Differentiated Human THP1 Cells. American journal of respiratory cell and molecular biology 25 30978295
2019 PRMT7 methylates and suppresses GLI2 binding to SUFU thereby promoting its activation. Cell death and differentiation 25 31000813
2016 Designer Nuclease-Mediated Generation of Knockout THP1 Cells. Methods in molecular biology (Clifton, N.J.) 24 26443227
2021 Gli2-regulated activation of hepatic stellate cells and liver fibrosis by TGF-β signaling. American journal of physiology. Gastrointestinal and liver physiology 23 33728992
2018 BCAR4 activates GLI2 signaling in prostate cancer to contribute to castration resistance. Aging 23 30513511
2014 GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis. Cell death & disease 23 24481442
2020 Major multilevel molecular divergence between THP-1 cells from different biorepositories. International journal of cancer 22 32163592
2014 Lycopene modulates THP1 and Caco2 cells inflammatory state through transcriptional and nontranscriptional processes. Mediators of inflammation 22 24891766
2011 GLI2 is a potential therapeutic target in pediatric medulloblastoma. Journal of neuropathology and experimental neurology 22 21572341
2022 Icariin Treatment Rescues Diabetes Induced Bone Loss via Scavenging ROS and Activating Primary Cilia/Gli2/Osteocalcin Signaling Pathway. Cells 21 36552853
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 Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling. Oncogene 20 35418691
2019 Arsenic inhibited cholesterol efflux of THP-1 macrophages via ROS-mediated ABCA1 hypermethylation. Toxicology 20 31150806
2018 Gli2 modulates cell cycle re-entry through autophagy-mediated regulation of the length of primary cilia. Journal of cell science 20 30463852
2022 Selective cleavage of ncRNA and antiviral activity by RNase2/EDN in THP1-induced macrophages. Cellular and molecular life sciences : CMLS 19 35347428
2017 Chromium contributes to human bronchial epithelial cell carcinogenesis by activating Gli2 and inhibiting autophagy. Toxicology research 19 30090501
2009 Transcription at the proximity of the nuclear pore: a role for the THP1-SAC3-SUS1-CDC31 (THSC) complex. RNA biology 19 19229139
2020 Relative Levels of Gli1 and Gli2 Determine the Response of Ventral Neural Stem Cells to Demyelination. Stem cell reports 18 33125874
2014 Determinants of Gli2 co-activation of wildtype and naturally truncated androgen receptors. The Prostate 18 25132524
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
2024 Identification of Fasudil as a collaborator to promote the anti-tumor effect of lenvatinib in hepatocellular carcinoma by inhibiting GLI2-mediated hedgehog signaling pathway. Pharmacological research 15 38280440
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
2022 Hedgehog-Gli2 Signaling Promotes Chemoresistance in Ovarian Cancer Cells by Regulating MDR1. Frontiers in oncology 15 35059317
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 15 36252002
2021 DKK1 suppresses WWP2 to enhance bortezomib resistance in multiple myeloma via regulating GLI2 ubiquitination. Carcinogenesis 15 34546340
2017 Effects of fusariotoxin co-exposure on THP-1 human immune cells. Cell biology and toxicology 15 28822000
2008 Gene silencing of transcription factor Gli2 inhibits basal cell carcinomalike tumor growth in vivo. International journal of cancer 15 17721996
2023 Atheroprotective Effect of Fucoidan in THP-1 Macrophages by Potential Upregulation of ABCA1. Biomedicines 14 38001931
2022 Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes. Open life sciences 14 35415237
2017 α-Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP-1 Monocytes. Journal of cellular biochemistry 14 28059487
2015 MicroRNAs Promote Granule Cell Expansion in the Cerebellum Through Gli2. Cerebellum (London, England) 14 25910616
2020 Gli2 mediates the development of castration‑resistant prostate cancer. International journal of oncology 13 32319599
2024 TGF-β1/SMAD3-driven GLI2 isoform expression contributes to aggressive phenotypes of hepatocellular carcinoma. Cancer letters 12 38453045
2020 GLI2-Mediated Inflammation in the Tumor Microenvironment. Advances in experimental medicine and biology 12 32588323

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