Affinage

TEAD4

Transcriptional enhancer factor TEF-3 · UniProt Q15561

Length
434 aa
Mass
48.3 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TEAD4 is a TEA-domain transcription factor that serves as the principal DNA-binding effector of the Hippo signaling pathway, integrating co-activator (YAP/TAZ) and co-repressor (VGLL family) inputs to control cell proliferation, lineage specification, and metabolic gene programs. TEAD4 binds MCAT and other cis-regulatory elements through its α3 helix-containing TEA domain and recruits YAP or TAZ via an immunoglobulin-like C-terminal domain; its transcriptional output is toggled by LATS-mediated YAP phosphorylation (which promotes YAP cytoplasmic retention), by NF2-induced TEAD4 depalmitoylation and ubiquitin-dependent degradation, and by alternative co-factor complexes such as VGLL4–CtBP2 repressor assemblies and TEAD4–TCF4 or TEAD4–Smad2/3 complexes that operate independently of YAP (PMID:19289085, PMID:20123908, PMID:28368398, PMID:38522513, PMID:28051067, PMID:30209132, PMID:36806855). TEAD4 undergoes autopalmitoylation at a conserved cysteine that stabilizes its protein conformation, and a dominant-negative splice isoform (TEAD4-S) lacking the DNA-binding domain sequesters YAP to suppress proliferation (PMID:28960584, PMID:27291620). Uniquely among TEAD family members, TEAD4 localizes to mitochondria where it binds mtDNA and recruits POLRMT to drive transcription of electron transport chain components and maintain oxidative phosphorylation, a function essential for trophectoderm development—Tead4-null mouse embryos fail to specify trophectoderm, lack Cdx2 and other TE genes, and die before implantation (PMID:30201685, PMID:23903192, PMID:17913785).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 Medium

    Establishing that TEAD4 (RTEF-1) is a transcriptional activator of muscle-specific promoters through M-CAT elements and responds to α1-adrenergic signaling in cardiac myocytes provided the first functional characterization of TEAD4 as a stimulus-responsive transcription factor with promoter-specific cofactor requirements.

    Evidence Reporter assays with M-CAT mutagenesis and gel shift in neonatal rat cardiac myocytes; Ser-322 mutagenesis abolishing adrenergic response

    PMID:10764782 PMID:9670917

    Open questions at the time
    • Cofactors mediating promoter selectivity not identified
    • In vivo cardiac phenotype of TEAD4 loss not tested
  2. 2004 Medium

    Demonstrating that TEAD4 binds an Sp1 response element (not M-CAT) in the VEGF promoter to stimulate angiogenic gene expression in hypoxic endothelial cells revealed that TEAD4 can occupy non-canonical binding sites, expanding its regulatory repertoire beyond the M-CAT element.

    Evidence EMSA, ChIP, VEGF promoter mutagenesis, and tube formation assays in endothelial cells

    PMID:15073166

    Open questions at the time
    • Mechanism of TEAD4 binding to Sp1 sites versus M-CAT sites unresolved
    • In vivo angiogenic role of TEAD4 not demonstrated
  3. 2007 High

    Knockout studies established that TEAD4 is essential for trophectoderm specification: Tead4-null embryos fail to express Cdx2, Eomes, and Fgfr2, default to ICM identity in all blastomeres, and die before implantation, defining TEAD4 as the master transcription factor for the first mammalian cell-fate decision.

    Evidence Constitutive and conditional Tead4 knockout mice with immunofluorescence and gene expression analysis, replicated in two independent labs

    PMID:17913785 PMID:18083014

    Open questions at the time
    • Downstream target hierarchy not mapped genome-wide
    • Whether other TEAD family members partially compensate post-implantation unclear
  4. 2009 High

    Linking Hippo-pathway kinase LATS to cytoplasmic retention of YAP in inner blastomeres explained how cell-position information is transduced into differential TEAD4 transcriptional activity, establishing the Hippo–YAP–TEAD4 axis as the lineage-specifying switch in preimplantation embryos.

    Evidence Genetic modulation of Tead4/Yap in mouse embryos and ES cells, immunofluorescence for YAP localization

    PMID:19289085

    Open questions at the time
    • Upstream signals activating LATS at cell contacts not fully defined
    • Quantitative thresholds of nuclear YAP required for TE fate unknown
  5. 2010 High

    Crystal structures of the TEAD4 C-terminal domain in complex with YAP revealed an immunoglobulin-like fold engaging YAP through helices and a PXXΦhiP loop, providing the structural basis for the TEAD4–YAP interaction and enabling structure-guided disruption of its oncogenic activity.

    Evidence X-ray crystallography with interface mutagenesis abolishing transformation

    PMID:20123908

    Open questions at the time
    • Full-length TEAD4–YAP–DNA ternary complex structure not available
    • Structural basis for differential cofactor (VGLL vs YAP) selection not resolved
  6. 2012 High

    ChIP-seq and forced nuclear localization experiments demonstrated that nuclear versus cytoplasmic partitioning of TEAD4 itself—not just YAP—determines trophectoderm transcription, revealing a second layer of regulation beyond YAP phosphorylation.

    Evidence Genome-wide ChIP-seq for TEAD4, live-cell imaging, forced NLS-TEAD4 in inner blastomeres

    PMID:22529382

    Open questions at the time
    • Signal controlling TEAD4 nuclear exclusion from inner cells not identified
    • Relationship between TEAD4 localization and its palmitoylation state not examined
  7. 2013 High

    Discovery that TEAD4 uniquely localizes to mitochondria and is required to maintain mitochondrial membrane potential and limit ROS during blastocoel formation revealed a non-transcriptional (nuclear) role for TEAD4 in organellar homeostasis.

    Evidence Fluorescence imaging, ROS/membrane potential assays, rescue by antioxidant culture conditions

    PMID:23903192

    Open questions at the time
    • Mitochondrial import mechanism of TEAD4 unknown
    • Whether mitochondrial TEAD4 binds mtDNA directly not yet shown
  8. 2016 High

    Identification of the dominant-negative splice isoform TEAD4-S (lacking the TEA domain but retaining the YAP-binding domain) and the VGLL4–CtBP2 co-repressor complex revealed endogenous negative-feedback mechanisms that restrain YAP–TEAD4 transcriptional output.

    Evidence Splice isoform characterization with Co-IP and xenograft (TEAD4-S); Co-IP and ChIP defining TEAD4–VGLL4–CtBP2 ternary complex on PPARγ promoter

    PMID:27291620 PMID:30209132

    Open questions at the time
    • Tissue distribution and regulation of TEAD4-S splicing incompletely characterized
    • Whether VGLL4–CtBP2 complex operates genome-wide or at select loci unknown
  9. 2017 High

    Crystal structure of the TEAD4 TEA domain bound to MCAT DNA defined how the α3 helix contacts both grooves to confer DNA-binding specificity, while demonstration that TEAD4 associates with TCF4 to co-regulate Wnt targets positioned TEAD4 as an integrator of Hippo and Wnt pathways.

    Evidence X-ray crystallography of TEA domain–DNA complex with mutagenesis; Co-IP and ChIP showing TEAD4–TCF4 co-occupancy in CRC cells

    PMID:28051067 PMID:28368398

    Open questions at the time
    • Full TEA domain–YBD–DNA–YAP quaternary structure not solved
    • Stoichiometry of TEAD4–TCF4 versus TEAD4–YAP complexes on shared loci unresolved
  10. 2017 High

    Biochemical and NMR studies established that TEAD4 catalyzes autopalmitoylation at a conserved cysteine (Cys360), which stabilizes protein conformation without altering YAP/TAZ binding affinity, identifying palmitoylation as a druggable regulatory mechanism.

    Evidence In vitro palmitoylation reconstitution, NMR spectroscopy, C360S mutagenesis, flufenamic acid inhibition

    PMID:28960584 PMID:29760238

    Open questions at the time
    • In vivo consequences of palmitoylation loss on TEAD4 function in animal models not tested
    • Enzyme(s) responsible for TEAD4 depalmitoylation not identified
  11. 2018 High

    Demonstrating that mitochondrial TEAD4 binds mtDNA and recruits POLRMT to promote transcription of ETC components completed the mechanistic picture of how TEAD4 supports oxidative phosphorylation—resolving the earlier observation of mitochondrial membrane potential defects upon TEAD4 loss.

    Evidence Mitochondrial fractionation, mtDNA ChIP, POLRMT Co-IP, OXPHOS functional assays in trophoblast stem cells

    PMID:30201685

    Open questions at the time
    • How TEAD4 is imported into mitochondria without a canonical MTS remains unknown
    • Whether mitochondrial TEAD4 function extends to non-trophoblast tissues not established
  12. 2021 High

    Discovery that arginine-mTOR signaling retains TEAD4 in the nucleus independently of YAP to activate OXPHOS gene transcription via histone acetylation connected nutrient sensing to TEAD4-dependent metabolic gene regulation in cancer.

    Evidence ChIP, subcellular fractionation, metabolic assays, siRNA knockdown in prostate cancer cells and xenografts

    PMID:33893278

    Open questions at the time
    • Direct phosphorylation event linking mTOR to TEAD4 nuclear retention not identified
    • Whether this nutrient-sensing circuit operates in normal tissues unknown
  13. 2023 Medium

    TEAD4 was shown to mitigate TGF-β signaling in a YAP-independent manner by sequestering Smad2/3 away from p300, while also suppressing senescence by maintaining closed chromatin at SASP enhancers, expanding TEAD4's role as a YAP-independent transcriptional modulator.

    Evidence Co-IP of TEAD4–Smad2/3/4, YAP-binding mutagenesis confirming independence; ATAC-seq and H3K27ac ChIP-seq showing chromatin opening upon TEAD4 loss

    PMID:36806855 PMID:37856006

    Open questions at the time
    • Whether TEAD4–Smad interaction is direct or requires bridging factors not resolved
    • Genome-wide map of TEAD4-dependent senescence-suppressive loci incomplete
    • Single-lab findings await independent confirmation
  14. 2024 High

    NF2 was identified as a direct TEAD4-binding partner that destabilizes TEAD4 by inhibiting its palmitoylation and promoting its cytoplasmic translocation and ubiquitination, independently of LATS1/2 and YAP—providing a LATS-independent tumor-suppressive mechanism that converges directly on TEAD4.

    Evidence Reciprocal Co-IP, domain mapping, palmitoylation and ubiquitination assays, subcellular fractionation

    PMID:38522513

    Open questions at the time
    • E3 ligase responsible for NF2-induced TEAD4 ubiquitination not conclusively identified in this study
    • In vivo validation of NF2–TEAD4 axis in NF2-mutant tumors pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the mechanism by which TEAD4 is imported into mitochondria, the structural basis for differential cofactor selection (YAP/TAZ vs. VGLL family members) in a chromatin context, and whether the mitochondrial and YAP-independent transcriptional functions of TEAD4 are broadly operative across adult tissues or restricted to specific lineages.
  • No mitochondrial targeting signal or import pathway identified
  • No full-length TEAD4 ternary complex structure with DNA and cofactor
  • Tissue specificity of mitochondrial TEAD4 function unexplored beyond trophoblast

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4 GO:0016740 transferase activity 2
Localization
GO:0005634 nucleus 5 GO:0005739 mitochondrion 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3
Partners
HHEXKLF5NF2POLRMTVGLL1VGLL4WWTR1YAP1
Complex memberships
TEAD4–TCF4TEAD4–VGLL4–CtBP2YAP–TEAD4

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Tead4 coactivator YAP localizes to nuclei of outside cells of the mouse preimplantation embryo, where it activates Cdx2 and other trophoblast genes; in inside cells, Hippo pathway component Lats phosphorylates YAP, causing its cytoplasmic retention and suppression of Tead4 transcriptional activity, thereby determining trophectoderm vs. inner cell mass fate. Genetic loss-of-function (Tead4/Yap modulation in embryos and ES cells), immunofluorescence for YAP localization, Cdx2 expression readout Developmental cell High 19289085
2007 TEAD4 is required for specification of the trophectoderm lineage: Tead4-/- mouse embryos fail to express trophectoderm-specific genes (Cdx2, Eomes, Fgfr2) and instead express ICM markers (Oct4, Nanog) in all blastomeres, resulting in failure of blastocyst/blastocoel formation and pre-implantation lethality. Conditional and constitutive knockout mouse, immunofluorescence, gene expression analysis Development (Cambridge, England) High 17913785 18083014
2010 Crystal structure of the YAP-interacting C-terminal domain of TEAD4 in complex with the TEAD-interacting N-terminal domain of YAP revealed that YAP's N-terminal region folds into two short helices with an extended PXXPhiP-motif loop, and TEAD4's C-terminal domain adopts an immunoglobulin-like fold; point mutations at the interface abolished TEAD4 transforming activity. X-ray crystallography, site-directed mutagenesis, functional transformation assay Genes & development High 20123908
2010 Gata3 expression in the mouse blastocyst depends on Tead4 and acts in a parallel pathway with Cdx2 downstream of Tead4 to promote trophoblast lineage gene expression. Genetic epistasis in Tead4-/- and Cdx2-/- embryos, bioinformatic and functional genomic strategies, ES cell overexpression assays Development (Cambridge, England) High 20081188
2012 Nuclear localization of TEAD4—rather than its expression level—determines trophectoderm-specific transcription in the mouse preimplantation embryo; TEAD4 is excluded from nuclei of inner blastomeres, and forced nuclear localization of TEAD4 in inner blastomeres maintains the TE transcriptional program and prevents ICM segregation. ChIP-sequencing for genome-wide TEAD4 targets, live-cell imaging/immunofluorescence for localization, forced nuclear localization experiments in embryos Proceedings of the National Academy of Sciences of the United States of America High 22529382
2013 TEAD4 localizes to mitochondria (uniquely among TEAD family members) and is required to prevent oxidative stress during blastocoel formation; loss of Tead4 reduces mitochondrial membrane potential and elevates reactive oxygen species; blastocysts can form without TEAD4 under conditions that alleviate oxidative stress. Fluorescence imaging of ectopically expressed TEAD4 to mitochondria, ROS measurements, mitochondrial membrane potential assay, embryo culture under antioxidant conditions Development (Cambridge, England) High 23903192
2017 Crystal structure of the TEAD4 TEA domain in complex with an MCAT DNA element revealed that the α3 helix determines DNA-binding specificity through contacts with both major and minor grooves; structure-guided mutations at two interface sites abolished TEAD4 promoter occupancy, YAP-induced transactivation, and cancer cell growth. X-ray crystallography, site-directed mutagenesis, ChIP, colony formation assay Oncogene High 28368398
2017 TEAD4 associates with TCF4 to form a complex that co-binds target gene loci; VGLL4 disrupts this TEAD4–TCF4 complex, suppressing TCF4 transactivation and thereby co-regulating both Hippo–YAP and Wnt/β-catenin signaling in colorectal cancer. Co-immunoprecipitation, ChIP, luciferase reporter assay, peptide mimetic functional studies in CRC cells and mouse model Nature communications High 28051067
2018 TEAD4 localizes to mitochondria in mouse trophectoderm and trophoblast stem cells, binds mitochondrial DNA, and recruits mitochondrial RNA polymerase (POLRMT) to promote transcription of mtDNA-encoded electron transport chain components; loss of TEAD4 reduces POLRMT recruitment and impairs oxidative phosphorylation. Mitochondrial fractionation, mtDNA ChIP, POLRMT co-immunoprecipitation, mitochondrial transcription assay, OXPHOS functional assays Development (Cambridge, England) High 30201685
2013 TEAD4 nuclear localization is associated with YAP1 co-localization in gastric cancer cells, and TEAD4 knockdown reduces gastric cancer cell growth in vitro and in vivo; ChIP-seq identified novel direct TEAD4 target genes involved in cell proliferation and migration (ADM, ANG, ARID5B, CALD1, EDN2, FSCN1, OSR2). ChIP-seq, microarray, immunohistochemistry, siRNA knockdown, xenograft model Carcinogenesis Medium 24325916
2011 TEAD4 directly binds promoters of myogenin (Myogenin), CDKN1A, and Caveolin 3 to promote C2C12 myoblast differentiation, and represses CTGF to facilitate differentiation; selective shRNA knockdown of TEAD4 results in shortened myotubes and reduced expression of structural proteins and unfolded protein response genes. ChIP-chip (ChIP coupled to array hybridization), RNA-seq, shRNA knockdown in C2C12 cells, dominant-negative TEAD expression Cell death and differentiation High 21701496
2013 YAP and TAZ bind to essentially the same site on TEAD4 with similar affinities, but make critical contacts through different residues; biochemical and biophysical (surface plasmon resonance, NMR modeling) analyses define the TEAD4–YAP/TAZ binding interface. Biochemical binding assays, biophysical assays (SPR), molecular modeling/structural biology Chembiochem : a European journal of chemical biology Medium 23780915
2016 TEAD4 undergoes alternative splicing (facilitated by tumor suppressor RBM4) to produce a truncated isoform, TEAD4-S, which lacks the N-terminal DNA-binding domain but retains the YAP-interaction domain; TEAD4-S acts as a dominant-negative isoform that sequesters YAP and suppresses cancer cell proliferation and migration. Alternative splicing characterization, YAP co-IP, dominant-negative overexpression, xenograft tumor model Nature communications High 27291620
2016 RAC-TRIO signaling inhibits LATS1/2-mediated YAP phosphorylation, causing YAP to dissociate from RUNX3 and associate with TEAD4; conversely, LATS1/2-phosphorylated YAP preferentially binds RUNX3 over TEAD4, revealing a switch between two YAP-binding partners controlled by the Hippo and RAC pathways. Co-immunoprecipitation, Drosophila genetic screen (epistasis), mammalian cell overexpression/knockdown assays Oncogene High 27425596
2017 TEAD4 acylation (palmitoylation at a conserved cysteine) does not change its affinity for YAP or TAZ in biochemical and cellular assays, but significantly enhances TEAD4 protein stability, suggesting palmitoylation helps TEAD4 maintain its active conformation; mTEAD4 can catalyze autopalmitoylation and flufenamic acid inhibits this autopalmitoylation. In vitro palmitoylation assay, NMR spectroscopy, C360S mutagenesis, biochemical binding assays Protein science : a publication of the Protein Society High 28960584
2018 NMR spectroscopy identified residues in mTEAD4 that interact with compounds occupying the palmitate-binding and YAP-binding pockets; purified mTEAD4 can catalyze autopalmitoylation, and the C360S mutant abolishes palmitoylation without significantly altering YAP binding. NMR spectroscopy, fragment screening, autopalmitoylation assay, C360S mutagenesis The Biochemical journal High 29760238
2014 Vgll1-derived peptides bind to the same site on TEAD4 as YAP/TAZ, using a β-strand:loop:α-helix motif; Vgll1 lacks a key secondary structure element required for tight binding by YAP and TAZ, yet still binds with nanomolar affinity. Peptide binding assays (biochemical/biophysical), structural analysis Chembiochem : a European journal of chemical biology Medium 24504694
2019 Glucocorticoid receptor (GR) interacts with TEAD4 upon glucocorticoid treatment, forming a complex that is recruited to the TEAD4 promoter to boost TEAD4 transcription (positive autoregulatory loop), and the GC-activated TEAD4 promotes breast cancer stem cell maintenance and chemoresistance. Co-immunoprecipitation, ChIP, luciferase reporter assay, in vitro and in vivo functional assays Cancer research Medium 31289134
2021 In prostate cancer cells, arginine retains TEAD4 in the nucleus in an mTOR-dependent but YAP1-independent manner; nuclear TEAD4 is recruited to promoter/enhancer regions of OXPHOS genes, and arginine activates lysine acetyltransferases to increase histone acetylation and acetyl-CoA, facilitating TEAD4 recruitment and coordinated OXPHOS gene upregulation. ChIP, subcellular fractionation, siRNA knockdown, in vitro and xenograft in vivo models, metabolic assays Nature communications High 33893278
2019 VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and myotubes (interaction proteomics); VGLL3 does not interact with Hippo kinase cascade components (unlike YAP/TAZ), and its overexpression promotes myogenic differentiation while knockdown suppresses myoblast proliferation. Interaction proteomics (mass spectrometry), functional knockdown/overexpression, differentiation assays Journal of cell science Medium 31138678
2018 TEAD4 forms a ternary repressor complex with VGLL4 and CtBP2 to suppress adipogenesis; VGLL4 acts as an adaptor that enhances TEAD4–CtBP2 interaction; this complex occupies promoters of PPARγ and Adipoq to repress their transcription in a YAP/TAZ-independent manner. Co-immunoprecipitation, ChIP, luciferase reporter assay, siRNA knockdown in 3T3-L1 preadipocytes The Journal of biological chemistry High 30209132
2018 TEAD4 directly binds to and transcriptionally activates YAP1, identified by ChIP-qPCR and luciferase reporter assay, revealing a TEAD4→YAP1 positive transcriptional feedback loop in colorectal tumorigenesis. ChIP-qPCR, luciferase reporter assay, RNA-seq, GSEA Cell cycle (Georgetown, Tex.) Medium 29157094
2016 AP-1 factors (FOS/JUN) bind vascular genes cooperatively with TEAD4 in blood development; AP-1 is required for de novo binding of TEAD4 to cis-regulatory elements, indicating that AP-1 enables TEAD4 chromatin occupancy at specific vascular/hematopoietic loci. Genome-wide ChIP-seq, dominant-negative FOS inhibition, embryonic stem cell differentiation model Development (Cambridge, England) Medium 27802171
2020 TEAD4 directly regulates cell cycle genes in both mouse and human trophoblast stem cells (TSCs) to maintain self-renewal; loss of Tead4 in postimplantation mouse TSCs impairs self-renewal, and rescue of TEAD4 in patient-derived RPL trophoblast stem cells restores self-renewal. Genomics (RNA-seq, ChIP-seq), mouse conditional knockout, human TSC derivation and rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 32669432
2020 TEAD4 directly binds the promoter region of MNX1-AS1 and activates its transcription in gastric cancer, as demonstrated by ChIP and luciferase reporter assay. ChIP, luciferase reporter assay Molecular cancer Medium 31924214
2019 TEAD4 binds KLF5 and together they repress p27Kip1 transcription; depletion of either TEAD4 or KLF5 activates the p27 promoter and increases p27 mRNA, while p27 depletion partially rescues growth inhibition caused by TEAD4 or KLF5 knockdown in triple-negative breast cancer cells. Co-immunoprecipitation (TEAD4–KLF5 interaction), luciferase reporter assay, siRNA knockdown, xenograft model Oncotarget Medium 25970772
2016 YAP-TEAD4 complex directly binds and activates CCNE1/2 promoters in bladder cancer cells; YAP1 precipitates specifically TEAD4 (not other TEADs) in bladder cancer cells; metformin inhibits this axis via AMPKα-mediated YAP1 suppression. Co-immunoprecipitation, dual-luciferase reporter, bioinformatics, siRNA knockdown, xenograft model Journal of experimental & clinical cancer research : CR Medium 31455378
2022 HHEX physically associates with and stabilizes the YAP–TEAD4 complex at regulatory genomic loci; CK2 phosphorylates HHEX and enhances its interaction with TEAD4; CK2 inhibition (CX-4945) diminishes HHEX–TEAD4 interaction and decreases YAP/TEAD target gene expression. Co-immunoprecipitation, ChIP, CK2 kinase assay, pharmacological inhibition, colorectal cancer functional assays Nature communications High 36008411
2023 SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at regulatory genomic loci; PKCζ phosphorylates SP1 and enhances its interaction with TEAD4, boosting transcription of YAP/TEAD targets including VISTA, which suppresses CD8+ T cell anti-tumor function in colorectal cancer. Co-immunoprecipitation, ChIP, kinase assay, functional immune suppression assay Cell death and differentiation Medium 39875519
2024 NF2 directly interacts with TEAD4 through its FERM domain and C-terminal tail; NF2 decreases TEAD4 protein stability independently of LATS1/2 and YAP by inhibiting TEAD4 palmitoylation and inducing its cytoplasmic translocation, leading to TEAD4 ubiquitination; NF2–TEAD4 interaction is required for NF2's tumor suppressive function. Co-immunoprecipitation (reciprocal), domain-mapping experiments, palmitoylation assay, ubiquitination assay, subcellular fractionation, cell proliferation assay The Journal of biological chemistry High 38522513
2021 NT5DC2 interacts with unpalmitoylated TEAD4 to protect it from TRIM27-mediated K27/K48-linked ubiquitination and proteasomal degradation; TEAD4 in turn binds the NT5DC2 promoter and activates NT5DC2 transcription, forming a positive feedback loop. Co-immunoprecipitation, ubiquitination assay (identifying TRIM27 as E3 ligase and Lys278 as site), dual-luciferase assay, knockdown/xenograft Journal of cellular and molecular medicine Medium 33993634
2023 TEAD4 mitigates TGF-β signaling in a YAP-independent manner by associating with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing binding of Smad2/3 to the histone acetyltransferase p300 and suppressing target gene transcription. Co-immunoprecipitation (TEAD4–Smad2/3/4 interaction), TEAD4–YAP interaction mutagenesis, siRNA depletion of YAP/TAZ, functional xenograft model Journal of molecular cell biology Medium 36806855
2023 TEAD4 occupies H3K27ac-marked enhancer regions and prevents chromatin accessibility at senescence-activated loci; TEAD4 suppression allows chromatin opening at these enhancers, leading to increased SASP gene expression and promoting cellular senescence. ATAC-seq, ChIP-seq (H3K27ac), siRNA knockdown with SASP gene expression readout Cellular and molecular life sciences : CMLS Medium 37856006
2019 TEAD4 (with YAP1 and WWTR1/TAZ) directly represses Sox2 expression prior to the 16-cell stage in mouse embryos, preventing premature activation of the pluripotency program; this repression is sensitive to LATS kinase activity. Tead4/Yap1/Wwtr1 genetic loss-of-function in mouse embryos, ChIP/reporter evidence for direct Sox2 repression, LATS inhibitor experiments Development (Cambridge, England) Medium 31444221
1998 RTEF-1 (TEAD4 ortholog) transactivates both beta-myosin heavy chain and skeletal alpha-actin promoters and potentiates their alpha1-adrenergic responses in neonatal cardiac myocytes; the M-CAT element is required for betaMyHC but not for the SKA promoter response to RTEF-1, implying promoter-specific cofactor interactions. Cotransfection reporter assay in neonatal rat cardiac myocytes, M-CAT mutagenesis, competition gel shift assay Circulation research Medium 9670917
2000 The carboxyl-terminal domain of RTEF-1 (TEAD4 ortholog) mediates alpha1-adrenergic signaling in cardiac myocytes; site-directed mutagenesis of Ser-322 (a unique serine in RTEF-1 absent in TEF-1) reduced alpha1-adrenergic activation of RTEF-1 by 70%, identifying phosphorylation at Ser-322 as the primary mechanism. Chimeric protein construction, site-directed mutagenesis, reporter assay in neonatal rat cardiac myocytes The Journal of biological chemistry Medium 10764782
2004 RTEF-1 (TEAD4 ortholog) binds directly to the first Sp1 response element (-97 to -87) in the VEGF promoter (not to M-CAT elements) and stimulates VEGF transcription in hypoxic endothelial cells, promoting endothelial cell proliferation and vascular tube formation. Sequential deletion and site-directed mutation of VEGF promoter, EMSA, ChIP, reporter assay, tube formation/proliferation assays The Journal of biological chemistry Medium 15073166
2024 TEAD4 and TFAP2C promote embryo polarization and loss of totipotency, while paradoxically both promoting and inhibiting Hippo signaling before lineage diversification; TFAP2C and TEAD4 drive expression of Hippo regulators and promote apical domain formation (which inactivates Hippo), and asymmetric apical domain segregation resolves the bistable switch into TE (Hippo OFF) or ICM (Hippo ON) fate. Genetic loss-of-function (mouse and human embryo experiments), live imaging, transcriptomics Nature structural & molecular biology Medium 38789684
2024 VGLL1 partners with TEAD4 to regulate chromatin accessibility at target gene loci through histone acetylation, acting in cooperation with GATA3 and TFAP2C to control human trophectoderm lineage specification and trophoblast stem cell self-renewal. Co-immunoprecipitation, ATAC-seq, ChIP for histone acetylation, loss-of-function in human TELCs/TSCs Nature communications Medium 38233381
2023 YAP/TAZ–TEAD4 complex directly binds the enhancer region of CCBE1 in colorectal cancer cells and cancer-associated fibroblasts, transcriptionally upregulating CCBE1 expression, which enhances VEGFC proteolysis and promotes tumor lymphangiogenesis. ChIP, luciferase reporter assay, Co-IP, lymphatic endothelial tube formation assay, xenograft model The Journal of biological chemistry Medium 36781122
2023 YTHDF2 recognizes WTAP-mediated m6A methylation of TEAD4 mRNA to promote its stability and expression in nasopharyngeal carcinoma; up-regulated TEAD4 transcriptionally activates BZW2 to drive the AKT oncogenic pathway, independently of YAP/TAZ. m6A methylation assay, RNA immunoprecipitation (RIP), luciferase reporter assay, ChIP, functional knockdown/rescue experiments Science advances Medium 36608137

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Developmental cell 854 19289085
2007 Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development (Cambridge, England) 432 17913785
2007 Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mechanisms of development 388 18083014
2010 Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development (Cambridge, England) 376 20081188
2010 Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes & development 213 20123908
2012 Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment. Proceedings of the National Academy of Sciences of the United States of America 140 22529382
2017 VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nature communications 132 28051067
2018 Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma. Cancer discovery 127 29510988
2015 Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial-mesenchymal transition and metastasis in a YAP-independent manner. Oncogene 123 26387538
2018 miR-375 is involved in Hippo pathway by targeting YAP1/TEAD4-CTGF axis in gastric carcinogenesis. Cell death & disease 122 29367737
2020 TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2. Molecular cancer 116 31924214
2020 TEAD4 ensures postimplantation development by promoting trophoblast self-renewal: An implication in early human pregnancy loss. Proceedings of the National Academy of Sciences of the United States of America 115 32669432
2019 Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression. Cancer research 89 31289134
2013 Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer. Carcinogenesis 87 24325916
2021 Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells. Nature communications 85 33893278
2019 Metformin targets a YAP1-TEAD4 complex via AMPKα to regulate CCNE1/2 in bladder cancer cells. Journal of experimental & clinical cancer research : CR 78 31455378
2011 Transcription factor TEAD4 regulates expression of myogenin and the unfolded protein response genes during C2C12 cell differentiation. Cell death and differentiation 76 21701496
2015 The interplay between TEAD4 and KLF5 promotes breast cancer partially through inhibiting the transcription of p27Kip1. Oncotarget 75 25970772
2016 A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation. Nature communications 69 27291620
2013 TEAD4 establishes the energy homeostasis essential for blastocoel formation. Development (Cambridge, England) 69 23903192
2013 The TEAD4-YAP/TAZ protein-protein interaction: expected similarities and unexpected differences. Chembiochem : a European journal of chemical biology 68 23780915
1998 Transcription factor RTEF-1 mediates alpha1-adrenergic reactivation of the fetal gene program in cardiac myocytes. Circulation research 66 9670917
2019 VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle. Journal of cell science 63 31138678
2023 Bulk and single-cell transcriptome profiling reveal extracellular matrix mechanical regulation of lipid metabolism reprograming through YAP/TEAD4/ACADL axis in hepatocellular carcinoma. International journal of biological sciences 62 37151879
2017 Effect of the acylation of TEAD4 on its interaction with co-activators YAP and TAZ. Protein science : a publication of the Protein Society 57 28960584
2017 DNA-binding mechanism of the Hippo pathway transcription factor TEAD4. Oncogene 54 28368398
2015 Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival. International journal of cancer 51 25628125
2020 TEAD4 promotes tumor development in patients with lung adenocarcinoma via ERK signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 50 32800942
2014 miR-125a-5p impairs endothelial cell angiogenesis in aging mice via RTEF-1 downregulation. Aging cell 49 25059272
2016 Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate. Development (Cambridge, England) 46 27802171
2020 Structural and Functional Overview of TEAD4 in Cancer Biology. OncoTargets and therapy 44 33116572
2019 TEAD4, YAP1 and WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage. Development (Cambridge, England) 43 31444221
2016 RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3. Oncogene 43 27425596
2004 RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. The Journal of biological chemistry 43 15073166
2022 CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis. Nature communications 41 36008411
2018 Regulation of energy metabolism during early mammalian development: TEAD4 controls mitochondrial transcription. Development (Cambridge, England) 39 30201685
2000 Identification of the functional domain in the transcription factor RTEF-1 that mediates alpha 1-adrenergic signaling in hypertrophied cardiac myocytes. The Journal of biological chemistry 39 10764782
1996 Cloning of human RTEF-1, a transcriptional enhancer factor-1-related gene preferentially expressed in skeletal muscle: evidence for an ancient multigene family. Genomics 39 8921372
2018 Structural and ligand-binding analysis of the YAP-binding domain of transcription factor TEAD4. The Biochemical journal 38 29760238
2018 TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1. Cell cycle (Georgetown, Tex.) 36 29157094
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 36 30209132
2018 TEAD4 exerts pro-metastatic effects and is negatively regulated by miR6839-3p in lung adenocarcinoma progression. Journal of cellular and molecular medicine 33 29667772
2017 TEAD4-YAP interaction regulates tumoral growth by controlling cell-cycle arrest at the G1 phase. Biochemical and biophysical research communications 33 28315328
2023 TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma. Science advances 31 36608137
2022 TEAD4 as an Oncogene and a Mitochondrial Modulator. Frontiers in cell and developmental biology 31 35602596
2014 The surprising features of the TEAD4-Vgll1 protein-protein interaction. Chembiochem : a European journal of chemical biology 29 24504694
2022 TEAD4 regulates trophectoderm differentiation upstream of CDX2 in a GATA3-independent manner in the human preimplantation embryo. Human reproduction (Oxford, England) 27 35700449
2016 Effects of downregulating TEAD4 transcripts by RNA interference on early development of bovine embryos. The Journal of reproduction and development 24 27941302
2022 Pan-cancer analysis, cell and animal experiments revealing TEAD4 as a tumor promoter in ccRCC. Life sciences 22 35065165
2021 Hippo/TEAD4 signaling pathway as a potential target for the treatment of breast cancer. Oncology letters 22 33692845
2018 Reciprocal regulation of TEAD4 and CCN2 for the trophectoderm development of the bovine blastocyst. Reproduction (Cambridge, England) 21 29661794
2023 MAD2L1 is transcriptionally regulated by TEAD4 and promotes cell proliferation and migration in colorectal cancer. Cancer gene therapy 20 36599972
2022 Knockdown of HSP110 attenuates hypoxia-induced pulmonary hypertension in mice through suppression of YAP/TAZ-TEAD4 pathway. Respiratory research 20 35986277
2021 Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state. Molecular oncology 20 34669238
2018 Epigenetic silencing of miR-1271 enhances MEK1 and TEAD4 expression in gastric cancer. Cancer medicine 20 29862663
2021 NT5DC2 promotes leiomyosarcoma tumour cell growth via stabilizing unpalmitoylated TEAD4 and generating a positive feedback loop. Journal of cellular and molecular medicine 18 33993634
2011 RTEF-1, an upstream gene of hypoxia-inducible factor-1α, accelerates recovery from ischemia. The Journal of biological chemistry 18 21540178
2021 The transcription factor TEAD4 enhances lung adenocarcinoma progression through enhancing PKM2 mediated glycolysis. Cell biology international 17 34196069
2020 Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening. Nucleic acids research 17 31777916
2020 Deciphering a distinct regulatory network of TEAD4, CDX2 and GATA3 in humans for trophoblast transition from embryonic stem cells. Biochimica et biophysica acta. Molecular cell research 17 32389642
2021 RTEF-1 Inhibits Vascular Smooth Muscle Cell Calcification through Regulating Wnt/β-Catenin Signaling Pathway. Calcified tissue international 16 33713163
2024 Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification. Nature structural & molecular biology 15 38789684
2023 The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer. The Journal of biological chemistry 15 36781122
2010 The endothelium-dependent effect of RTEF-1 in pressure overload cardiac hypertrophy: role of VEGF-B. Cardiovascular research 15 21169295
2007 Identification of novel alternatively spliced isoforms of RTEF-1 within human ocular vascular endothelial cells and murine retina. Investigative ophthalmology & visual science 15 17652751
2024 VGLL1 cooperates with TEAD4 to control human trophectoderm lineage specification. Nature communications 14 38233381
2019 Wnt3a disrupts GR-TEAD4-PPARγ2 positive circuits and cytoskeletal rearrangement in a β-catenin-dependent manner during early adipogenesis. Cell death & disease 14 30622240
2019 A framework for TRIM21-mediated protein depletion in early mouse embryos: recapitulation of Tead4 null phenotype over three days. BMC genomics 14 31638890
2017 GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models. Oncotarget 14 28978043
2015 RTEF-1 protects against oxidative damage induced by H2O2 in human umbilical vein endothelial cells through Klotho activation. Experimental biology and medicine (Maywood, N.J.) 14 26041389
2021 The interaction of TEA domain transcription factor 4 (TEAD4) and Yes-associated protein 1 (YAP1) promoted the malignant process mediated by serum/glucocorticoid regulated kinase 1 (SGK1). Bioengineered 13 33517828
2020 TEAD4 transcriptional regulates SERPINB3/4 and affect crosstalk between keratinocytes and T cells in psoriasis. Immunobiology 13 32962824
2023 TEAD4: A key regulator of tumor metastasis and chemoresistance - Mechanisms and therapeutic implications. Biochimica et biophysica acta. Reviews on cancer 12 38072284
2012 RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium. Circulation research 12 22843786
2022 TAZ promotes vasculogenic mimicry in gastric cancer through the upregulation of TEAD4. Journal of gastroenterology and hepatology 11 35062042
2013 Expression patterns of Oct4, Cdx2, Tead4, and Yap1 proteins during blastocyst formation in embryos of the marsupial, Monodelphis domestica Wagner. Evolution & development 11 23607301
2024 Radiation-induced YAP/TEAD4 binding confers non-small cell lung cancer radioresistance via promoting NRP1 transcription. Cell death & disease 10 39187525
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 10 34396425
2021 Narciclasine is a novel YAP inhibitor that disturbs interaction between YAP and TEAD4. BBA advances 10 37082014
2018 Effect of TEAD4 on multilineage differentiation of muscle-derived stem cells. American journal of translational research 10 29636889
2025 YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer. Cell death and differentiation 9 39875519
2024 KAT6A/YAP/TEAD4 pathway modulates osteoclastogenesis by regulating the RANKL/OPG ratio on the compression side during orthodontic tooth movement. Progress in orthodontics 9 39129034
2023 Tea domain transcription factor TEAD4 mitigates TGF-β signaling and hepatocellular carcinoma progression independently of YAP. Journal of molecular cell biology 9 36806855
2023 Transcription factor TEAD4 facilitates glycolysis and proliferation of gastric cancer cells by activating PKMYT1. Molecular and cellular probes 9 37729973
2022 G-quadruplexes formation within the promoter of TEAD4 oncogene and their interaction with Vimentin. Frontiers in chemistry 9 36186582
2021 Systematic screening identifies a TEAD4-S100A13 axis modulating cisplatin sensitivity of oral squamous cell carcinoma cells. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 9 34358353
2024 TEAD4 regulates KRT8 and YAP in preimplantation embryos in mice but not in cattle. Reproduction (Cambridge, England) 8 38206180
2024 The role of TEAD4 in trophectoderm commitment and development is not conserved in non-rodent mammals. Development (Cambridge, England) 8 39171364
2016 Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor. Pediatric blood & cancer 8 27966820
2014 Endothelial differentiation gene-1, a new downstream gene is involved in RTEF-1 induced angiogenesis in endothelial cells. PloS one 8 24520353
2025 Hypoxia preconditioned MSC exosomes attenuate high-altitude cerebral edema via the miR-125a-5p/RTEF-1 axis to protect vascular endothelial cells. Bioactive materials 7 40599343
2023 TFAP2C exacerbates psoriasis-like inflammation by promoting Th17 and Th1 cells activation through regulating TEAD4 transcription. Allergologia et immunopathologia 7 37169570
2021 A novel tumor suppressor role of myosin light chain kinase splice variants through downregulation of the TEAD4/CD44 axis. Carcinogenesis 7 34000008
2020 WITHDRAWN: Circular RNA circUBA1 promotes gastric cancer proliferation and metastasis by acting as a competitive endogenous RNA through sponging miR-375 and regulating TEAD4. Cancer letters 7 32087308
2020 Rational Design and Intramolecular Cyclization of Hotspot Peptide Segments at YAP-TEAD4 Complex Interface. Protein and peptide letters 7 32286937
2025 WISP1 inhibition of YAP phosphorylation drives breast cancer growth and chemoresistance via TEAD4 activation. Anti-cancer drugs 6 39774151
2024 The tumor suppressor NF2 modulates TEAD4 stability and activity in Hippo signaling via direct interaction. The Journal of biological chemistry 6 38522513
2023 TEAD4 antagonizes cellular senescence by remodeling chromatin accessibility at enhancer regions. Cellular and molecular life sciences : CMLS 6 37856006
2022 TEAD4 nuclear localization and regulation by miR-4269 and miR-1343-3p in colorectal carcinoma. Pathology, research and practice 6 35124548
2022 TEAD4 overexpression suppresses thyroid cancer progression and metastasis in vitro by modulating Wnt signaling. Journal of biosciences 5 34951409