{"gene":"TEAD3","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":1997,"finding":"Human TEAD3 (hTEF-5) binds cooperatively to tandemly repeated functional elements (GT-IIC and SphI/SphII enhansons) in the human chorionic somatomammotropin-B gene enhancer, and a single base mutation disrupting these sites abolishes binding; monoclonal antibodies against the TEA domain block binding of the endogenous placental factor, identifying it as a TEAD family member.","method":"Electrophoretic mobility shift assay (EMSA), monoclonal antibody supershift, site-directed mutagenesis of natural variant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro DNA-binding assay with mutagenesis, antibody interference, and cooperative binding characterization in a single rigorous study","pmids":["9148898"],"is_preprint":false},{"year":1999,"finding":"Full-length TEAD3 (TEF-5) protein (~53 kDa generated in vitro) binds specifically to GT-IIC and SphI/SphII oligonucleotides and transactivates the human chorionic somatomammotropin enhancer and SV40 enhancer (including artificial GT-IIC repeat enhancers) but not OCT enhancers; elements within the 5' untranslated region or translation initiation context are required for its transactivation function.","method":"In vitro transcription/translation, EMSA, transient transfection reporter assay in BeWo cells, deletion/mutation analysis of untranslated regions","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding assay plus cell-based transactivation with multiple constructs, single rigorous study","pmids":["10379887"],"is_preprint":false},{"year":2002,"finding":"TEAD3 (DTEF-1) is phosphorylated in vivo, and α1-adrenergic stimulation increases while phosphatase treatment decreases its MCAT element binding activity in neonatal rat cardiac myocytes; a TEF-1/DTEF-1 chimera localises the α1-adrenergic responsiveness to the DTEF-1 portion, and endogenous DTEF-1 accounts for up to 5% of MCAT binding activity.","method":"32P orthophosphate labeling, epitope-tag immunoprecipitation, EMSA, chimeric factor analysis, phosphatase treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct phosphorylation detection by metabolic labeling plus functional EMSA with phosphatase and domain-swap chimera, single rigorous study","pmids":["11986313"],"is_preprint":false},{"year":2019,"finding":"VGLL3 interacts with TEAD1, TEAD3, and TEAD4 (but not with Hippo kinase cascade components) in myoblasts and/or myotubes; unlike YAP/TAZ, the VGLL3-TEAD interaction does not involve the Hippo kinase cascade, and VGLL3 operates through these TEADs to regulate myogenic genes including Myf5, Pitx2, Pitx3, and certain Wnts/IGFBPs.","method":"Interaction proteomics (co-immunoprecipitation mass spectrometry), siRNA knockdown, overexpression, reporter assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction proteomics with functional siRNA and OE validation, replicated across cell types","pmids":["31138678"],"is_preprint":false},{"year":2019,"finding":"YAP physically interacts with TEAD3 during cardiovascular progenitor cell (CVPC) differentiation; RNAi-mediated silencing of TEAD3 mimics YAP inhibition by blocking cardiomyocyte differentiation from hiPSCs, retaining cells at the CVPC stage.","method":"Co-immunoprecipitation, siRNA knockdown, verteporfin pharmacological inhibition, hiPSC differentiation assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus phenotypic KD validation, single lab study","pmids":["31541452"],"is_preprint":false},{"year":2021,"finding":"TEAD3 contains a palmitoylation pocket that can be covalently engaged; a covalent TEAD3-selective inhibitor (DC-TEAD3in03) achieves >100-fold selectivity over TEAD1/2/4 in activity-based protein profiling (ABPP), inhibits TEAD3 transcriptional activity in GAL4-TEAD reporter assays, and reduces growth of zebrafish caudal fins, demonstrating TEAD3 activity is required for proportional appendage growth.","method":"Activity-based protein profiling (ABPP), covalent chemistry optimization, GAL4-TEAD reporter assay, zebrafish fin growth assay","journal":"Acta pharmaceutica sinica. B","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical ABPP assay with IC50 determination, cell-based reporter, and in vivo zebrafish model in a single rigorous study","pmids":["34729310"],"is_preprint":false},{"year":2023,"finding":"MALAT1 lncRNA binds TEAD3 protein in macrophages/osteoclasts, blocking TEAD3 from binding and activating NFATC1, a master regulator of osteoclastogenesis; loss of Malat1 in mice promotes osteoclast differentiation and osteoporosis, which is rescued by Malat1 add-back.","method":"RNA-protein interaction assay (MALAT1-TEAD3 binding), genetic knockout and rescue in mice, gene expression analysis","journal":"Research square (PREPRINT)","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-protein binding plus in vivo genetic rescue, but preprint only","pmids":["36993303"],"is_preprint":true},{"year":2025,"finding":"TEAD1 and TEAD3 are required for HLA-G transcription in human extravillous trophoblasts in a YAP-independent manner; identified by genome-wide CRISPR-Cas9 knockout screen and validated as trans-acting factors at trophoblast-specific cis-regulatory elements controlling HLA-G.","method":"Genome-wide CRISPR-Cas9 knockout screen, functional validation in EVT cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genome-wide CRISPR screen with functional validation establishing YAP-independent transcriptional requirement","pmids":["40096597"],"is_preprint":false},{"year":2025,"finding":"TEAD3 and TEAD4 play redundant roles in bovine preimplantation development: single TEAD3 knockdown does not prevent blastocyst formation, but combined disruption of TEAD3 and TEAD4 blocks blastocyst progression and downregulates trophectoderm lineage genes KRT8, KRT18, and EZR and Hippo pathway components.","method":"RNA interference knockdown, base editing, single-cell RNA sequencing, RNA sequencing, immunofluorescence","journal":"Reproduction (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with multiple orthogonal readouts (RNA-seq, IF, base editing) establishing functional redundancy","pmids":["39679917"],"is_preprint":false},{"year":2025,"finding":"In Schwann cells, RhoA signals through a YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis to regulate microtubule dynamics and myelination; RhoA conditional knockout reduces TEAD3-dependent CDK2 expression, causing hypomyelination, which is rescued by CDK2 overexpression.","method":"Conditional RhoA knockout in mice, bulk RNA sequencing, in vivo and in vitro overexpression, pharmacological inhibition, myelination functional assays","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with rescue, in vivo myelination phenotype, pathway epistasis; TEAD3-specific role inferred from pathway placement rather than direct TEAD3 KO","pmids":["41178531"],"is_preprint":false},{"year":2025,"finding":"Pharmacological inhibition of TEAD3 (but not pan-YAP/TAZ-TEAD inhibition) specifically affects sterol/cholesterol biosynthetic and metabolic processes without altering cell proliferation in glioblastoma stem cells, revealing a TEAD3-specific transcriptional role in cholesterol homeostasis.","method":"TEAD3-selective pharmacological inhibition, patient-derived glioblastoma stem cell cultures, transcriptomic analysis","journal":"Brain pathology (Zurich, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2–3 — pharmacological inhibition in up to five cell lines with transcriptomic readout, single lab study","pmids":["40457844"],"is_preprint":false},{"year":2026,"finding":"TEAD3 is methylated at arginine 55 (R55) within its TEA domain DNA-binding region; disruption of R55 methylation (R55K mutation) promotes TEAD3 homodimer condensate formation that spatially sequesters RUNX2, suppressing its transcriptional activity and inhibiting osteogenic differentiation, without disrupting Hippo signaling functions; R55K also confers heightened sensitivity to the TEA domain-targeting inhibitory peptide TEAi.","method":"Arginine methylation mapping, R55K mutagenesis, co-condensate/phase separation imaging, reporter assays, PDLSC osteogenic differentiation assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 — PTM identification with site-specific mutagenesis, mechanistic condensate imaging, functional differentiation assay, and inhibitor sensitivity in a single rigorous study","pmids":["41556418"],"is_preprint":false}],"current_model":"TEAD3 is a TEA-domain transcription factor that binds MCAT/GT-IIC/SphI elements to transactivate target genes (including HSD3B, HCS enhancers, and trophectoderm genes), interacts with co-activators YAP and VGLL3 (and is blocked by MALAT1 lncRNA from binding NFATC1), is regulated post-translationally by phosphorylation (modulating DNA-binding in cardiac myocytes) and arginine methylation at R55 (controlling homodimerization/condensate formation and RUNX2 sequestration during osteogenesis), harbors a palmitoylation pocket that can be covalently targeted for isoform-selective inhibition, and operates in a YAP1/TEAD3/CDK2 axis downstream of RhoA to control Schwann cell myelination and in HLA-G transcription in trophoblasts in a YAP-independent manner."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that TEAD3 directly and cooperatively binds GT-IIC/SphI enhancer elements answered the fundamental question of which transcription factor family member engages placental enhancers, grounding TEAD3 as a sequence-specific DNA-binding protein.","evidence":"EMSA with monoclonal antibody supershift and site-directed mutagenesis of the human chorionic somatomammotropin-B enhancer","pmids":["9148898"],"confidence":"High","gaps":["Cooperativity mechanism at the structural level not resolved","In vivo chromatin occupancy not tested"]},{"year":1999,"claim":"Demonstrating that full-length TEAD3 transactivates GT-IIC-dependent enhancers but not unrelated (OCT) enhancers established TEAD3 as an activating transcription factor with target-element specificity, and identified a role for its 5′ UTR in controlling protein production.","evidence":"In vitro transcription/translation, EMSA, and transient reporter assays in BeWo trophoblast cells","pmids":["10379887"],"confidence":"High","gaps":["Activation domain boundaries not mapped","Endogenous chromatin targets not identified"]},{"year":2002,"claim":"Showing that TEAD3 is phosphorylated in vivo and that α1-adrenergic signaling enhances its DNA-binding activity in cardiac myocytes revealed the first post-translational regulatory mechanism for this factor, linking it to signal-responsive gene control in the heart.","evidence":"32P metabolic labeling, immunoprecipitation, EMSA with phosphatase treatment, and TEF-1/DTEF-1 chimeric factor analysis in neonatal rat cardiomyocytes","pmids":["11986313"],"confidence":"High","gaps":["Specific phosphorylation sites not mapped","Responsible kinase not identified","Downstream cardiac gene targets not determined"]},{"year":2019,"claim":"Identification of VGLL3 as a Hippo-kinase-independent TEAD3 co-activator in myoblasts, alongside the YAP-TEAD3 interaction during cardiomyocyte differentiation, established that TEAD3 integrates inputs from multiple co-activator families to control distinct transcriptional programs.","evidence":"Co-IP mass spectrometry and siRNA/overexpression in myoblasts (VGLL3); Co-IP and siRNA in hiPSC-derived cardiovascular progenitors (YAP)","pmids":["31138678","31541452"],"confidence":"High","gaps":["Whether VGLL3 and YAP compete for the same TEAD3 interface not tested","Direct promoter occupancy by VGLL3-TEAD3 not shown"]},{"year":2021,"claim":"Discovery that a covalent inhibitor targeting the TEAD3 palmitoylation pocket achieves >100-fold isoform selectivity demonstrated that TEAD paralogs have druggably distinct lipid-binding sites, and that TEAD3 activity is required for zebrafish appendage growth.","evidence":"Activity-based protein profiling, GAL4-TEAD reporter assays, and zebrafish caudal fin growth assay","pmids":["34729310"],"confidence":"High","gaps":["Crystal structure of inhibitor-TEAD3 complex not reported","Selectivity mechanism at atomic level unknown"]},{"year":2025,"claim":"Multiple studies converged to define TEAD3's YAP-independent functions: TEAD3 is required for HLA-G transcription in trophoblasts without YAP involvement, and TEAD3-selective inhibition in glioblastoma stem cells specifically disrupts cholesterol biosynthesis genes rather than proliferation, separating TEAD3's transcriptional outputs from canonical Hippo-YAP signaling.","evidence":"Genome-wide CRISPR knockout screen in extravillous trophoblasts; TEAD3-selective pharmacological inhibition with transcriptomics in patient-derived glioblastoma stem cells","pmids":["40096597","40457844"],"confidence":"High","gaps":["Mechanism of YAP-independent TEAD3 activation unknown","Cholesterol pathway regulation not validated by genetic TEAD3 knockout","Cofactor(s) mediating YAP-independent activity not identified"]},{"year":2025,"claim":"Establishing functional redundancy between TEAD3 and TEAD4 in trophectoderm specification, and positioning TEAD3 within a RhoA/YAP1/CDK2 axis controlling Schwann cell myelination, expanded TEAD3's known developmental roles and placed it within a defined signaling epistasis in the peripheral nervous system.","evidence":"RNAi and base editing with scRNA-seq in bovine preimplantation embryos; conditional RhoA knockout with CDK2 rescue in mouse Schwann cells","pmids":["39679917","41178531"],"confidence":"Medium","gaps":["TEAD3-specific contribution versus TEAD4 in trophectoderm not separable by single KD","Direct TEAD3 knockout in Schwann cells not performed","TEAD3-CDK2 promoter occupancy not demonstrated"]},{"year":2026,"claim":"Identification of R55 arginine methylation as a switch controlling TEAD3 homodimerization, condensate formation, and RUNX2 sequestration during osteogenesis revealed a non-canonical PTM mechanism that operates independently of Hippo signaling and governs lineage commitment via phase separation.","evidence":"Arginine methylation mapping, R55K mutagenesis, phase-separation imaging, reporter assays, and PDLSC osteogenic differentiation","pmids":["41556418"],"confidence":"High","gaps":["Methyltransferase responsible for R55 methylation not identified","In vivo bone phenotype not reported","Whether R55 methylation status changes dynamically during differentiation not tracked"]},{"year":null,"claim":"Key open questions include the identity of kinases and methyltransferases that regulate TEAD3, the structural basis for isoform-selective drug binding, the cofactors mediating YAP-independent transcription, and whether TEAD3 condensate formation is a general regulatory mechanism across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No kinase identified for signal-responsive phosphorylation","No methyltransferase identified for R55","No genome-wide chromatin occupancy map for TEAD3 in any tissue","Structural basis of palmitoylation pocket isoform selectivity unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,10,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,7,11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8,9]}],"complexes":[],"partners":["YAP1","VGLL3","TEAD4","RUNX2","TEAD1"],"other_free_text":[]},"mechanistic_narrative":"TEAD3 is a TEA-domain transcription factor that binds MCAT/GT-IIC/SphI enhancer elements to activate gene expression programs in placental trophoblasts, cardiac myocytes, myoblasts, Schwann cells, and osteogenic progenitors. TEAD3 cooperates with the co-activators YAP and VGLL3 to drive target gene transcription, but also functions in YAP-independent contexts such as HLA-G regulation in extravillous trophoblasts and cholesterol biosynthesis gene control in glioblastoma stem cells [PMID:31138678, PMID:40096597, PMID:40457844]. Its DNA-binding activity is modulated by phosphorylation downstream of α1-adrenergic signaling and by arginine methylation at R55, which controls TEA-domain homodimerization and condensate formation that can sequester RUNX2 to suppress osteogenic differentiation [PMID:11986313, PMID:41556418]. TEAD3 harbors a palmitoylation pocket enabling isoform-selective covalent inhibition, and it acts redundantly with TEAD4 in trophectoderm specification during preimplantation development [PMID:34729310, PMID:39679917]."},"prefetch_data":{"uniprot":{"accession":"Q99594","full_name":"Transcriptional enhancer factor TEF-5","aliases":["DTEF-1","TEA domain family member 3","TEAD-3"],"length_aa":435,"mass_kda":48.7,"function":"Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99594/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEAD3","classification":"Not Classified","n_dependent_lines":184,"n_total_lines":1208,"dependency_fraction":0.152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEAD3","total_profiled":1310},"omim":[{"mim_id":"614135","title":"EPIPHYSEAL DYSPLASIA, MULTIPLE, 6; EDM6","url":"https://www.omim.org/entry/614135"},{"mim_id":"614134","title":"STICKLER SYNDROME, TYPE IV; STL4","url":"https://www.omim.org/entry/614134"},{"mim_id":"603170","title":"TEA DOMAIN FAMILY MEMBER 3; TEAD3","url":"https://www.omim.org/entry/603170"},{"mim_id":"601729","title":"TEA DOMAIN FAMILY MEMBER 2; TEAD2","url":"https://www.omim.org/entry/601729"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEAD3"},"hgnc":{"alias_symbol":["TEF-5","ETFR-1"],"prev_symbol":["TEAD5"]},"alphafold":{"accession":"Q99594","domains":[{"cath_id":"-","chopping":"38-137","consensus_level":"high","plddt":76.4077,"start":38,"end":137},{"cath_id":"2.70.50.80","chopping":"226-434","consensus_level":"high","plddt":91.4667,"start":226,"end":434}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99594","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99594-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99594-F1-predicted_aligned_error_v6.png","plddt_mean":75.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEAD3","jax_strain_url":"https://www.jax.org/strain/search?query=TEAD3"},"sequence":{"accession":"Q99594","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99594.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99594/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99594"}},"corpus_meta":[{"pmid":"31138678","id":"PMC_31138678","title":"VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31138678","citation_count":63,"is_preprint":false},{"pmid":"9148898","id":"PMC_9148898","title":"Human TEF-5 is preferentially expressed in placenta and binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9148898","citation_count":61,"is_preprint":false},{"pmid":"34729310","id":"PMC_34729310","title":"Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/34729310","citation_count":41,"is_preprint":false},{"pmid":"31541452","id":"PMC_31541452","title":"YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31541452","citation_count":28,"is_preprint":false},{"pmid":"10379887","id":"PMC_10379887","title":"Human placental TEF-5 transactivates the human chorionic somatomammotropin gene enhancer.","date":"1999","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10379887","citation_count":25,"is_preprint":false},{"pmid":"11986313","id":"PMC_11986313","title":"Mouse DTEF-1 (ETFR-1, TEF-5) is a transcriptional activator in alpha 1-adrenergic agonist-stimulated cardiac myocytes.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11986313","citation_count":23,"is_preprint":false},{"pmid":"36907139","id":"PMC_36907139","title":"TEAD3 inhibits the proliferation and metastasis of prostate cancer via suppressing ADRBK2.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36907139","citation_count":6,"is_preprint":false},{"pmid":"40096597","id":"PMC_40096597","title":"The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40096597","citation_count":5,"is_preprint":false},{"pmid":"39679917","id":"PMC_39679917","title":"TEAD3 and TEAD4 play overlapping role in bovine preimplantation development.","date":"2025","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39679917","citation_count":5,"is_preprint":false},{"pmid":"21293071","id":"PMC_21293071","title":"Gene silencing of Tead3 abrogates radiation-induced adaptive response in cultured mouse limb bud cells.","date":"2011","source":"Journal of radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/21293071","citation_count":3,"is_preprint":false},{"pmid":"40457844","id":"PMC_40457844","title":"Hippo pathway effectors are associated with glioma patient survival, control cell proliferation and sterol metabolism through TEAD3.","date":"2025","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40457844","citation_count":2,"is_preprint":false},{"pmid":"22775265","id":"PMC_22775265","title":"Molecular characterization of the porcine TEAD3 (TEF-5) gene: examination of a promoter mutation as the causal mutation of a quantitative trait loci affecting the androstenone level in boar fat.","date":"2011","source":"Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/22775265","citation_count":2,"is_preprint":false},{"pmid":"36993303","id":"PMC_36993303","title":"Long noncoding RNA Malat1 inhibits Tead3-Nfatc1-mediated osteoclastogenesis to suppress osteoporosis and bone metastasis.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/36993303","citation_count":1,"is_preprint":false},{"pmid":"41178531","id":"PMC_41178531","title":"RhoA Enhances Schwann Cell Microtubule Dynamics and Myelination via a YAP1/TEAD3/CDK2/ASPM/p60-Katanin Axis.","date":"2025","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/41178531","citation_count":1,"is_preprint":false},{"pmid":"41556418","id":"PMC_41556418","title":"Arginine Methylation Antagonizes TEAD3-Mediated Repression to Promote Osteogenic Differentiation by Disrupting RUNX2-Sequestrating Condensates.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41556418","citation_count":0,"is_preprint":false},{"pmid":"41034991","id":"PMC_41034991","title":"TEAD3 + high-risk melanoma cells crosstalk with GAS6 + macrophages via the GAS6-TYRO3 ligand-receptor axis to modulate propionate metabolism and drive melanoma progression.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41034991","citation_count":0,"is_preprint":false},{"pmid":"41711168","id":"PMC_41711168","title":"Novel EWSR1::TEAD3 Fusion in an Adolescent With a Highly Aggressive Peritoneal Mesothelioma.","date":"2026","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41711168","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9952,"output_tokens":3203,"usd":0.03895},"stage2":{"model":"claude-opus-4-6","input_tokens":6566,"output_tokens":2454,"usd":0.14127},"total_usd":0.18022,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human TEAD3 (hTEF-5) binds cooperatively to tandemly repeated functional elements (GT-IIC and SphI/SphII enhansons) in the human chorionic somatomammotropin-B gene enhancer, and a single base mutation disrupting these sites abolishes binding; monoclonal antibodies against the TEA domain block binding of the endogenous placental factor, identifying it as a TEAD family member.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), monoclonal antibody supershift, site-directed mutagenesis of natural variant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro DNA-binding assay with mutagenesis, antibody interference, and cooperative binding characterization in a single rigorous study\",\n      \"pmids\": [\"9148898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length TEAD3 (TEF-5) protein (~53 kDa generated in vitro) binds specifically to GT-IIC and SphI/SphII oligonucleotides and transactivates the human chorionic somatomammotropin enhancer and SV40 enhancer (including artificial GT-IIC repeat enhancers) but not OCT enhancers; elements within the 5' untranslated region or translation initiation context are required for its transactivation function.\",\n      \"method\": \"In vitro transcription/translation, EMSA, transient transfection reporter assay in BeWo cells, deletion/mutation analysis of untranslated regions\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding assay plus cell-based transactivation with multiple constructs, single rigorous study\",\n      \"pmids\": [\"10379887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TEAD3 (DTEF-1) is phosphorylated in vivo, and α1-adrenergic stimulation increases while phosphatase treatment decreases its MCAT element binding activity in neonatal rat cardiac myocytes; a TEF-1/DTEF-1 chimera localises the α1-adrenergic responsiveness to the DTEF-1 portion, and endogenous DTEF-1 accounts for up to 5% of MCAT binding activity.\",\n      \"method\": \"32P orthophosphate labeling, epitope-tag immunoprecipitation, EMSA, chimeric factor analysis, phosphatase treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct phosphorylation detection by metabolic labeling plus functional EMSA with phosphatase and domain-swap chimera, single rigorous study\",\n      \"pmids\": [\"11986313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL3 interacts with TEAD1, TEAD3, and TEAD4 (but not with Hippo kinase cascade components) in myoblasts and/or myotubes; unlike YAP/TAZ, the VGLL3-TEAD interaction does not involve the Hippo kinase cascade, and VGLL3 operates through these TEADs to regulate myogenic genes including Myf5, Pitx2, Pitx3, and certain Wnts/IGFBPs.\",\n      \"method\": \"Interaction proteomics (co-immunoprecipitation mass spectrometry), siRNA knockdown, overexpression, reporter assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction proteomics with functional siRNA and OE validation, replicated across cell types\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP physically interacts with TEAD3 during cardiovascular progenitor cell (CVPC) differentiation; RNAi-mediated silencing of TEAD3 mimics YAP inhibition by blocking cardiomyocyte differentiation from hiPSCs, retaining cells at the CVPC stage.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, verteporfin pharmacological inhibition, hiPSC differentiation assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus phenotypic KD validation, single lab study\",\n      \"pmids\": [\"31541452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEAD3 contains a palmitoylation pocket that can be covalently engaged; a covalent TEAD3-selective inhibitor (DC-TEAD3in03) achieves >100-fold selectivity over TEAD1/2/4 in activity-based protein profiling (ABPP), inhibits TEAD3 transcriptional activity in GAL4-TEAD reporter assays, and reduces growth of zebrafish caudal fins, demonstrating TEAD3 activity is required for proportional appendage growth.\",\n      \"method\": \"Activity-based protein profiling (ABPP), covalent chemistry optimization, GAL4-TEAD reporter assay, zebrafish fin growth assay\",\n      \"journal\": \"Acta pharmaceutica sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical ABPP assay with IC50 determination, cell-based reporter, and in vivo zebrafish model in a single rigorous study\",\n      \"pmids\": [\"34729310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MALAT1 lncRNA binds TEAD3 protein in macrophages/osteoclasts, blocking TEAD3 from binding and activating NFATC1, a master regulator of osteoclastogenesis; loss of Malat1 in mice promotes osteoclast differentiation and osteoporosis, which is rescued by Malat1 add-back.\",\n      \"method\": \"RNA-protein interaction assay (MALAT1-TEAD3 binding), genetic knockout and rescue in mice, gene expression analysis\",\n      \"journal\": \"Research square (PREPRINT)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein binding plus in vivo genetic rescue, but preprint only\",\n      \"pmids\": [\"36993303\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEAD1 and TEAD3 are required for HLA-G transcription in human extravillous trophoblasts in a YAP-independent manner; identified by genome-wide CRISPR-Cas9 knockout screen and validated as trans-acting factors at trophoblast-specific cis-regulatory elements controlling HLA-G.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, functional validation in EVT cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen with functional validation establishing YAP-independent transcriptional requirement\",\n      \"pmids\": [\"40096597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEAD3 and TEAD4 play redundant roles in bovine preimplantation development: single TEAD3 knockdown does not prevent blastocyst formation, but combined disruption of TEAD3 and TEAD4 blocks blastocyst progression and downregulates trophectoderm lineage genes KRT8, KRT18, and EZR and Hippo pathway components.\",\n      \"method\": \"RNA interference knockdown, base editing, single-cell RNA sequencing, RNA sequencing, immunofluorescence\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with multiple orthogonal readouts (RNA-seq, IF, base editing) establishing functional redundancy\",\n      \"pmids\": [\"39679917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Schwann cells, RhoA signals through a YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis to regulate microtubule dynamics and myelination; RhoA conditional knockout reduces TEAD3-dependent CDK2 expression, causing hypomyelination, which is rescued by CDK2 overexpression.\",\n      \"method\": \"Conditional RhoA knockout in mice, bulk RNA sequencing, in vivo and in vitro overexpression, pharmacological inhibition, myelination functional assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with rescue, in vivo myelination phenotype, pathway epistasis; TEAD3-specific role inferred from pathway placement rather than direct TEAD3 KO\",\n      \"pmids\": [\"41178531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pharmacological inhibition of TEAD3 (but not pan-YAP/TAZ-TEAD inhibition) specifically affects sterol/cholesterol biosynthetic and metabolic processes without altering cell proliferation in glioblastoma stem cells, revealing a TEAD3-specific transcriptional role in cholesterol homeostasis.\",\n      \"method\": \"TEAD3-selective pharmacological inhibition, patient-derived glioblastoma stem cell cultures, transcriptomic analysis\",\n      \"journal\": \"Brain pathology (Zurich, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pharmacological inhibition in up to five cell lines with transcriptomic readout, single lab study\",\n      \"pmids\": [\"40457844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TEAD3 is methylated at arginine 55 (R55) within its TEA domain DNA-binding region; disruption of R55 methylation (R55K mutation) promotes TEAD3 homodimer condensate formation that spatially sequesters RUNX2, suppressing its transcriptional activity and inhibiting osteogenic differentiation, without disrupting Hippo signaling functions; R55K also confers heightened sensitivity to the TEA domain-targeting inhibitory peptide TEAi.\",\n      \"method\": \"Arginine methylation mapping, R55K mutagenesis, co-condensate/phase separation imaging, reporter assays, PDLSC osteogenic differentiation assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — PTM identification with site-specific mutagenesis, mechanistic condensate imaging, functional differentiation assay, and inhibitor sensitivity in a single rigorous study\",\n      \"pmids\": [\"41556418\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD3 is a TEA-domain transcription factor that binds MCAT/GT-IIC/SphI elements to transactivate target genes (including HSD3B, HCS enhancers, and trophectoderm genes), interacts with co-activators YAP and VGLL3 (and is blocked by MALAT1 lncRNA from binding NFATC1), is regulated post-translationally by phosphorylation (modulating DNA-binding in cardiac myocytes) and arginine methylation at R55 (controlling homodimerization/condensate formation and RUNX2 sequestration during osteogenesis), harbors a palmitoylation pocket that can be covalently targeted for isoform-selective inhibition, and operates in a YAP1/TEAD3/CDK2 axis downstream of RhoA to control Schwann cell myelination and in HLA-G transcription in trophoblasts in a YAP-independent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEAD3 is a TEA-domain transcription factor that binds MCAT/GT-IIC/SphI enhancer elements to activate gene expression programs in placental trophoblasts, cardiac myocytes, myoblasts, Schwann cells, and osteogenic progenitors. TEAD3 cooperates with the co-activators YAP and VGLL3 to drive target gene transcription, but also functions in YAP-independent contexts such as HLA-G regulation in extravillous trophoblasts and cholesterol biosynthesis gene control in glioblastoma stem cells [PMID:31138678, PMID:40096597, PMID:40457844]. Its DNA-binding activity is modulated by phosphorylation downstream of α1-adrenergic signaling and by arginine methylation at R55, which controls TEA-domain homodimerization and condensate formation that can sequester RUNX2 to suppress osteogenic differentiation [PMID:11986313, PMID:41556418]. TEAD3 harbors a palmitoylation pocket enabling isoform-selective covalent inhibition, and it acts redundantly with TEAD4 in trophectoderm specification during preimplantation development [PMID:34729310, PMID:39679917].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that TEAD3 directly and cooperatively binds GT-IIC/SphI enhancer elements answered the fundamental question of which transcription factor family member engages placental enhancers, grounding TEAD3 as a sequence-specific DNA-binding protein.\",\n      \"evidence\": \"EMSA with monoclonal antibody supershift and site-directed mutagenesis of the human chorionic somatomammotropin-B enhancer\",\n      \"pmids\": [\"9148898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperativity mechanism at the structural level not resolved\", \"In vivo chromatin occupancy not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that full-length TEAD3 transactivates GT-IIC-dependent enhancers but not unrelated (OCT) enhancers established TEAD3 as an activating transcription factor with target-element specificity, and identified a role for its 5′ UTR in controlling protein production.\",\n      \"evidence\": \"In vitro transcription/translation, EMSA, and transient reporter assays in BeWo trophoblast cells\",\n      \"pmids\": [\"10379887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation domain boundaries not mapped\", \"Endogenous chromatin targets not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that TEAD3 is phosphorylated in vivo and that α1-adrenergic signaling enhances its DNA-binding activity in cardiac myocytes revealed the first post-translational regulatory mechanism for this factor, linking it to signal-responsive gene control in the heart.\",\n      \"evidence\": \"32P metabolic labeling, immunoprecipitation, EMSA with phosphatase treatment, and TEF-1/DTEF-1 chimeric factor analysis in neonatal rat cardiomyocytes\",\n      \"pmids\": [\"11986313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites not mapped\", \"Responsible kinase not identified\", \"Downstream cardiac gene targets not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of VGLL3 as a Hippo-kinase-independent TEAD3 co-activator in myoblasts, alongside the YAP-TEAD3 interaction during cardiomyocyte differentiation, established that TEAD3 integrates inputs from multiple co-activator families to control distinct transcriptional programs.\",\n      \"evidence\": \"Co-IP mass spectrometry and siRNA/overexpression in myoblasts (VGLL3); Co-IP and siRNA in hiPSC-derived cardiovascular progenitors (YAP)\",\n      \"pmids\": [\"31138678\", \"31541452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VGLL3 and YAP compete for the same TEAD3 interface not tested\", \"Direct promoter occupancy by VGLL3-TEAD3 not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that a covalent inhibitor targeting the TEAD3 palmitoylation pocket achieves >100-fold isoform selectivity demonstrated that TEAD paralogs have druggably distinct lipid-binding sites, and that TEAD3 activity is required for zebrafish appendage growth.\",\n      \"evidence\": \"Activity-based protein profiling, GAL4-TEAD reporter assays, and zebrafish caudal fin growth assay\",\n      \"pmids\": [\"34729310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of inhibitor-TEAD3 complex not reported\", \"Selectivity mechanism at atomic level unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple studies converged to define TEAD3's YAP-independent functions: TEAD3 is required for HLA-G transcription in trophoblasts without YAP involvement, and TEAD3-selective inhibition in glioblastoma stem cells specifically disrupts cholesterol biosynthesis genes rather than proliferation, separating TEAD3's transcriptional outputs from canonical Hippo-YAP signaling.\",\n      \"evidence\": \"Genome-wide CRISPR knockout screen in extravillous trophoblasts; TEAD3-selective pharmacological inhibition with transcriptomics in patient-derived glioblastoma stem cells\",\n      \"pmids\": [\"40096597\", \"40457844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of YAP-independent TEAD3 activation unknown\", \"Cholesterol pathway regulation not validated by genetic TEAD3 knockout\", \"Cofactor(s) mediating YAP-independent activity not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing functional redundancy between TEAD3 and TEAD4 in trophectoderm specification, and positioning TEAD3 within a RhoA/YAP1/CDK2 axis controlling Schwann cell myelination, expanded TEAD3's known developmental roles and placed it within a defined signaling epistasis in the peripheral nervous system.\",\n      \"evidence\": \"RNAi and base editing with scRNA-seq in bovine preimplantation embryos; conditional RhoA knockout with CDK2 rescue in mouse Schwann cells\",\n      \"pmids\": [\"39679917\", \"41178531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEAD3-specific contribution versus TEAD4 in trophectoderm not separable by single KD\", \"Direct TEAD3 knockout in Schwann cells not performed\", \"TEAD3-CDK2 promoter occupancy not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of R55 arginine methylation as a switch controlling TEAD3 homodimerization, condensate formation, and RUNX2 sequestration during osteogenesis revealed a non-canonical PTM mechanism that operates independently of Hippo signaling and governs lineage commitment via phase separation.\",\n      \"evidence\": \"Arginine methylation mapping, R55K mutagenesis, phase-separation imaging, reporter assays, and PDLSC osteogenic differentiation\",\n      \"pmids\": [\"41556418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase responsible for R55 methylation not identified\", \"In vivo bone phenotype not reported\", \"Whether R55 methylation status changes dynamically during differentiation not tracked\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the identity of kinases and methyltransferases that regulate TEAD3, the structural basis for isoform-selective drug binding, the cofactors mediating YAP-independent transcription, and whether TEAD3 condensate formation is a general regulatory mechanism across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No kinase identified for signal-responsive phosphorylation\", \"No methyltransferase identified for R55\", \"No genome-wide chromatin occupancy map for TEAD3 in any tissue\", \"Structural basis of palmitoylation pocket isoform selectivity unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YAP1\",\n      \"VGLL3\",\n      \"TEAD4\",\n      \"RUNX2\",\n      \"TEAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}