{"gene":"TEAD3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1997,"finding":"hTEF-5 (TEAD3) binds to multiple functional enhansons of the human chorionic somatomammotropin-B (hCS-B) gene enhancer, including a novel tandemly repeated element to which it binds cooperatively, and the corresponding element in the inactive hCS-A enhancer is disrupted by a single base mutation that abolishes hTEF-5 binding.","method":"EMSA/DNA binding assays, mutagenesis of enhancer elements, monoclonal antibody disruption of TEA domain binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding assays with mutagenesis and antibody validation, single lab with multiple orthogonal methods","pmids":["9148898"],"is_preprint":false},{"year":1999,"finding":"TEF-5 (TEAD3) protein (~53 kDa) binds specifically to GT-IIC and SphI/SphII oligonucleotides in vitro, and overexpression of TEF-5 using the intact 3033-bp cDNA (including untranslated regions) transactivates the hCS and SV40 enhancers as well as artificial tandemly repeated GT-IIC enhansons but not OCT enhansons; elements within the untranslated regions or initiation site control TEF-5 expression and influence its transactivation function.","method":"In vitro transcription/translation, EMSA, transient transfection reporter assays in BeWo cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays plus cell-based reporter assays, single lab with two orthogonal methods","pmids":["10379887"],"is_preprint":false},{"year":2002,"finding":"DTEF-1 (mouse ortholog of TEAD3/TEF-5) is phosphorylated in vivo, and alpha1-adrenergic stimulation increases its MCAT-binding activity and transcriptional activation of the skeletal muscle alpha-actin gene in neonatal rat cardiac myocytes; phosphatase treatment reduces MCAT binding by DTEF-1, opposite to the effect on TEF-1 itself.","method":"Orthophosphate labeling, immunoprecipitation of epitope-tagged DTEF-1, EMSA with MCAT element, chimeric TEF-1/DTEF-1 construct analysis, reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo phosphorylation confirmed by radiolabeling/IP and EMSA with phosphatase treatment, single lab with multiple orthogonal methods","pmids":["11986313"],"is_preprint":false},{"year":2019,"finding":"VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes, but unlike YAP/TAZ, VGLL3 does not interact with proteins of the Hippo kinase cascade.","method":"Interaction proteomics (co-immunoprecipitation/mass spectrometry) in myoblasts and myotubes","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction proteomics with negative result for Hippo kinase components, single lab","pmids":["31138678"],"is_preprint":false},{"year":2019,"finding":"YAP interacts with TEAD3 to regulate cardiac lineage commitment of human iPSCs during the cardiovascular progenitor cell stage; RNAi-mediated silencing of TEAD3 phenocopies YAP inhibitor (verteporfin) treatment, causing cells to be retained at the cardiovascular progenitor cell stage.","method":"Co-immunoprecipitation of YAP-TEAD3, RNAi knockdown of TEAD3, verteporfin pharmacological inhibition, differentiation stage marker analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNAi phenocopy, single lab with two orthogonal approaches","pmids":["31541452"],"is_preprint":false},{"year":2021,"finding":"A covalent inhibitor (DC-TEAD3in03) targeting the palmitoylation pocket of TEAD3 selectively inhibits TEAD3 transcriptional activity with >100-fold selectivity over other TEAD isoforms; TEAD3 inhibition reduces growth rate of zebrafish caudal fins, demonstrating a role for TEAD3 in controlling proportional appendage growth.","method":"Activity-based protein profiling (ABPP), GAL4-TEAD reporter assays, zebrafish fin growth assay, biochemical IC50 measurements","journal":"Acta pharmaceutica sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical and cell-based assays plus in vivo zebrafish model, single lab with multiple orthogonal methods","pmids":["34729310"],"is_preprint":false},{"year":2023,"finding":"MALAT1 lncRNA binds TEAD3 protein and blocks TEAD3 from binding and activating NFATC1, a master regulator of osteoclastogenesis, thereby inhibiting osteoclast differentiation; Tead3 is identified as a macrophage-osteoclast-specific TEAD family member.","method":"RNA-protein binding assay (MALAT1-Tead3 interaction), genetic knockout and rescue experiments in mice, transcriptional reporter/target gene analysis","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein binding plus genetic rescue experiments, preprint with multiple methods but not yet peer-reviewed","pmids":["36993303"],"is_preprint":true},{"year":2025,"finding":"TEAD1 and TEAD3 are required for HLA-G transcription in extravillous trophoblasts (EVT) in a YAP-independent manner; identified by genome-wide CRISPR-Cas9 knockout screen.","method":"Genome-wide CRISPR-Cas9 knockout screen in EVT cells, validation of HLA-G expression loss","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen with functional readout, single lab","pmids":["40096597"],"is_preprint":false},{"year":2025,"finding":"TEAD3 and TEAD4 play essential and redundant roles upstream of trophectoderm fate decisions during bovine preimplantation development; dual knockdown (TEAD3 siRNA + TEAD4 base editing) abolishes blastocyst formation and downregulates trophectoderm-specific genes KRT8, KRT18, and EZR.","method":"Single-cell RNA sequencing, RNA interference (siRNA), base editing of TEAD4, immunofluorescence, RNA sequencing","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-knockdown with defined trophectoderm phenotype and transcriptomic readout, single lab","pmids":["39679917"],"is_preprint":false},{"year":2025,"finding":"In glioblastoma, specific pharmacological inhibition of TEAD3 does not impact cell proliferation but affects sterol/cholesterol biosynthetic and metabolic processes.","method":"Pharmacological TEAD3 inhibition in patient-derived glioblastoma stem cell cultures, cell proliferation assays, pathway/metabolic analysis","journal":"Brain pathology (Zurich, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single pharmacological method, limited mechanistic detail in abstract","pmids":["40457844"],"is_preprint":false},{"year":2025,"finding":"RhoA regulates Schwann cell microtubule dynamics and myelination via a YAP1/TEAD3/CDK2/ASPM/p60-Katanin signaling axis; TEAD3 functions downstream of YAP1 and upstream of CDK2 in this pathway.","method":"RhoA conditional knockout mice, bulk mRNA sequencing, in vitro and in vivo experiments with genetic ablation and pharmacological inhibition, CDK2 overexpression rescue","journal":"Glia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — TEAD3's specific role in the axis is inferred from pathway analysis rather than direct TEAD3 manipulation; single lab","pmids":["41178531"],"is_preprint":false},{"year":2026,"finding":"TEAD3 is methylated at arginine 55 (R55) within its DNA-binding TEA domain; disruption of R55 methylation (R55K mutation) enhances formation of TEAD3 homodimer condensates that spatially constrain RUNX2 transcriptional activity without disrupting Hippo signaling functions, thereby repressing osteogenic differentiation.","method":"Arginine methylation mapping, R55K point mutation analysis, condensate formation assays, RUNX2 activity reporter assays, TEA domain-targeting inhibitory peptide (TEAi) sensitivity assay","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis combined with condensate and functional assays, single lab with multiple orthogonal approaches","pmids":["41556418"],"is_preprint":false},{"year":2023,"finding":"TEAD3 overexpression in prostate cancer cells inhibits proliferation and migration by suppressing ADRBK2 mRNA levels; rescue assays confirmed that ADRBK2 reverses the anti-proliferative and anti-migratory effects of TEAD3 overexpression.","method":"Overexpression of TEAD3, MTT assay, clone formation assay, scratch assay, next-generation sequencing, rescue assays with ADRBK2","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional overexpression with rescue assay, single lab, mechanistic link to ADRBK2 is transcriptional regulation without direct binding evidence","pmids":["36907139"],"is_preprint":false}],"current_model":"TEAD3 is a TEA domain transcription factor that binds GT-IIC/MCAT cis-elements to directly activate target genes (including hCS-B, skeletal muscle alpha-actin, HLA-G, and NFATC1 targets); its activity is regulated by phosphorylation (enhanced by alpha1-adrenergic signaling), arginine methylation at R55 (which controls homodimer condensate formation and RUNX2 sequestration), and covalent modification of its palmitoylation pocket; it partners with co-activators YAP and VGLL3 (but not the Hippo kinase cascade when bound to VGLL3) to control cardiac, skeletal muscle, trophoblast, and osteoclast differentiation, and is blocked from activating NFATC1 by the lncRNA MALAT1."},"narrative":{"mechanistic_narrative":"TEAD3 is a TEA-domain transcription factor that binds GT-IIC/MCAT and SphI/SphII cis-elements to directly activate developmental and tissue-specific target genes, including the human chorionic somatomammotropin-B (hCS-B) enhancer, where it engages tandemly repeated enhansons cooperatively and is exquisitely sensitive to single-base mutations in the binding site [PMID:9148898, PMID:10379887]. Its DNA-binding and transactivation output is controlled by post-translational modification: phosphorylation enhances MCAT binding under alpha1-adrenergic stimulation in cardiac myocytes (in contrast to the opposite effect seen on TEF-1) [PMID:11986313], and methylation of arginine 55 within the TEA domain restrains formation of TEAD3 homodimer condensates that otherwise spatially sequester RUNX2 to repress osteogenic differentiation [PMID:41556418]. TEAD3 partners with the co-activators YAP and VGLL3, with VGLL3 engaging TEAD3 independently of the Hippo kinase cascade [PMID:31138678, PMID:31541452]. Through these interactions and DNA-binding activities TEAD3 governs differentiation across multiple lineages: cardiac lineage commitment of iPSC-derived cardiovascular progenitors via YAP [PMID:31541452], trophectoderm and extravillous trophoblast programs—including YAP-independent HLA-G transcription and KRT8/KRT18/EZR-dependent blastocyst formation [PMID:40096597, PMID:39679917]—and osteoclastogenesis, where TEAD3 activates the master regulator NFATC1 and is blocked from doing so by the lncRNA MALAT1 [PMID:36993303]. A covalent inhibitor targeting the TEAD3 palmitoylation pocket selectively suppresses its transcriptional activity and constrains proportional appendage growth in zebrafish [PMID:34729310].","teleology":[{"year":1997,"claim":"Established TEAD3 (hTEF-5) as a sequence-specific DNA-binding factor by showing it recognizes functional enhansons of the hCS-B enhancer, with allele-discriminating sensitivity to single-base changes.","evidence":"EMSA, enhancer-element mutagenesis, and antibody disruption of TEA-domain binding","pmids":["9148898"],"confidence":"Medium","gaps":["Did not define co-activator requirements or in vivo target gene set","Mechanism of cooperative binding to tandem elements not resolved structurally"]},{"year":1999,"claim":"Connected TEAD3 DNA binding to functional output by demonstrating GT-IIC/SphI element binding and transactivation of hCS and SV40 enhancers, and showed untranslated regions modulate its expression.","evidence":"In vitro transcription/translation, EMSA, and transient reporter assays in BeWo cells","pmids":["10379887"],"confidence":"Medium","gaps":["Did not identify co-activators driving transactivation","Element specificity (GT-IIC vs OCT) characterized in vitro only"]},{"year":2002,"claim":"Identified phosphorylation as a positive regulator of TEAD3 DNA binding, linking alpha1-adrenergic signaling to MCAT-driven muscle gene activation and distinguishing TEAD3 regulation from TEF-1.","evidence":"Orthophosphate labeling, IP of tagged DTEF-1, EMSA with phosphatase treatment, and reporter assays in rat cardiac myocytes","pmids":["11986313"],"confidence":"Medium","gaps":["Phosphosites and responsible kinase not mapped","Used mouse ortholog DTEF-1; human residue conservation not addressed"]},{"year":2019,"claim":"Defined the co-activator landscape of TEAD3, showing VGLL3 binds TEAD3 independently of the Hippo kinase cascade while YAP couples TEAD3 to cardiac lineage commitment.","evidence":"Interaction proteomics in myoblasts/myotubes; Co-IP and RNAi phenocopy of verteporfin in iPSC cardiac differentiation","pmids":["31138678","31541452"],"confidence":"Medium","gaps":["Direct target genes downstream of YAP-TEAD3 in cardiac progenitors not defined","VGLL3 vs YAP target-gene partitioning unresolved"]},{"year":2021,"claim":"Demonstrated the palmitoylation pocket is a tractable regulatory site, with a TEAD3-selective covalent inhibitor revealing a role in controlling proportional appendage growth.","evidence":"Activity-based protein profiling, GAL4-TEAD reporter assays, IC50 measurements, and zebrafish fin growth assay","pmids":["34729310"],"confidence":"Medium","gaps":["Endogenous lipid modification stoichiometry and physiological regulator not defined","Mammalian growth-control targets not identified"]},{"year":2023,"claim":"Showed TEAD3 activity is gated by a non-coding RNA, with MALAT1 binding TEAD3 to block NFATC1 activation and thereby restrain osteoclast differentiation.","evidence":"RNA-protein binding assay and genetic knockout/rescue in mice with target-gene analysis (preprint)","pmids":["36993303"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Binding interface between MALAT1 and TEAD3 not mapped"]},{"year":2025,"claim":"Extended TEAD3's developmental roles to trophoblast biology, establishing requirement for YAP-independent HLA-G transcription in EVT and redundant control of trophectoderm fate.","evidence":"Genome-wide CRISPR-Cas9 screen in EVT cells; siRNA/base-editing dual knockdown with scRNA-seq in bovine embryos","pmids":["40096597","39679917"],"confidence":"Medium","gaps":["Co-activator(s) supporting YAP-independent activation not identified","Direct vs indirect control of KRT8/KRT18/EZR not distinguished"]},{"year":2026,"claim":"Revealed arginine methylation as a switch controlling TEAD3 biophysical state, where R55 methylation limits homodimer condensate formation that otherwise sequesters RUNX2 to repress osteogenesis.","evidence":"Arginine methylation mapping, R55K mutagenesis, condensate and RUNX2 reporter assays, TEA-domain peptide sensitivity","pmids":["41556418"],"confidence":"Medium","gaps":["Methyltransferase responsible for R55 not identified","Relationship between condensate state and canonical DNA binding not fully resolved"]},{"year":null,"claim":"The full set of direct TEAD3 target genes and the rules partitioning its co-activators (YAP vs VGLL3) and modifications (phosphorylation, methylation, palmitoylation) across distinct differentiation programs remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide direct binding map across tissues","Enzymes controlling each PTM mostly unidentified","Isoform-specific functions vs TEAD1/TEAD4 incompletely separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,6,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,10]}],"complexes":[],"partners":["YAP1","VGLL3","MALAT1","RUNX2","NFATC1"],"other_free_text":[]}},"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":43,"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":6,"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":6,"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":4,"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":"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":"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":"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":"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":"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":"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":10722,"output_tokens":3233,"usd":0.04033,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10724,"output_tokens":3090,"usd":0.065435,"stage2_stop_reason":"end_turn"},"total_usd":0.105765,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"hTEF-5 (TEAD3) binds to multiple functional enhansons of the human chorionic somatomammotropin-B (hCS-B) gene enhancer, including a novel tandemly repeated element to which it binds cooperatively, and the corresponding element in the inactive hCS-A enhancer is disrupted by a single base mutation that abolishes hTEF-5 binding.\",\n      \"method\": \"EMSA/DNA binding assays, mutagenesis of enhancer elements, monoclonal antibody disruption of TEA domain binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding assays with mutagenesis and antibody validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9148898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TEF-5 (TEAD3) protein (~53 kDa) binds specifically to GT-IIC and SphI/SphII oligonucleotides in vitro, and overexpression of TEF-5 using the intact 3033-bp cDNA (including untranslated regions) transactivates the hCS and SV40 enhancers as well as artificial tandemly repeated GT-IIC enhansons but not OCT enhansons; elements within the untranslated regions or initiation site control TEF-5 expression and influence its transactivation function.\",\n      \"method\": \"In vitro transcription/translation, EMSA, transient transfection reporter assays in BeWo cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays plus cell-based reporter assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"10379887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DTEF-1 (mouse ortholog of TEAD3/TEF-5) is phosphorylated in vivo, and alpha1-adrenergic stimulation increases its MCAT-binding activity and transcriptional activation of the skeletal muscle alpha-actin gene in neonatal rat cardiac myocytes; phosphatase treatment reduces MCAT binding by DTEF-1, opposite to the effect on TEF-1 itself.\",\n      \"method\": \"Orthophosphate labeling, immunoprecipitation of epitope-tagged DTEF-1, EMSA with MCAT element, chimeric TEF-1/DTEF-1 construct analysis, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo phosphorylation confirmed by radiolabeling/IP and EMSA with phosphatase treatment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11986313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes, but unlike YAP/TAZ, VGLL3 does not interact with proteins of the Hippo kinase cascade.\",\n      \"method\": \"Interaction proteomics (co-immunoprecipitation/mass spectrometry) in myoblasts and myotubes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction proteomics with negative result for Hippo kinase components, single lab\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP interacts with TEAD3 to regulate cardiac lineage commitment of human iPSCs during the cardiovascular progenitor cell stage; RNAi-mediated silencing of TEAD3 phenocopies YAP inhibitor (verteporfin) treatment, causing cells to be retained at the cardiovascular progenitor cell stage.\",\n      \"method\": \"Co-immunoprecipitation of YAP-TEAD3, RNAi knockdown of TEAD3, verteporfin pharmacological inhibition, differentiation stage marker analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNAi phenocopy, single lab with two orthogonal approaches\",\n      \"pmids\": [\"31541452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A covalent inhibitor (DC-TEAD3in03) targeting the palmitoylation pocket of TEAD3 selectively inhibits TEAD3 transcriptional activity with >100-fold selectivity over other TEAD isoforms; TEAD3 inhibition reduces growth rate of zebrafish caudal fins, demonstrating a role for TEAD3 in controlling proportional appendage growth.\",\n      \"method\": \"Activity-based protein profiling (ABPP), GAL4-TEAD reporter assays, zebrafish fin growth assay, biochemical IC50 measurements\",\n      \"journal\": \"Acta pharmaceutica sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical and cell-based assays plus in vivo zebrafish model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34729310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MALAT1 lncRNA binds TEAD3 protein and blocks TEAD3 from binding and activating NFATC1, a master regulator of osteoclastogenesis, thereby inhibiting osteoclast differentiation; Tead3 is identified as a macrophage-osteoclast-specific TEAD family member.\",\n      \"method\": \"RNA-protein binding assay (MALAT1-Tead3 interaction), genetic knockout and rescue experiments in mice, transcriptional reporter/target gene analysis\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein binding plus genetic rescue experiments, preprint with multiple methods but not yet peer-reviewed\",\n      \"pmids\": [\"36993303\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEAD1 and TEAD3 are required for HLA-G transcription in extravillous trophoblasts (EVT) in a YAP-independent manner; identified by genome-wide CRISPR-Cas9 knockout screen.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen in EVT cells, validation of HLA-G expression loss\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen with functional readout, single lab\",\n      \"pmids\": [\"40096597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEAD3 and TEAD4 play essential and redundant roles upstream of trophectoderm fate decisions during bovine preimplantation development; dual knockdown (TEAD3 siRNA + TEAD4 base editing) abolishes blastocyst formation and downregulates trophectoderm-specific genes KRT8, KRT18, and EZR.\",\n      \"method\": \"Single-cell RNA sequencing, RNA interference (siRNA), base editing of TEAD4, immunofluorescence, RNA sequencing\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-knockdown with defined trophectoderm phenotype and transcriptomic readout, single lab\",\n      \"pmids\": [\"39679917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In glioblastoma, specific pharmacological inhibition of TEAD3 does not impact cell proliferation but affects sterol/cholesterol biosynthetic and metabolic processes.\",\n      \"method\": \"Pharmacological TEAD3 inhibition in patient-derived glioblastoma stem cell cultures, cell proliferation assays, pathway/metabolic analysis\",\n      \"journal\": \"Brain pathology (Zurich, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single pharmacological method, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40457844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RhoA regulates Schwann cell microtubule dynamics and myelination via a YAP1/TEAD3/CDK2/ASPM/p60-Katanin signaling axis; TEAD3 functions downstream of YAP1 and upstream of CDK2 in this pathway.\",\n      \"method\": \"RhoA conditional knockout mice, bulk mRNA sequencing, in vitro and in vivo experiments with genetic ablation and pharmacological inhibition, CDK2 overexpression rescue\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — TEAD3's specific role in the axis is inferred from pathway analysis rather than direct TEAD3 manipulation; single lab\",\n      \"pmids\": [\"41178531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TEAD3 is methylated at arginine 55 (R55) within its DNA-binding TEA domain; disruption of R55 methylation (R55K mutation) enhances formation of TEAD3 homodimer condensates that spatially constrain RUNX2 transcriptional activity without disrupting Hippo signaling functions, thereby repressing osteogenic differentiation.\",\n      \"method\": \"Arginine methylation mapping, R55K point mutation analysis, condensate formation assays, RUNX2 activity reporter assays, TEA domain-targeting inhibitory peptide (TEAi) sensitivity assay\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis combined with condensate and functional assays, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41556418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TEAD3 overexpression in prostate cancer cells inhibits proliferation and migration by suppressing ADRBK2 mRNA levels; rescue assays confirmed that ADRBK2 reverses the anti-proliferative and anti-migratory effects of TEAD3 overexpression.\",\n      \"method\": \"Overexpression of TEAD3, MTT assay, clone formation assay, scratch assay, next-generation sequencing, rescue assays with ADRBK2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional overexpression with rescue assay, single lab, mechanistic link to ADRBK2 is transcriptional regulation without direct binding evidence\",\n      \"pmids\": [\"36907139\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD3 is a TEA domain transcription factor that binds GT-IIC/MCAT cis-elements to directly activate target genes (including hCS-B, skeletal muscle alpha-actin, HLA-G, and NFATC1 targets); its activity is regulated by phosphorylation (enhanced by alpha1-adrenergic signaling), arginine methylation at R55 (which controls homodimer condensate formation and RUNX2 sequestration), and covalent modification of its palmitoylation pocket; it partners with co-activators YAP and VGLL3 (but not the Hippo kinase cascade when bound to VGLL3) to control cardiac, skeletal muscle, trophoblast, and osteoclast differentiation, and is blocked from activating NFATC1 by the lncRNA MALAT1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEAD3 is a TEA-domain transcription factor that binds GT-IIC/MCAT and SphI/SphII cis-elements to directly activate developmental and tissue-specific target genes, including the human chorionic somatomammotropin-B (hCS-B) enhancer, where it engages tandemly repeated enhansons cooperatively and is exquisitely sensitive to single-base mutations in the binding site [#0, #1]. Its DNA-binding and transactivation output is controlled by post-translational modification: phosphorylation enhances MCAT binding under alpha1-adrenergic stimulation in cardiac myocytes (in contrast to the opposite effect seen on TEF-1) [#2], and methylation of arginine 55 within the TEA domain restrains formation of TEAD3 homodimer condensates that otherwise spatially sequester RUNX2 to repress osteogenic differentiation [#11]. TEAD3 partners with the co-activators YAP and VGLL3, with VGLL3 engaging TEAD3 independently of the Hippo kinase cascade [#3, #4]. Through these interactions and DNA-binding activities TEAD3 governs differentiation across multiple lineages: cardiac lineage commitment of iPSC-derived cardiovascular progenitors via YAP [#4], trophectoderm and extravillous trophoblast programs—including YAP-independent HLA-G transcription and KRT8/KRT18/EZR-dependent blastocyst formation [#7, #8]—and osteoclastogenesis, where TEAD3 activates the master regulator NFATC1 and is blocked from doing so by the lncRNA MALAT1 [#6]. A covalent inhibitor targeting the TEAD3 palmitoylation pocket selectively suppresses its transcriptional activity and constrains proportional appendage growth in zebrafish [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established TEAD3 (hTEF-5) as a sequence-specific DNA-binding factor by showing it recognizes functional enhansons of the hCS-B enhancer, with allele-discriminating sensitivity to single-base changes.\",\n      \"evidence\": \"EMSA, enhancer-element mutagenesis, and antibody disruption of TEA-domain binding\",\n      \"pmids\": [\"9148898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define co-activator requirements or in vivo target gene set\", \"Mechanism of cooperative binding to tandem elements not resolved structurally\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected TEAD3 DNA binding to functional output by demonstrating GT-IIC/SphI element binding and transactivation of hCS and SV40 enhancers, and showed untranslated regions modulate its expression.\",\n      \"evidence\": \"In vitro transcription/translation, EMSA, and transient reporter assays in BeWo cells\",\n      \"pmids\": [\"10379887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify co-activators driving transactivation\", \"Element specificity (GT-IIC vs OCT) characterized in vitro only\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified phosphorylation as a positive regulator of TEAD3 DNA binding, linking alpha1-adrenergic signaling to MCAT-driven muscle gene activation and distinguishing TEAD3 regulation from TEF-1.\",\n      \"evidence\": \"Orthophosphate labeling, IP of tagged DTEF-1, EMSA with phosphatase treatment, and reporter assays in rat cardiac myocytes\",\n      \"pmids\": [\"11986313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites and responsible kinase not mapped\", \"Used mouse ortholog DTEF-1; human residue conservation not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the co-activator landscape of TEAD3, showing VGLL3 binds TEAD3 independently of the Hippo kinase cascade while YAP couples TEAD3 to cardiac lineage commitment.\",\n      \"evidence\": \"Interaction proteomics in myoblasts/myotubes; Co-IP and RNAi phenocopy of verteporfin in iPSC cardiac differentiation\",\n      \"pmids\": [\"31138678\", \"31541452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target genes downstream of YAP-TEAD3 in cardiac progenitors not defined\", \"VGLL3 vs YAP target-gene partitioning unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated the palmitoylation pocket is a tractable regulatory site, with a TEAD3-selective covalent inhibitor revealing a role in controlling proportional appendage growth.\",\n      \"evidence\": \"Activity-based protein profiling, GAL4-TEAD reporter assays, IC50 measurements, and zebrafish fin growth assay\",\n      \"pmids\": [\"34729310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous lipid modification stoichiometry and physiological regulator not defined\", \"Mammalian growth-control targets not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TEAD3 activity is gated by a non-coding RNA, with MALAT1 binding TEAD3 to block NFATC1 activation and thereby restrain osteoclast differentiation.\",\n      \"evidence\": \"RNA-protein binding assay and genetic knockout/rescue in mice with target-gene analysis (preprint)\",\n      \"pmids\": [\"36993303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Binding interface between MALAT1 and TEAD3 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TEAD3's developmental roles to trophoblast biology, establishing requirement for YAP-independent HLA-G transcription in EVT and redundant control of trophectoderm fate.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen in EVT cells; siRNA/base-editing dual knockdown with scRNA-seq in bovine embryos\",\n      \"pmids\": [\"40096597\", \"39679917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-activator(s) supporting YAP-independent activation not identified\", \"Direct vs indirect control of KRT8/KRT18/EZR not distinguished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed arginine methylation as a switch controlling TEAD3 biophysical state, where R55 methylation limits homodimer condensate formation that otherwise sequesters RUNX2 to repress osteogenesis.\",\n      \"evidence\": \"Arginine methylation mapping, R55K mutagenesis, condensate and RUNX2 reporter assays, TEA-domain peptide sensitivity\",\n      \"pmids\": [\"41556418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methyltransferase responsible for R55 not identified\", \"Relationship between condensate state and canonical DNA binding not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full set of direct TEAD3 target genes and the rules partitioning its co-activators (YAP vs VGLL3) and modifications (phosphorylation, methylation, palmitoylation) across distinct differentiation programs remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide direct binding map across tissues\", \"Enzymes controlling each PTM mostly unidentified\", \"Isoform-specific functions vs TEAD1/TEAD4 incompletely separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YAP1\", \"VGLL3\", \"MALAT1\", \"RUNX2\", \"NFATC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}