Affinage

VGLL4

Transcription cofactor vestigial-like protein 4 · UniProt Q14135

Length
290 aa
Mass
30.9 kDa
Annotated
2026-06-11
60 papers in source corpus 31 papers cited in narrative 33 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VGLL4 is an intrinsically disordered transcriptional co-factor that governs TEAD-dependent transcription, acting principally as a repressor by competing with YAP for binding to TEAD1-4 through its tandem Tondu (TDU) domains, which are necessary and sufficient for its inhibitory activity and which form the basis of a peptide that suppresses tumor growth (PMID:24525233, PMID:24458094, PMID:34075638). Biophysical reconstitution shows VGLL4 carries two TEAD-binding sites of differing affinity and forms dimeric complexes with TEAD4, and that its action is stoichiometry-dependent: by driving TEAD4 multimerization VGLL4 enhances YAP recruitment to DNA-bound TEAD at low VGLL4:TEAD ratios but inhibits it at high ratios (PMID:34075638, PMID:41965334). Genetic epistasis establishes that the major physiological role of YAP is to antagonize VGLL4, since Vgll4 inactivation bypasses the requirement for YAP in liver and lung development (PMID:36522128). Beyond simple competition, VGLL4 nucleates distinct TEAD4-containing multiprotein complexes that repress or activate specific programs — a TEAD4-VGLL4-CtBP2 complex represses adipogenic PPARγ/Adipoq promoters (PMID:30209132), a TEAD4-VGLL4-SMAD3 complex maintains chondrocyte extracellular matrix homeostasis with osteoarthritis arising upon loss (PMID:41125571), a VGLL4-TEAD1-MENIN complex restrains β-cell proliferation (PMID:36662616), and VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes drive Paneth cell differentiation and defensin expression in the intestine (PMID:41629625); it can also act as a TEAD4 co-activator, stabilizing MyoD-TEAD4 to promote MyoG transactivation during muscle differentiation (PMID:31328806). VGLL4 additionally suppresses Wnt/β-catenin signaling by disrupting a TEAD4-TCF4 complex (PMID:28051067) and is required for heart valve and cardiomyocyte development through restraint of YAP targets (PMID:30789911, PMID:27720608). VGLL4 abundance and activity are tightly controlled: CDK1 phosphorylation and K225 acetylation inhibit TEAD binding (PMID:28739871, PMID:27720608), deubiquitination by USP11 and USP15 stabilizes the protein (PMID:28042509, PMID:38431034), and SAMD4A/B and FTO regulate VGLL4 mRNA stability and m6A modification (PMID:42014888, PMID:42264087).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2014 High

    Establishing how VGLL4 opposes YAP defined the core mechanism: it answered whether VGLL4 is a passive bystander or an active competitor for the oncogenic transcriptional output of the Hippo pathway.

    Evidence Co-IP, competitive binding assays, domain deletion/mutagenesis, and a TDU-mimicking peptide tested in tumor models

    PMID:24458094 PMID:24525233

    Open questions at the time
    • Did not resolve binding stoichiometry or affinity differences between the two TDU sites
    • Did not address VGLL4's roles outside competition
  2. 2016 High

    Identification of inhibitory acetylation at K225 and TEAD1 destabilization showed VGLL4 activity is post-translationally tuned and that it can deplete TEAD1 protein, not only block its complex.

    Evidence Mass spectrometry PTM mapping, K225R acetylation-refractory mutant, Co-IP, and neonatal mouse heart proliferation assays

    PMID:27720608

    Open questions at the time
    • Acetyltransferase/deacetylase responsible for K225 not identified
    • Mechanism linking VGLL4 to TEAD1 proteasomal degradation unresolved
  3. 2016 Medium

    USP11-mediated deubiquitination revealed that VGLL4 protein levels are set by regulated turnover, linking its tumor-suppressive dosage to the ubiquitin system.

    Evidence Co-IP, domain mapping, deubiquitination assay, and USP11 knockdown with YAP-dependent growth rescue

    PMID:28042509

    Open questions at the time
    • E3 ligase that ubiquitinates VGLL4 not identified
    • Single lab, ubiquitin linkage type not defined
  4. 2017 High

    Discovery that VGLL4 disrupts a TEAD4-TCF4 complex and that CDK1 phosphorylates VGLL4 broadened its reach beyond YAP, coupling it to Wnt signaling and to mitotic kinase control.

    Evidence Co-IP, ChIP, reporter assays, mouse CRC model (TCF4); in vitro kinase assay and phosphomutant VGLL4-4A binding/tumor assays (CDK1)

    PMID:28051067 PMID:28739871

    Open questions at the time
    • Whether the same VGLL4 pool simultaneously engages TEAD-YAP and TEAD-TCF4 is unclear
    • Physiological trigger for CDK1 phosphorylation of VGLL4 outside mitosis not addressed
  5. 2018 High

    VGLL4 was shown to act as a positive adaptor in defined ternary complexes (TEAD4-CtBP2) and to stabilize partner proteins (IRF2BP2), redefining it as more than a competitive repressor.

    Evidence Reciprocal Co-IP, ChIP on PPARγ/Adipoq promoters in preadipocytes; Co-IP, proteasome inhibition, and Vgll4-knockout syngeneic tumor/PD-L1 models

    PMID:30209132 PMID:30396996

    Open questions at the time
    • How VGLL4 switches between repressive competition and adaptor/stabilizer roles unresolved
    • Direct structural basis of the ternary complexes not defined here
  6. 2019 High

    In vivo conditional knockouts and dual-role analyses placed VGLL4 upstream of YAP targets in tissue development and revealed YAP-independent co-activator functions.

    Evidence Endothelial-specific Vgll4 KO with YAP genetic epistasis in valve development; Vgll4 KO with MyoD-TEAD4 Co-IP in muscle regeneration; CRISPR zebrafish vgll4b KO mapping IRF2BP2 sequestration

    PMID:30789911 PMID:31328806 PMID:31539803

    Open questions at the time
    • Determinants that select repressive versus co-activator outcome in different tissues not defined
    • Mechanism of context-specific partner choice unclear
  7. 2021 High

    Biophysical reconstitution established VGLL4 as an intrinsically disordered protein with two TEAD-binding sites of distinct affinity, providing a physical model for dimeric and bridging modes of engagement.

    Evidence Surface plasmon resonance, size-exclusion chromatography, and intrinsic disorder characterization of full-length VGLL4 and Drosophila Tgi

    PMID:34075638

    Open questions at the time
    • In-cell relevance of the bridging mode not established
    • How disorder relates to PTM-based regulation not addressed
  8. 2022 High

    Antagonistic genetic epistasis demonstrated that VGLL4 is the principal physiological effector opposed by YAP, since Vgll4 loss rescues YAP-null lethality in liver and lung.

    Evidence Vgll4 KO rescue of YAP-null developmental lethality, Nf2/Vgll4 double-knockout tumor model, CCl4 liver injury in mice

    PMID:36522128

    Open questions at the time
    • Tissues where VGLL4 is not the dominant TEAD repressor not delineated
    • Quantitative contribution of competition versus other complexes in vivo unresolved
  9. 2023 Medium

    Multiple studies expanded VGLL4's TEAD-partnered complexes (MENIN, TET2, FLI1) and identified additional regulatory inputs (USP15 deubiquitination), connecting it to β-cell proliferation, vascular cell specification, and immune evasion.

    Evidence β-cell-specific KO with split-GFP/Y2H interaction assays; Co-IP and reporter assays in hESC-derived VSMC and endothelial differentiation; K48-specific deubiquitination assay for USP15-VGLL4

    PMID:36657637 PMID:36662616 PMID:37468661 PMID:38431034

    Open questions at the time
    • Whether VGLL4 directly or indirectly activates TET2/FLI1 not fully resolved
    • USP15 findings from single lab
  10. 2024 High

    Single-molecule biophysics resolved the stoichiometry-dependent dual behavior of VGLL4, showing it drives TEAD4 multimerization that can either enhance or inhibit YAP recruitment depending on ratio.

    Evidence Fluorescence-combined optical tweezers and single-molecule DNA-binding assays with controlled VGLL4:TEAD4 stoichiometry

    PMID:41965334

    Open questions at the time
    • Cellular concentrations that set the switch point not measured in vivo
    • Whether PTMs shift the stoichiometric threshold not tested
  11. 2025 High

    Structural mapping of a TEAD4-VGLL4-SMAD3 chondrocyte complex with defined interface residues, plus mutant-rescue, established a specific therapeutic mechanism in cartilage homeostasis and osteoarthritis.

    Evidence Col2-CreERT2;Vgll4fl/fl conditional KO, structural interface analysis, Co-IP, interaction-deficient mutants, and AAV rescue

    PMID:41125571

    Open questions at the time
    • Generality of the SMAD3-bridging mechanism to other tissues unknown
    • How VGLL4 selects SMAD3 over other partners not defined
  12. 2026 Medium

    Upstream RNA-level regulation (SAMD4A/B, FTO) and in vivo dual-mechanism dissection in zebrafish defined how VGLL4 abundance is set and confirmed both YAP-dependent and YAP-independent TEAD repression operate together.

    Evidence Genome-wide siRNA screen with RNA stability assays and SAMD4B transgenic mice; MeRIP m6A mapping with FTO manipulation; zebrafish loss/gain-of-function epistasis with transcriptional reporters; intestinal-specific KO with Co-IP of ATOH1/TCF4 complexes

    PMID:41629625 PMID:42014888 PMID:42032219 PMID:42264087

    Open questions at the time
    • Integration of multiple upstream RNA regulators into a single dosage model lacking
    • Relative in vivo weight of YAP-dependent versus independent repression not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how VGLL4's many context-specific complex assemblies and post-translational/RNA-level regulatory inputs are integrated into a unified rule that determines, in a given cell, whether VGLL4 represses or activates TEAD-dependent transcription.
  • No unified model linking stoichiometry, PTM state, and partner availability to functional output
  • Endogenous VGLL4 concentration and complex occupancy across tissues unmeasured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
CTBP2IRF2BP2SMAD3TEAD1TEAD4USP11USP15YAP1
Complex memberships
TEAD4-VGLL4-CtBP2TEAD4-VGLL4-SMAD3VGLL4-TEAD1-MENINVGLL4-TEAD4-TCF4

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 VGLL4 directly competes with YAP for binding to TEAD transcription factors via its tandem Tondu (TDU) domains, which are both necessary and sufficient for its inhibitory activity toward YAP. A peptide mimicking VGLL4's TDU domains potently suppresses tumor growth in vitro and in vivo. Co-IP, competitive binding assays, domain deletion/mutagenesis, in vitro and in vivo tumor suppression assays with VGLL4-mimicking peptide Cancer Cell High 24525233
2014 VGLL4 inhibits formation of the YAP-TEAD transcriptional complex in lung cancer by directly competing with YAP for TEAD binding, acting through two TDU domains. Co-IP, competitive binding assays, ectopic expression in lung cancer cells, de novo mouse lung cancer model Cell Research High 24458094
2017 VGLL4 targets a TEAD4-TCF4 transcriptional complex to simultaneously suppress both Hippo-YAP and Wnt/β-catenin signaling; TEAD4 and TCF4 physically associate and co-bind target gene promoters, and VGLL4 disrupts this complex to suppress TCF4 transactivation. Co-IP, chromatin immunoprecipitation, reporter assays, knockdown experiments, de novo mouse CRC model Nature Communications High 28051067
2016 VGLL4 is acetylated at lysine 225, and this acetylation negatively regulates its binding to TEAD1. VGLL4 inhibits cardiomyocyte proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for proteasomal degradation. An acetylation-refractory VGLL4 mutant (K225R) shows enhanced TEAD1 degradation and limits neonatal CM proliferation. Mass spectrometry identification of acetylation site, acetylation-refractory mutant overexpression, Co-IP, in vivo neonatal mouse heart experiments Developmental Cell High 27720608
2016 USP11 (ubiquitin-specific protease 11) interacts with VGLL4 via its USP domain binding to the N-terminal region of VGLL4, and stabilizes VGLL4 protein by promoting its deubiquitination. Knockdown of USP11 promotes cell growth in a YAP-dependent manner. Co-IP, domain mapping, deubiquitination assay, USP11 knockdown with phenotypic rescue American Journal of Cancer Research Medium 28042509
2017 CDK1 phosphorylates VGLL4 during mitosis at Ser-58, Ser-155, Thr-159, and Ser-280. The non-phosphorylatable mutant VGLL4-4A (S58A/S155A/T159A/S280A) shows higher binding affinity to TEAD1 than wild-type VGLL4 and suppresses tumorigenesis more potently, indicating that mitotic CDK1 phosphorylation inhibits VGLL4's tumor-suppressive activity. In vitro kinase assay, site-directed mutagenesis, phosphomutant expression in pancreatic cancer cells, TEAD1 binding assay, in vitro and in vivo tumor suppression assays Journal of Biological Chemistry High 28739871
2018 VGLL4 acts as an adaptor protein forming a ternary complex with TEAD4 and CtBP2 to repress adipogenesis; VGLL4 enhances the interaction between TEAD4 and CtBP2. This TEAD4-VGLL4-CtBP2 complex dynamically exists at the early stage of adipogenesis and directly represses PPARγ and Adipoq promoters. Co-IP, knockdown of TEAD1-4 in 3T3-L1 preadipocytes, ChIP on PPARγ/Adipoq promoters, ternary complex characterization Journal of Biological Chemistry High 30209132
2018 Loss of VGLL4 reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability by inhibiting proteasome-mediated degradation of IRF2BP2. Loss of IRF2BP2 leads to persistent binding of IRF2 (a transcriptional repressor) to the PD-L1 promoter, thereby reducing PD-L1. Additionally, YAP inhibits IFNγ-inducible PD-L1 expression partly by suppressing VGLL4 and IRF1 via miR-130a. Co-IP, proteasome inhibitor experiments, syngeneic mouse tumor models with Vgll4 knockout, promoter binding assays The EMBO Journal High 30396996
2019 VGLL4 interacts with STAT3 and suppresses STAT3 phosphorylation/activation, leading to inactivation of STAT3 downstream transcription in triple-negative breast cancer cells. Co-IP, VGLL4 overexpression/knockdown, STAT3 reporter assays, in vivo nude mouse tumor model Experimental & Molecular Medicine Medium 31748508
2019 VGLL4 expressed in endothelial cell lineage is required for heart valve development; tissue-specific knockout of VGLL4 in endothelial cells leads to valve malformation with expanded expression of YAP targets. Genetic semi-knockout of YAP in VGLL4-ablated hearts significantly constrains hyper-proliferation of arterial valve interstitial cells, placing VGLL4 upstream of YAP targets in valve development. Tissue-specific conditional knockout in mice, genetic epistasis (semi-knockout of YAP in VGLL4-null background), histology, immunostaining PLoS Genetics High 30789911
2019 VGLL4 plays dual roles in muscle regeneration: (1) as a conventional repressor of YAP during the proliferation stage; (2) as a co-activator of TEAD4 to promote MyoG transactivation in a YAP-independent manner during differentiation. VGLL4 stabilizes protein-protein interactions between MyoD and TEAD4 to achieve efficient MyoG transactivation. VGLL4 knockout in mice, Co-IP for MyoD-TEAD4 interaction, reporter assays, in vivo muscle regeneration phenotype analysis The EMBO Journal High 31328806
2022 Genetic inactivation of Vgll4 bypasses the requirement for YAP in liver and lung development (striking antagonistic epistasis), establishing that the major physiological function of YAP is to antagonize VGLL4. Vgll4 inactivation dramatically enhanced intrahepatic cholangiocarcinoma in Nf2-deficient livers and ameliorated CCl4-induced liver damage. Genetic epistasis in mice: Vgll4 knockout rescuing YAP-null developmental lethality; Nf2/Vgll4 double knockout tumor model; CCl4 liver injury model Genes & Development High 36522128
2021 Biochemical characterization shows that full-length VGLL4 and Drosophila Tgi are intrinsically disordered proteins. VGLL4 has two TEAD4-binding sites with one high-affinity site (100-fold tighter than the low-affinity site). In solution, VGLL4 predominantly forms dimeric complexes with TEAD4 via the high-affinity site; at high concentrations or when TEAD4 is immobilized/bound to DNA, one VGLL4 molecule can bridge two TEAD molecules, potentially enhancing repression at DNA-bound TEADs. Surface plasmon resonance (SPR) binding assays, size exclusion chromatography, biophysical characterization of intrinsic disorder Protein Science High 34075638
2023 VGLL4 and MENIN function as TEAD1 co-repressors in pancreatic β cells; both proteins bind TEAD1 and repress expression of target genes FZD7 and CCN2, leading to inhibition of β cell proliferation. β cell-specific deletion of YAP/TAZ does not affect proliferation, whereas TEAD1 deletion increases proliferation, implicating VGLL4/MENIN as the relevant TEAD1 co-repressors. β cell-specific TEAD1/YAP/TAZ knockout mice, split-GFP system and yeast two-hybrid for VGLL4/MENIN-TEAD1 interaction, reporter assays for FZD7/CCN2 Cell Reports High 36662616
2019 In zebrafish, VGLL4 (vgll4b) sequesters IRF2BP2 via its TDU1 domain interacting with IRF2BP2's ring finger domain, thereby preventing IRF2BP2 from repressing alas2 expression and heme biosynthesis. This places VGLL4 downstream of NOTCH1/HIF1α in an oxygen-sensing pathway controlling erythroid terminal differentiation. CRISPR/Cas9 vgll4b knockout zebrafish, domain mapping (TDU1 and IRF2BP2 ring finger), rescue experiments with irf2bp2 depletion, heme/erythroid phenotype analysis Redox Biology Medium 31539803
2023 VGLL4 promotes vascular smooth muscle cell (VSMC) differentiation from hESCs by interacting with TEAD1; the VGLL4-TEAD1 complex directly activates TET2 (a DNA dioxygenase) expression, which in turn demethylates VSMC marker genes to facilitate their expression. CRISPR/Cas9 VGLL4 knockdown hESCs, PiggyBac VGLL4 overexpression, Co-IP for VGLL4-TEAD1 interaction, luciferase reporter assay for TET2 promoter, VSMC differentiation assay Journal of Molecular and Cellular Cardiology Medium 36657637
2023 VGLL4 promotes vascular endothelial cell specification from hESCs by binding TEAD1 and facilitating expression of endothelial master transcription factor FLI1; TEAD1 overexpression rescues the inhibitory effects of VGLL4 knockdown on endothelial differentiation. Co-IP for VGLL4-TEAD1 interaction, inducible VGLL4 overexpression (PiggyBac), VGLL4 heterozygous knockout (CRISPR), 3D vascular organoids and 2D endothelial differentiation assays Cellular and Molecular Life Sciences Medium 37468661
2025 VGLL4 forms a complex with TEAD4 and SMAD3 in chondrocytes to maintain extracellular matrix homeostasis; structural analysis defined that TEAD4 residues E263/D266/Q269/H427 bind SMAD3 residues K81/F260 via hydrogen bonds and hydrophobic contacts, while VGLL4 residues H240/F241 engage TEAD4 residues F337/F373 via π-stacking. VGLL4 deficiency causes ECM disorganization and osteoarthritis; interaction-deficient mutants lose therapeutic efficacy. Conditional KO mice (Col2-CreERT2;Vgll4fl/fl), structural interaction analysis, Co-IP, AAV-mediated gene delivery rescue, interaction-deficient mutants Nature Communications High 41125571
2024 VGLL4 drives TEAD4 multimerization, which increases TEAD4 DNA residence time and promotes YAP recruitment to DNA-bound TEAD4. At low VGLL4:TEAD4 ratios, VGLL4 enhances YAP recruitment to DNA-bound TEAD4 multimers; at high VGLL4:TEAD4 ratios, VGLL4 inhibits YAP recruitment. Both YAP and VGLL4 can promote TEAD4 multimerization. Fluorescence-combined optical tweezers, single-molecule DNA binding assays, stoichiometry-dependent co-factor recruitment experiments Nature Communications High 41965334
2026 In zebrafish, Vgll4 restricts Tead-dependent transcription through two co-existing mechanisms: (1) competition with Yap1 for Tead binding (Yap1-dependent repression) and (2) Tead-dependent repression independent of Yap1. Loss- and gain-of-function epistasis experiments and transcriptional reporters confirmed both mechanisms operate in vivo. Loss- and gain-of-function in zebrafish posterior lateral line, genetic epistasis experiments, transcriptional reporter quantification, pharmacological treatments Communications Biology High 42032219
2026 SAMD4A/B RNA-binding proteins destabilize VGLL4 mRNA and repress its translation, thereby activating TEAD-dependent transcription. Inhibiting SAMD4A/B elevates VGLL4 mRNA levels, suppresses TEAD activity, and inhibits cancer progression. Liver-specific SAMD4B transgenic mice show accelerated intrahepatic cholangiocarcinoma development in Nf2-deficient background. Whole-genome siRNA screen, SAMD4A/B knockdown, RNA stability and translation assays, SAMD4B liver-specific transgenic mice with Nf2 knockout Oncogene Medium 42014888
2026 VGLL4 forms a complex with TEAD4 and ATOH1 to stimulate GFI1 expression and promote Paneth cell differentiation; separately, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining intestinal microbiota composition and intestinal homeostasis. Intestinal epithelium-specific VGLL4 knockout mice, Co-IP for VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes, gene expression analysis, Paneth cell number quantification EMBO Reports Medium 41629625
2023 VGLL4 inhibits ubiquitination and proteasomal degradation of LDHA, increasing LDHA protein levels and lactate production in response to hypoxia. This neuroprotective mechanism reduces APP amyloidogenic processing. Sodium oxamate (LDHA inhibitor) blocks this neuroprotective function of VGLL4. VGLL4 overexpression in AD model cells, ubiquitination assay for LDHA, pharmacological inhibition with sodium oxamate, APP processing assay FASEB Journal Low 37921465
2024 USP15 deubiquitinates VGLL4 via K48-linked ubiquitin chains, stabilizing VGLL4 protein. This USP15-mediated VGLL4 stabilization suppresses STAT3 activation and PD-L1 transcription. SART3 regulates VGLL4 stability by influencing the nuclear translocation of USP15. Co-IP, deubiquitination assay (K48-linkage specificity), STAT3 reporter, PD-L1 expression analysis, CD8+ T cell infiltration assays Cancer Letters Medium 38431034
2024 Select sulfonamide TEAD lipid-pocket-binding small molecules promote TEAD interaction with VGLL4 (a cofactor switch from YAP to VGLL4), inducing chemically-driven VGLL4-TEAD complexes that repress pro-growth gene networks. Genetic deletion of VGLL4 causes resistance to these compounds in vitro and in vivo, demonstrating that VGLL4 is required for their anti-proliferative activity. Co-IP after compound treatment, chromatin assays, VGLL4 genetic deletion with compound resistance phenotype, in vitro and in vivo proliferation assays bioRxivpreprint Medium
2024 VGLL4 containing intact TDU domains regulates classical brown adipose tissue (BAT) adipogenesis; deletion of TDU domains causes perinatal lethality and paucity of interscapular BAT. AAV-mediated brown adipocyte-specific VGLL4 overexpression increases BAT volume. Genomic studies indicate the VGLL4/TEAD1 complex directly regulates myogenic and adipogenic gene expression programs in BAT. TDU-domain deletion mouse mutant, histology, MRI, AAV-mediated overexpression, genomic/ChIP studies of VGLL4/TEAD1 complex bioRxivpreprint Medium
2013 VGLL4 overexpression in human embryonic stem cells significantly decreases cell death in response to dissociation stress, enhances colony formation from single cells, and decreases activity of initiator and effector caspases. An interaction between VGLL4 and the Rho/ROCK pathway was identified in hESC survival context. Gain-of-function ORF screen, caspase activity assays, colony formation assays, Rho/ROCK pathway interaction experiments Stem Cells Low 23765749
2021 KDM6B (JMJD3) demethylase activity promotes VGLL4 expression in the hippocampus during LPS-induced neuroinflammation; KDM6B inhibition with GSK-J4 attenuates LPS-induced VGLL4, STAT3, IL-1β, and microglial activation. VGLL4 knockdown prevents LPS-induced anxiety-like behavior and STAT3/IL-1β upregulation, placing VGLL4 downstream of KDM6B in a neuroinflammatory pathway. KDM6B inhibitor (GSK-J4), adeno-associated virus-mediated Vgll4 shRNA knockdown, behavioral assays, western blotting Behavioural Brain Research Low 33865886
2021 VGLL4 knockdown attenuates hypoxia-induced pulmonary hypertension and STAT3 signaling in mice; VGLL4 acetylation is enhanced by chronic normobaric hypoxia and increases interaction with ac-H3K9 and p-STAT3. Abrogation of VGLL4 acetylation reverses hypoxia-induced pulmonary arterial remodeling and suppresses STAT3 signaling. AAV-mediated VGLL4 knockdown/overexpression in mice, VGLL4 acetylation mutant, Co-IP for ac-H3K9/VGLL4/STAT3 interaction, immunoprecipitation, pulmonary hypertension model FASEB Journal Medium 34314061
2023 ACSL4 reduces VGLL4 expression to promote NF-κB signal transduction in microglia; ACSL4 knockdown increases VGLL4 levels and decreases proinflammatory cytokine production, placing VGLL4 downstream of ACSL4 as a negative regulator of NF-κB signaling in microglial neuroinflammation. ACSL4 knockdown in microglia, VGLL4 expression measurement, NF-κB signaling assays, in vivo LPS and MPTP mouse models Brain, Behavior, and Immunity Low 36791893
2024 VGLL4 suppresses cardiomyocyte maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway; disrupting VGLL4-TEAD interaction abolishes this inhibition of PI3K-AKT. VGLL4 activation in neonatal rat ventricular myocytes and postnatal mouse heart, PI3K-AKT pathway measurements, VGLL4 interaction-disrupting mutant Cells Medium 39195232
2026 FTO (m6A demethylase) reduces m6A modification levels on VGLL4 mRNA, leading to decreased VGLL4 expression and consequent activation of STAT3 signaling in triple-negative breast cancer. MeRIP assay confirmed VGLL4 as the target of FTO-mediated m6A modification. MeRIP (m6A-RNA immunoprecipitation), RNA immunoprecipitation, RNA stability assay, FTO overexpression/knockdown, STAT3 signaling readout Journal of Biological Chemistry Medium 42264087
2024 TEAD4 directly binds RUNX2 to repress RUNX2-driven osteogenesis, and VGLL4 antagonizes this repression by disrupting TEAD4-RUNX2 interactions; Co-IP confirmed VGLL4 reduces TEAD4-RUNX2 binding, and VGLL4 knockdown diminishes osteoblast differentiation. Co-IP and proximity ligation assay (PLA) for TEAD4-RUNX2 interaction, VGLL4 knockdown in BMSCs, osteogenic differentiation assays, OVX rat model Journal of Ethnopharmacology Low 39142621

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer cell 536 24525233
2014 VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell research 258 24458094
2017 VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nature communications 133 28051067
1995 Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA research : an international journal for rapid publication of reports on genes and genomes 124 8590280
2016 Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth. Developmental cell 98 27720608
2023 ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression. Brain, behavior, and immunity 92 36791893
2018 VGLL4 is a transcriptional cofactor acting as a novel tumor suppressor via interacting with TEADs. American journal of cancer research 68 30034932
2017 VGLL4 Selectively Represses YAP-Dependent Gene Induction and Tumorigenic Phenotypes in Breast Cancer. Scientific reports 53 28733631
2018 Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion. The EMBO journal 50 30396996
2019 VGLL4 plays a critical role in heart valve development and homeostasis. PLoS genetics 47 30789911
2019 VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer. Experimental & molecular medicine 42 31748508
2015 VGLL4 inhibits EMT in part through suppressing Wnt/β-catenin signaling pathway in gastric cancer. Medical oncology (Northwood, London, England) 42 25701461
2015 miR-222/VGLL4/YAP-TEAD1 regulatory loop promotes proliferation and invasion of gastric cancer cells. American journal of cancer research 39 26045994
2018 The TEA domain family transcription factor TEAD4 represses murine adipogenesis by recruiting the cofactors VGLL4 and CtBP2 into a transcriptional complex. The Journal of biological chemistry 37 30209132
2019 Dual function of VGLL4 in muscle regeneration. The EMBO journal 36 31328806
2022 YAP-VGLL4 antagonism defines the major physiological function of the Hippo signaling effector YAP. Genes & development 31 36522128
2016 Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4 protein. American journal of cancer research 31 28042509
2021 VGLL4 inhibits YAP1/TEAD signaling to suppress the epidermal squamous cell carcinoma cancer phenotype. Molecular carcinogenesis 27 34004031
2018 MicroRNA-301a-3p suppressed the progression of hepatocellular carcinoma via targeting VGLL4. Pathology, research and practice 26 30322806
2014 Downregulation of VGLL4 in the progression of esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 25352025
2019 The NOTCH1-dependent HIF1α/VGLL4/IRF2BP2 oxygen sensing pathway triggers erythropoiesis terminal differentiation. Redox biology 19 31539803
2018 miR-130b promotes bladder cancer cell proliferation, migration and invasion by targeting VGLL4. Oncology reports 19 29512748
2020 The lncRNA MEG3/miR-16-5p/VGLL4 regulatory axis is involved in etoposide-induced senescence of tumor cells. The journal of gene medicine 18 33141998
2017 Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity. The Journal of biological chemistry 17 28739871
2013 Brief report: VGLL4 is a novel regulator of survival in human embryonic stem cells. Stem cells (Dayton, Ohio) 17 23765749
2023 Hypoxia-sensing VGLL4 promotes LDHA-driven lactate production to ameliorate neuronal dysfunction in a cellular model relevant to Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 37921465
2021 Upregulation of KDM6B contributes to lipopolysaccharide-induced anxiety-like behavior via modulation of VGLL4 in mice. Behavioural brain research 15 33865886
2023 VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation. Cell reports 14 36662616
2020 VGLL4 Protects against Oxidized-LDL-Induced Endothelial Cell Dysfunction and Inflammation by Activating Hippo-YAP/TEAD1 Signaling Pathway. Mediators of inflammation 14 33456372
2018 Adenovirus armed with VGLL4 selectively kills hepatocellular carcinoma with G2/M phase arrest and apoptosis promotion. Biochemical and biophysical research communications 13 30119884
2021 LINC00641 regulates prostate cancer cell growth and apoptosis via the miR-365a-3p/VGLL4 axis. European review for medical and pharmacological sciences 12 33506898
2023 Lycorine weakens tamoxifen resistance of breast cancer via abrogating HAGLR-mediated epigenetic suppression on VGLL4 by DNMT1. The Kaohsiung journal of medical sciences 11 36606584
2021 HOXB13 suppresses proliferation, migration and invasion, and promotes apoptosis of gastric cancer cells through transcriptional activation of VGLL4 to inhibit the involvement of TEAD4 in the Hippo signaling pathway. Molecular medicine reports 11 34396425
2022 Hsa_circ_0006427 Suppresses Multiplication, Migration and Invasion of Non-Small Cell Lung Cancer Cells through miR-346/VGLL4 Pathway. Cell journal 10 35717572
2024 K48-linked deubiquitination of VGLL4 by USP15 enhances the efficacy of tumor immunotherapy in triple-negative breast cancer. Cancer letters 9 38431034
2022 The opposite effects of VGLL1 and VGLL4 genes on granulosa cell proliferation and apoptosis of hen ovarian prehierarchical follicles. Theriogenology 9 35074718
2023 VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model. Cellular and molecular life sciences : CMLS 8 37468661
2021 Critical role of VGLL4 in the regulation of chronic normobaric hypoxia-induced pulmonary hypertension in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 34314061
2023 VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2. Journal of molecular and cellular cardiology 6 36657637
2024 Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4. Neuro-oncology advances 5 39380691
2022 Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development. Cells 5 36139407
2024 Bu-Sui-Dan Enhances Osteoblast Differentiation by Upregulating VGLL4 to Counteract TEAD4-Mediated RUNX2 Transcription Suppression in Ovariectomized Rats. Journal of ethnopharmacology 4 39142621
2021 Biochemical properties of VGLL4 from Homo sapiens and Tgi from Drosophila melanogaster and possible biological implications. Protein science : a publication of the Protein Society 4 34075638
2025 Targeting VGLL4 maintains extracellular matrix homeostasis and mitigates osteoarthritis in a preclinical model. Nature communications 2 41125571
2024 Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib. Biomedicines 2 38255254
2024 Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4. bioRxiv : the preprint server for biology 2 38854109
2024 Activation of VGLL4 Suppresses Cardiomyocyte Maturational Hypertrophic Growth. Cells 2 39195232
2022 [Conditional medium of gastric cancer mesenchymal stem cells promotes PD-L1 expression in gastric cancer cells and tumor growth via upregulating VGLL4]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 2 35583061
2026 Two distinct modes of Vgll4-mediated Tead regulation control organ size in zebrafish. Communications biology 1 42032219
2025 Expression Pattern of AIFM3, VGLL4, and WNT4 in Patients with Different Stages of Colorectal Cancer. Cancers 1 39857952
2025 A non-coding RNA circGNAI2 suppresses triple-negative breast cancer progression by sponging miR-454-3p to inhibit the VGLL4-STAT3 signaling. The Journal of biological chemistry 1 40784450
2023 Generation of Vgll4-DreER transgenic mouse for visualizing and manipulating VGLL4-expressing cells in vivo. Journal of biochemical and molecular toxicology 1 37352117
2026 VGLL4 modulates Paneth cells and sustains intestinal homeostasis. EMBO reports 0 41629625
2026 VGLL4 promotes hepatocellular carcinoma progression via the Wnt/β-catenin pathway. Tissue & cell 0 41722266
2026 VGLL4-driven TEAD4 multimerization orchestrates DNA binding and YAP recruitment. Nature communications 0 41965334
2026 VGLL4 regulates the Wnt/β-catenin signaling pathway and acts as an oncogenic factor in acute myeloid leukemia. Hematology (Amsterdam, Netherlands) 0 41983974
2026 SAMD4 represses VGLL4 mRNA to activate TEAD and promote cancer progression. Oncogene 0 42014888
2026 FTO Promotes Cancer Progression by Regulating VGLL4 m6A Levels to Activate STAT3 Signaling in Triple-Negative Breast Cancer. The Journal of biological chemistry 0 42264087
2025 Stapled peptide inhibitors target VGLL4/TEAD4 interactions to accelerate cutaneous wound healing. European journal of medicinal chemistry 0 41478010
2022 Retracted: VGLL4 Protects against Oxidized-LDL-Induced Endothelial Cell Dysfunction and Inflammation by Activating Hippo-YAP/TEAD1 Signaling Pathway. Mediators of inflammation 0 35530978

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