Affinage

TEAD4

Transcriptional enhancer factor TEF-3 · UniProt Q15561

Length
434 aa
Mass
48.3 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TEAD4 is a TEA-domain sequence-specific transcription factor that serves as the DNA-binding effector of the Hippo pathway, partnering with the co-activators YAP/TAZ to drive transcriptional programs governing cell fate, proliferation, and metabolism (PMID:19289085, PMID:20123908). Its TEA domain recognizes MCAT DNA elements through an α3 recognition helix that contacts both major and minor grooves (PMID:28368398), while a separate immunoglobulin-like C-terminal domain binds YAP/TAZ through a shared hydrophobic interface, with point mutations at this surface abolishing co-activator binding and transforming activity (PMID:20123908, PMID:23780915). This same C-terminal cavity harbors an autopalmitoylation activity; acylation is dispensable for YAP/TAZ binding but stabilizes the active conformation of the protein (PMID:29760238). The earliest defined biological role is in preimplantation development, where TEAD4 acts upstream of Cdx2/Gata3 to specify the trophectoderm lineage, with outer-versus-inner cell fate decided by nuclear-versus-cytoplasmic TEAD4 localization and by Lats-controlled nuclear YAP availability (PMID:17913785, PMID:18083014, PMID:20123908, PMID:20081188, PMID:22529382); postimplantation, TEAD4 sustains trophoblast progenitor self-renewal in mouse and human placenta by directly regulating cell-cycle genes (PMID:32669432). Beyond canonical nuclear transcription, TEAD4 uniquely localizes to mitochondria where it binds mtDNA and recruits POLRMT to drive mitochondrial transcription and oxidative phosphorylation, and it suppresses reactive oxygen species during blastocoel formation (PMID:23903192, PMID:30201685). TEAD4 activity is tuned by combinatorial cofactor exchange — VGLL1/3/4, KLF5, RUNX3, glucocorticoid receptor, HHEX, SP1, TCF4, CtBP2, and Smad2/3/4 — many engagements occurring through the same co-activator pocket and producing context-specific activation or repression, frequently independent of YAP/TAZ (PMID:24504694, PMID:28051067, PMID:30209132, PMID:27425596, PMID:31289134, PMID:36008411, PMID:25970772, PMID:36806855, PMID:39875519). Stability and localization are further controlled negatively by NF2, which inhibits palmitoylation and drives cytoplasmic translocation and ubiquitination of TEAD4 independently of LATS/YAP (PMID:38522513), and positively by m6A-YTHDF2-mediated protein stabilization (PMID:36608137). In its first-described context as cardiac/endothelial RTEF-1, TEAD4 transactivates MCAT- and Sp1-element targets including β-MyHC, VEGF, and HIF-1α, mediating α1-adrenergic responses through phosphorylation at Ser-322 and promoting angiogenesis and metabolic control (PMID:9670917, PMID:10764782, PMID:15073166, PMID:21540178). Across cancers TEAD4 promotes EMT, proliferation, lymphangiogenesis, metabolic reprogramming, and immune evasion, often via YAP-independent transcriptional outputs and feed-forward autoregulation of its own and YAP1 expression (PMID:33893278, PMID:26387538, PMID:29510988, PMID:29157094, PMID:39875519, PMID:36781122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Established TEAD4 as a required upstream determinant of the trophectoderm lineage, defining its first concrete developmental function.

    Evidence Tead4-/- mouse knockout with lineage-marker expression analysis

    PMID:17913785 PMID:18083014

    Open questions at the time
    • Did not define the cofactor driving TE-specific transcription
    • Did not address how the same factor is restricted to outer cells
  2. 2009 High

    Placed TEAD4 downstream of Hippo signaling, showing Lats/YAP control of TEAD4 transcriptional output distinguishes TE from ICM.

    Evidence Genetic epistasis and YAP localization in embryos and ES cells

    PMID:19289085

    Open questions at the time
    • Mechanism positioning TEAD4 itself differently in inner vs outer cells not resolved
    • Direct target gene set not yet mapped
  3. 2010 High

    Defined the structural basis of TEAD4-YAP coactivation and parallel downstream effectors, explaining how the complex drives transforming and trophoblast programs.

    Evidence X-ray crystallography with interface mutagenesis; genetic epistasis identifying Gata3 parallel to Cdx2

    PMID:20081188 PMID:20123908

    Open questions at the time
    • DNA-binding specificity not yet structurally defined
    • Other coactivators using the same interface not characterized
  4. 2012 High

    Showed that subcellular localization of TEAD4 itself, not just YAP, dictates the first cell-fate decision.

    Evidence ChIP-seq and forced nuclear restoration in preimplantation embryos

    PMID:22529382

    Open questions at the time
    • Molecular signal controlling TEAD4 nuclear import not identified
    • Relationship to YAP localization not fully separated
  5. 2013 High

    Revealed a non-canonical mitochondrial/ROS-suppressing role and reframed TEAD4 as essential for redox protection rather than strictly TE specification.

    Evidence Knockout under low-oxidative-stress conditions, ROS and mitochondrial membrane potential assays, subcellular localization; parallel biochemical mapping of the palmitoylation cavity

    PMID:23780915 PMID:23903192

    Open questions at the time
    • Mitochondrial import mechanism unknown
    • How nuclear and mitochondrial pools are partitioned not resolved
  6. 2014 Medium

    Demonstrated that diverse cofactors (VGLL1) engage the same TEAD4 surface as YAP/TAZ but with distinct structural requirements, foreshadowing combinatorial regulation.

    Evidence Biochemical peptide-binding and structural analysis

    PMID:24504694

    Open questions at the time
    • In-cell functional consequences of VGLL1 binding not shown here
    • Selectivity determinants among cofactors not fully mapped
  7. 2017 High

    Resolved the DNA-recognition mechanism and established functional consequences of disrupting promoter occupancy, and connected TEAD4 to Wnt signaling via TCF4.

    Evidence Crystal structure of TEA domain on MCAT DNA with mutagenesis; Co-IP/ChIP showing TEAD4-TCF4 complex disrupted by VGLL4

    PMID:28051067 PMID:28368398

    Open questions at the time
    • Genome-wide cofactor switching not quantified
    • How DNA binding integrates with cofactor pocket occupancy not addressed
  8. 2018 High

    Defined TEAD4 as a direct mitochondrial transcription factor and clarified that palmitoylation governs stability/conformation rather than coactivator binding.

    Evidence mtDNA ChIP and POLRMT Co-IP in trophoblast stem cells; NMR autopalmitoylation and C360S mutagenesis; VGLL4-CtBP2 repressor complex by Co-IP/ChIP

    PMID:28960584 PMID:29760238 PMID:30201685 PMID:30209132

    Open questions at the time
    • Whether mitochondrial TEAD4 requires palmitoylation not tested
    • Acyltransferase regulating TEAD4 in vivo not identified
  9. 2019 Medium

    Expanded the cofactor repertoire and signaling inputs, showing GR, VGLL3, and AMPK/YAP axes route TEAD4 into distinct transcriptional and proliferative programs.

    Evidence Co-IP/ChIP for GR autoregulatory loop; interaction proteomics for VGLL3; Co-IP and reporter for YAP1/TEAD4/CCNE axis

    PMID:31138678 PMID:31289134 PMID:31455378

    Open questions at the time
    • Single-method interaction evidence for several partners
    • Hierarchy among competing cofactors at shared sites unresolved
  10. 2021 High

    Established a metabolite-driven, YAP-independent mode in which arginine/mTOR retains TEAD4 in the nucleus to coordinately upregulate OXPHOS genes.

    Evidence ChIP-seq, amino acid deprivation, mTOR inhibition and metabolic assays in prostate cancer cells

    PMID:33893278

    Open questions at the time
    • Direct sensor linking arginine to TEAD4 retention not identified
    • Generalizability beyond prostate cancer not tested
  11. 2024 High

    Identified NF2 as a direct LATS/YAP-independent negative regulator controlling TEAD4 palmitoylation, localization, and ubiquitin-mediated turnover.

    Evidence Co-IP, domain mapping, palmitoylation/ubiquitination assays and localization in proliferation assays; VGLL1-chromatin accessibility and TEAD4/TFAP2C polarization studies

    PMID:38233381 PMID:38522513 PMID:38789684

    Open questions at the time
    • E3 ligase acting in the NF2 axis not defined here
    • Integration of NF2 control with mitochondrial pool unknown
  12. 2025 Medium

    Linked TEAD4 to immune evasion by showing PKCζ-phosphorylated SP1 stabilizes a TEAD4-SP1-YAP complex driving the VISTA immune checkpoint.

    Evidence Co-IP, ChIP-seq, PKCζ kinase assay and CD8+ T cell functional assays

    PMID:39875519

    Open questions at the time
    • Reciprocal validation of the ternary complex limited to one system
    • In vivo immune-checkpoint relevance not fully established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TEAD4 partitions between nuclear, cytoplasmic, and mitochondrial pools and how competing cofactors are selected at shared interfaces to specify opposing transcriptional outputs remains unresolved.
  • No unified model of localization control across compartments
  • Determinants of YAP-dependent vs YAP-independent activity not predictable
  • Quantitative cofactor competition at the C-terminal pocket not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
NF2RUNX3SP1TAZTCF4VGLL1VGLL4YAP1
Complex memberships
TEAD4-VGLL4-CtBP2TEAD4-YAP/TAZYAP-TEAD4-RUNX3YAP/TAZ-TEAD4-BRD4

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 TEAD4 is required for specification of the trophectoderm lineage in preimplantation mouse embryos; Tead4-/- embryos fail to express trophectoderm-specific genes (Cdx2, Eomes, Fgfr2) while expressing ICM-specific genes (Oct4, Nanog) in all blastomeres, demonstrating TEAD4 acts upstream of Cdx2 in TE specification. Gene knockout (Tead4-/- mice), immunofluorescence, gene expression analysis Development (Cambridge, England) High 17913785 18083014
2009 The Hippo pathway components Lats kinase and Yap regulate TEAD4 activity to distinguish trophectoderm from ICM: in outside cells, Yap localizes to nuclei and co-activates TEAD4 to induce Cdx2 and trophoblast genes; in inside cells, Lats-mediated phosphorylation retains Yap in the cytoplasm, suppressing TEAD4 transcriptional activity. Genetic epistasis, immunofluorescence of Yap localization, modulation of Tead4/Yap activity in embryos and ES cells, Cdx2 expression readout Developmental cell High 19289085
2010 Crystal structure of the YAP-interacting C-terminal domain of TEAD4 in complex with the N-terminal domain of YAP reveals an immunoglobulin-like fold in TEAD4; YAP interacts mainly through two short helices flanking a PXXPhiP motif-containing loop. Point mutations in TEAD4 at the interface abolish YAP interaction and transforming activity. X-ray crystallography, site-directed mutagenesis, functional transformation assay Genes & development High 20123908
2010 Gata3 expression in trophoblast is regulated downstream of Tead4 (and in parallel with Cdx2): Gata3 and Cdx2 act in parallel downstream of Tead4 to promote trophoblast fate, as shown by loss of both Gata3 and Cdx2 in Tead4-null embryos. Bioinformatic and functional genomic strategies, genetic epistasis in mouse embryos, ES cell differentiation assays Development (Cambridge, England) High 20081188
2012 Differential nuclear versus cytoplasmic localization of TEAD4 in outer versus inner blastomeres dictates first mammalian cell fate: TEAD4 lacks nuclear localization in inner cells, impairing TE-specific transcription. Forced nuclear restoration of TEAD4 in inner blastomeres maintains the TE transcriptional program and prevents ICM/TE segregation. ChIP-sequencing for genome-wide target identification, subcellular localization manipulation, loss-of-function in preimplantation embryos Proceedings of the National Academy of Sciences of the United States of America High 22529382
2013 TEAD4 is not required for trophectoderm specification per se but is essential for preventing oxidative stress during blastocoel formation: Tead4-/- embryos can form blastocysts and express TE genes under low-oxidative-stress culture conditions. TEAD4 suppresses reactive oxygen species (ROS) and maintains mitochondrial membrane potential. Ectopically expressed TEAD4 can localize to mitochondria as well as the nucleus—a property unique to TEAD4 among TEAD family members. Genetic knockout under altered culture conditions (low O2/antioxidant), ROS measurement, mitochondrial membrane potential assay, subcellular fractionation/localization Development (Cambridge, England) High 23903192
2013 TEAD4 binds the palmitoylation-binding hydrophobic cavity of its C-terminal domain. The YAP and TAZ co-activators bind essentially the same site on TEAD4 with similar affinities but use different residues for key contacts, as shown by biochemical and biophysical assays with peptides and molecular modeling. Biochemical binding assays (peptide affinity), biophysical assays, molecular modeling, structural biology Chembiochem : a European journal of chemical biology Medium 23780915
2014 VGLL1-derived peptides bind TEAD4 with nanomolar affinity via a β-strand:loop:α-helix motif, binding the same site used by YAP and TAZ but without the secondary structural element required by the latter two coactivators. Biochemical peptide binding assays, structural biology/molecular analysis Chembiochem : a European journal of chemical biology Medium 24504694
2011 TEAD4 occupies promoters of myogenic genes (including Myogenin, CDKN1A, Caveolin 3) in C2C12 myoblasts as shown by ChIP-chip, and is required for normal myotube differentiation; TEAD4 knockdown results in shortened myotubes and reduced expression of structural, regulatory, and unfolded protein response genes; TEAD4 represses CTGF to promote differentiation. shRNA knockdown, ChIP coupled to array hybridization (ChIP-chip), RNA-seq, dominant-negative TEAD expression Cell death and differentiation High 21701496
2017 TEAD4 forms a complex with TCF4 (TCF7L2) and co-binds target genes; VGLL4 disrupts this TEAD4-TCF4 complex to suppress TCF4 transactivation, directly linking Hippo-YAP and Wnt/β-catenin signaling at the transcription factor level in colorectal cancer. Co-immunoprecipitation, ChIP, genome-wide co-binding analysis, functional assays, VGLL4 peptide mimetic in mouse model Nature communications High 28051067
2017 Crystal structure of the TEAD4 TEA domain in complex with a muscle-CAT (MCAT) DNA element reveals that the α3 recognition helix determines DNA-binding specificity, interacting with both major and minor grooves. Mutations at two major binding-site residues substantially reduce promoter occupancy and impair YAP-induced transcription and cancer cell growth. X-ray crystallography, site-directed mutagenesis, ChIP-qPCR, colony formation assay Oncogene High 28368398
2016 The tumor suppressor RBM4 facilitates alternative splicing of TEAD4 to produce a truncated isoform TEAD4-S lacking the N-terminal DNA-binding domain but retaining the YAP-interaction domain; TEAD4-S localizes to both nucleus and cytoplasm and acts as a dominant-negative inhibitor of YAP activity, suppressing cancer cell proliferation and migration. Alternative splicing analysis, subcellular fractionation/localization, dominant-negative functional assay, xenograft mouse models, knockdown/rescue experiments Nature communications High 27291620
2018 TEAD4 localizes to mitochondria in trophoblast stem cells, binds mitochondrial DNA (mtDNA), and facilitates mitochondrial transcription by recruiting mitochondrial RNA polymerase (POLRMT). Loss of TEAD4 impairs POLRMT recruitment, reduces expression of mtDNA-encoded electron transport chain components, and inhibits oxidative phosphorylation. Mitochondrial fractionation, mtDNA ChIP, POLRMT co-immunoprecipitation, loss-of-function in trophoblast stem cells, metabolic assays Development (Cambridge, England) High 30201685
2018 TEAD4 acylation (palmitoylation) is not required for YAP or TAZ binding in biochemical and cellular assays; however, TEAD4 acylation significantly enhances its protein stability, suggesting palmitoylation helps maintain its active conformation rather than directly mediating co-activator binding. NMR studies further confirm mTEAD4 can catalyze autopalmitoylation, and flufenamic acid inhibits this reaction. NMR spectroscopy, biochemical binding assays, palmitoylation mutagenesis (C360S), in vitro autopalmitoylation assay, fragment screening The Biochemical journal High 29760238
2017 Acylation (palmitoylation) of TEAD4 does not serve as a prerequisite for YAP or TAZ binding (shown by biochemical and cellular assays comparing acylated vs. non-acylated TEAD4), but significantly enhances TEAD4 stability. Biochemical binding assays, cellular assays with acylated/non-acylated TEAD4 Protein science : a publication of the Protein Society Medium 28960584
2018 TEAD4 forms a complex with VGLL4 and CtBP2 to repress adipogenesis in 3T3-L1 preadipocytes; VGLL4 acts as an adaptor bridging TEAD4 and CtBP2; this ternary complex occupies promoters of PPARγ and Adipoq to suppress their transcription. This repression of adipogenesis is YAP/TAZ-independent. Co-immunoprecipitation, ChIP, promoter luciferase assay, siRNA knockdown with adipogenic differentiation readouts The Journal of biological chemistry High 30209132
2019 VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and myotubes (as shown by interaction proteomics); unlike YAP/TAZ, VGLL3 does not interact with Hippo kinase cascade proteins. VGLL3 mainly represses gene expression in a TEAD-dependent manner to regulate myogenesis. Interaction proteomics (affinity purification-MS), functional overexpression/knockdown with myogenic differentiation readouts Journal of cell science Medium 31138678
2016 RAC-TRIO signaling inhibits LATS1/2-mediated YAP phosphorylation, causing YAP to dissociate from RUNX3 and associate with TEAD4. RUNX3 contributes to both formation and dissociation of the YAP-TEAD4 complex, likely through formation of a YAP-TEAD4-RUNX3 ternary complex, functioning as a molecular switch between proliferative and tumor-suppressive states. Genetic epistasis in Drosophila, co-immunoprecipitation in mammalian cells, phosphorylation-deficient YAP mutants, cancer cell tumorigenicity assays Oncogene Medium 27425596
2019 Glucocorticoid receptor (GR) interacts with TEAD4 upon glucocorticoid treatment, forming a complex recruited to the TEAD4 promoter to boost its own transcription (positive autoregulatory loop). GR facilitates nuclear accumulation of TEAD4. Co-immunoprecipitation, ChIP, promoter reporter assay, nuclear fractionation, knockdown/overexpression with functional assays Cancer research Medium 31289134
2021 Arginine acts as an epigenetic regulator that retains TEAD4 in the nucleus in a YAP1-independent but mTOR-dependent manner in prostate cancer cells. Nuclear TEAD4 is recruited to promoter/enhancer regions of nuclear-encoded OXPHOS genes and mediates their coordinated upregulation. Arginine also activates lysine acetyltransferases, increasing acetyl-CoA and histone acetylation to facilitate TEAD4 chromatin recruitment. ChIP-seq, amino acid deprivation experiments, mTOR pathway inhibition, siRNA knockdown, metabolic assays, xenograft model Nature communications High 33893278
2019 Metformin inhibits BLCA cell proliferation via the AMPKα/YAP1/TEAD4/CCNE1/2 axis; YAP1 positively regulates CCNE1 and CCNE2 expression by forming a complex with TEAD4 (confirmed by Co-IP); TEAD4 is the only TEAD family member precipitated by YAP1 in bladder cancer cells. Co-immunoprecipitation, dual-luciferase reporter, bioinformatics, siRNA, xenograft model Journal of experimental & clinical cancer research : CR Medium 31455378
2015 TEAD4 promotes cell adhesion, EMT, and vimentin expression in colorectal cancer cells through a YAP-independent mechanism; a YAP-binding-defective TEAD4 mutant (Y429H) retains full ability to reverse mesenchymal-to-epithelial transition and increase vimentin expression, confirming YAP-independent transcriptional activity of TEAD4. Knockdown/rescue with TEAD4 mutant defective in YAP binding, microarray analysis, in vivo metastasis model, YAP knockdown negative control Oncogene Medium 26387538
2016 AP-1 (FOS/JUN) factors are required for de novo binding of TEAD4 to regulatory chromatin regions during vascular/hematopoietic development; AP-1 and TEAD4 co-occupy cis-regulatory hubs that regulate the balance between smooth muscle and hemogenic cell fates. Genome-wide ChIP-seq, dominant-negative FOS inhibition, ES cell differentiation assays Development (Cambridge, England) Medium 27802171
2020 TEAD4 ensures trophoblast progenitor self-renewal postimplantation; in both mouse and human, TEAD4 directly regulates cell cycle gene expression in trophoblast stem cells (TSCs). TEAD4 and its cofactor YAP1 are specifically expressed in cytotrophoblast progenitors of the first-trimester human placenta. Conditional trophoblast-specific Tead4 knockout in mouse, human TSC derivation from RPL patients, RNA-seq, ChIP-seq, functional rescue of TEAD4 expression Proceedings of the National Academy of Sciences of the United States of America High 32669432
2018 TEAD4 functions as a master regulator in a positive feedback loop with MYCN in high-risk neuroblastoma; silencing either gene collapses MYCN-amplified neuroblastoma transcriptional hallmarks and abrogates viability in vitro and in vivo. TEAD4 activity in this context is independent of the canonical Hippo coactivators YAP and TAZ. Transcriptional regulatory network analysis, gene silencing, in vitro and in vivo viability assays, multi-cohort analysis Cancer discovery Medium 29510988
2022 CK2 (casein kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4; HHEX associates with and stabilizes the YAP-TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes. A CK2 inhibitor (CX-4945) diminishes the HHEX-TEAD4 interaction, reducing target gene expression. Co-immunoprecipitation, ChIP-seq, kinase assay, CK2 inhibitor treatment, serum stimulation experiments Nature communications Medium 36008411
2024 NF2 directly interacts with TEAD4 through its FERM domain and C-terminal tail, decreasing TEAD4 protein stability independently of LATS1/2 and YAP. NF2 inhibits TEAD4 palmitoylation and induces cytoplasmic translocation of TEAD4, leading to its ubiquitination and functional inactivation. NF2-TEAD4 interaction is required for NF2's cell proliferation-suppressing activity. Co-immunoprecipitation, domain-mapping experiments, palmitoylation assay, subcellular fractionation, ubiquitination assay, cell proliferation assay The Journal of biological chemistry High 38522513
2024 TEAD4 and TFAP2C promote embryo polarization and accelerate loss of totipotency in mouse embryos; they paradoxically promote and inhibit Hippo signaling before lineage diversification, driving expression of multiple Hippo regulators while also promoting apical domain formation that inactivates Hippo. Asymmetric apical domain segregation resolves these opposing activities into TE (Hippo OFF) versus ICM (Hippo ON) fates. Genetic manipulation of TFAP2C and TEAD4, embryo polarization assays, Hippo pathway component expression analysis, live imaging Nature structural & molecular biology Medium 38789684
2022 TEAD4 directly binds the TEAD4 promoter to activate its own transcription, forming a positive feedback loop with NT5DC2 in leiomyosarcoma; NT5DC2 interacts with unpalmitoylated TEAD4 and reduces its degradation via the ubiquitin-proteasome pathway. The E3 ubiquitin ligase TRIM27 induces K27/K48-linked ubiquitination of unpalmitoylated TEAD4 at Lys278. Dual-luciferase assay, co-immunoprecipitation, ubiquitination assay, cell proliferation and in vivo xenograft assays Journal of cellular and molecular medicine Medium 33993634
2015 TEAD4 binds KLF5 and together they repress the CDK inhibitor p27 (CDKN1B) gene promoter, promoting triple-negative breast cancer cell proliferation; depletion of either TEAD4 or KLF5 activates p27 promoter and increases p27 mRNA levels. Co-immunoprecipitation, promoter reporter assay, siRNA knockdown, xenograft model Oncotarget Medium 25970772
1998 RTEF-1 (TEAD4) transactivates both the beta-myosin heavy chain and skeletal alpha-actin promoters through MCAT elements in cardiac myocytes and potentiates alpha1-adrenergic signaling responses, unlike TEF-1 which only activates betaMyHC. RTEF-1 can activate the SKA promoter through a mechanism independent of its MCAT element, suggesting promoter-specific cofactors. Cotransfection with promoter/reporter constructs in neonatal rat cardiac myocytes, MCAT mutation analysis, gel shift competition assay Circulation research Medium 9670917
2000 The C-terminal domain of RTEF-1 (TEAD4) mediates the alpha1-adrenergic response in cardiac myocytes; a single serine residue (Ser-322), not present in TEF-1, accounts for ~70% of the alpha1-adrenergic activation as demonstrated by site-directed mutagenesis, suggesting direct phosphorylation at Ser-322 by alpha1-adrenergic-dependent kinases. Chimeric protein analysis, site-directed mutagenesis of serine residues, cotransfection reporter assays in cardiac myocytes The Journal of biological chemistry Medium 10764782
2004 RTEF-1 (TEAD4) transcriptionally activates VEGF by binding to the first Sp1 element (-97 to -87) in the VEGF promoter GC-rich region, confirmed by EMSA and ChIP. This is distinct from HIF-1alpha binding and does not require MCAT elements. RTEF-1-driven VEGF activation promotes endothelial cell proliferation and vascular structure formation. Sequential deletion analysis, site-directed mutagenesis of VEGF promoter, EMSA, ChIP, endothelial cell functional assays The Journal of biological chemistry Medium 15073166
2011 RTEF-1 (TEAD4) transcriptionally regulates the HIF-1alpha gene by binding an MCAT-like element in the HIF-1alpha promoter (confirmed by ChIP). In VE-cadherin/RTEF-1 transgenic mice subjected to hindlimb ischemia, RTEF-1-driven HIF-1alpha upregulation accelerates blood flow recovery and increases capillary density. Sequential deletion of HIF-1alpha promoter, ChIP, siRNA knockdown, transgenic mouse hindlimb ischemia model The Journal of biological chemistry Medium 21540178
2023 TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, impairing the binding of Smad2/3 to the histone acetyltransferase p300, thereby suppressing TGF-β/Smad target gene transcription and HCC cell proliferation/migration. This function is independent of YAP (shown by point mutagenesis disrupting TEAD4-YAP interaction and by YAP/TAZ depletion). Co-immunoprecipitation, YAP-binding-defective mutagenesis, siRNA knockdown, xenograft model, luciferase reporter Journal of molecular cell biology Medium 36806855
2023 TEAD4 m6A methylation (mediated by WTAP) is recognized by YTHDF2, which stabilizes TEAD4 protein and leads to its aberrant upregulation in nasopharyngeal carcinoma. Upregulated TEAD4 drives NPC progression by transcriptionally activating BZW2, which induces the AKT oncogenic pathway; this activity is independent of YAP/TAZ. m6A methylation assay, YTHDF2/WTAP Co-IP and functional knockdown, ChIP and luciferase reporter for BZW2 transcription, AKT pathway analysis Science advances Medium 36608137
2024 VGLL1 partners with TEAD4 to regulate chromatin accessibility at target gene loci through histone acetylation during human trophectoderm specification and trophoblast stem cell self-renewal; VGLL1 cooperates with GATA3 and TFAP2C in this process. ChIP-seq/ATAC-seq for chromatin accessibility, histone acetylation assays, loss-of-function in human TELCs/TSCs Nature communications Medium 38233381
2020 A trophoblast-specific inter-chromosomal enhancer on chromosome 19 physically interacts with the Tead4 promoter on chromosome 6 and is required for appropriate Tead4 expression level in mouse blastocysts, as shown by chromatin conformation capture and deletion of a 1.5 kb genomic interval causing a 42% decrease in Tead4 expression. Chromatin conformation capture (3C), luciferase reporter assay, CRISPR/Cas9 enhancer deletion mouse lines, quantitative RT-PCR and RNA-seq Nucleic acids research Medium 31777916
2022 TEAD4 in TEAD4 in Tead4 knockout mouse embryos shows a dramatic decrease in nuclear YAP in outside cells of the morula, suggesting that TEAD4 directly regulates Hippo signaling (nuclear YAP localization) and trophectoderm epithelium integrity through Krt8 regulation. Bovine TEAD4 depletion does not affect CDX2, GATA3, or SOX2 expression, confirming species-specific role. Base editing for Tead4 knockout in mouse, RNA-seq, immunofluorescence for nuclear YAP and KRT8 Reproduction (Cambridge, England) Medium 38206180
2018 TEAD4 promotes colorectal tumorigenesis by directly binding the YAP1 gene promoter and transcriptionally activating YAP1 expression, establishing a TEAD4→YAP1 positive regulatory axis in CRC. ChIP-qPCR, luciferase reporter assay, RNA-seq/GSEA, siRNA knockdown with in vivo tumor growth Cell cycle (Georgetown, Tex.) Medium 29157094
2012 RTEF-1 (TEAD4) upregulates IGFBP-1 transcription by binding the insulin response element in the IGFBP-1 promoter; endothelium-specific RTEF-1 knockout mice show increased blood glucose and insulin resistance with decreased serum IGFBP-1, while RTEF-1 transgenic mice show improved glucose clearance. Transgenic/knockout mice, ChIP, promoter reporter assay with insulin response element, metabolic phenotyping Circulation research Medium 22843786
2025 PKCζ phosphorylates SP1 and enhances its interaction with TEAD4; SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes including VISTA (an immune checkpoint gene); TEAD4-SP1-YAP co-occupancy of the VISTA enhancer drives VISTA expression and CD8+ T cell suppression. Co-immunoprecipitation, ChIP-seq, kinase assay (PKCζ), luciferase reporter, T cell functional assays Cell death and differentiation Medium 39875519
2022 TEAD4 promotes YAP/TAZ-TEAD4-BRD4 complex-dependent transcriptional upregulation of CCBE1 by directly binding the CCBE1 enhancer region in CRC cells and cancer-associated fibroblasts, promoting VEGFC proteolysis and tumor lymphangiogenesis. ChIP, luciferase reporter, Co-IP, in vitro and in vivo lymphangiogenesis assays, BET inhibitor (JQ1) treatment The Journal of biological chemistry Medium 36781122
2019 TEAD4 (RTEF-1) inhibits beta-glycerophosphate-induced vascular smooth muscle cell calcification by suppressing the Wnt/β-catenin signaling pathway; RTEF-1 overexpression reduces Wnt3a and p-β-catenin (Ser675) levels while increasing phospho-β-catenin (Ser33/37), and a Wnt agonist (LiCl) reverses RTEF-1's protective effects. Overexpression/siRNA knockdown, alizarin red staining, calcium content assay, western blot pathway analysis, pharmacological rescue Calcified tissue international Medium 33713163

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 859 19289085
2007 Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development (Cambridge, England) 433 17913785
2007 Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mechanisms of development 389 18083014
2010 Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development (Cambridge, England) 378 20081188
2010 Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes & development 215 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 133 28051067
2018 Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma. Cancer discovery 131 29510988
2018 miR-375 is involved in Hippo pathway by targeting YAP1/TEAD4-CTGF axis in gastric carcinogenesis. Cell death & disease 124 29367737
2015 Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial-mesenchymal transition and metastasis in a YAP-independent manner. Oncogene 124 26387538
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 119 32669432
2020 TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2. Molecular cancer 116 31924214
2019 Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression. Cancer research 93 31289134
2013 Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer. Carcinogenesis 88 24325916
2021 Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells. Nature communications 87 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 80 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
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 67 37151879
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
2017 Effect of the acylation of TEAD4 on its interaction with co-activators YAP and TAZ. Protein science : a publication of the Protein Society 60 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) 44 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 42 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 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
2018 TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1. Cell cycle (Georgetown, Tex.) 36 29157094
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 32 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
2021 Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state. Molecular oncology 22 34669238
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
2018 Epigenetic silencing of miR-1271 enhances MEK1 and TEAD4 expression in gastric cancer. Cancer medicine 20 29862663
2021 RTEF-1 Inhibits Vascular Smooth Muscle Cell Calcification through Regulating Wnt/β-Catenin Signaling Pathway. Calcified tissue international 18 33713163
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
2024 Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification. Nature structural & molecular biology 16 38789684
2023 The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer. The Journal of biological chemistry 15 36781122
2019 A framework for TRIM21-mediated protein depletion in early mouse embryos: recapitulation of Tead4 null phenotype over three days. BMC genomics 15 31638890
2017 GTSE1: a novel TEAD4-E2F1 target gene involved in cell protrusions formation in triple-negative breast cancer cell models. Oncotarget 15 28978043
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
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 14 33517828
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
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
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
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
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
2025 YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer. Cell death and differentiation 10 39875519
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 10 40599343
2024 Radiation-induced YAP/TEAD4 binding confers non-small cell lung cancer radioresistance via promoting NRP1 transcription. Cell death & disease 10 39187525
2022 G-quadruplexes formation within the promoter of TEAD4 oncogene and their interaction with Vimentin. Frontiers in chemistry 10 36186582
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
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
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 The YAP/TEAD4 transcriptional complex in intestinal macrophages promotes M2 polarization and alleviates DSS-induced colitis via the regulation of C/EBPβ. Scientific reports 7 40189621
2024 The tumor suppressor NF2 modulates TEAD4 stability and activity in Hippo signaling via direct interaction. The Journal of biological chemistry 7 38522513
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 TEAD3 and TEAD4 play overlapping role in bovine preimplantation development. Reproduction (Cambridge, England) 6 39679917
2022 TEAD4 nuclear localization and regulation by miR-4269 and miR-1343-3p in colorectal carcinoma. Pathology, research and practice 6 35124548
2020 Gene Silencing of Transcription Factor TEAD4 Inhibits Esophageal Cancer Cells by Regulating TCF7. Cancer biotherapy & radiopharmaceuticals 6 32822226

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