{"gene":"TEAD2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2010,"finding":"Crystal structure of the YAP-binding domain (YBD) of human TEAD2 was solved, revealing an immunoglobulin-like beta-sandwich fold with two extra helix-turn-helix inserts. NMR studies showed that the TEAD-binding domain of YAP is natively unfolded and undergoes localized conformational changes upon TEAD2 binding. In vitro binding and in vivo functional assays defined an extensive conserved surface of TEAD2 YBD as the YAP-binding site.","method":"X-ray crystallography, NMR spectroscopy, in vitro binding assays, in vivo functional assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with NMR and functional validation in a single rigorous study","pmids":["20368466"],"is_preprint":false},{"year":2011,"finding":"TEAD2 and its transcriptional co-activator YAP cooperate in a signaling pathway downstream of the tyrosine kinase Yes in mouse embryonic stem cells. Kinase-active Yes binds and phosphorylates YAP, activates YAP-TEAD2-dependent transcription, and this pathway is required downstream of LIF for ES cell self-renewal. TEAD2 was shown to associate directly with the Oct-3/4 promoter, and activation of the Yes-YAP-TEAD2 pathway induced Oct-3/4 and Nanog promoter activity.","method":"Co-immunoprecipitation, kinase assay, promoter-reporter assays, siRNA knockdown, chromatin association assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase assay, reporter assays, and siRNA knockdown with defined cellular phenotype in a single study","pmids":["21385842"],"is_preprint":false},{"year":2008,"finding":"Tead1 and Tead2 are functionally redundant in mouse embryonic development. Tead1−/−;Tead2−/− double-knockout embryos die at E9.5 with severe growth defects, lack of notochord maintenance, and defects in yolk sac vasculature. Genetic interaction experiments demonstrated that Tead1 and Tead2 use YAP as a major coactivator in vivo. Double-knockout embryos showed reduced cell proliferation and increased apoptosis.","method":"Mouse knockout genetics, genetic epistasis with Yap mutants, histological and molecular analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double knockout plus genetic epistasis with YAP mutants, replicated across developmental stages","pmids":["18332127"],"is_preprint":false},{"year":2004,"finding":"Tead2 binds to a neural crest enhancer element in the Pax3 genomic locus and activates Pax3 expression. Mutation of the Tead2 binding site in Pax3 transgenic constructs abolished neural expression. A Tead2-Engrailed repressor fusion suppressed Pax3 expression in P19 cells and in vivo. Tead2 and its co-activator YAP65 are co-expressed with Pax3 in the dorsal neural tube.","method":"Transgenic mouse reporter assays, co-transfection, dominant-negative Tead2-Engrailed fusion, site-directed mutagenesis of binding site","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic enhancer assays with binding site mutation and dominant-negative, replicated in cell culture","pmids":["14736747"],"is_preprint":false},{"year":2005,"finding":"Tead2 directly activates the Fgfr4 promoter through an M-CAT motif (5'-CATTCCT-3'). Mutation of this M-CAT motif abolished Tead2-driven Fgfr4 promoter activity in co-transfection assays. MyoD directly bound two E-boxes in the first intron of Tead2 (by ChIP), and co-transfection of MyoD activated Tead2 intronic reporter activity in a dose-dependent manner, establishing a MyoD-Tead2-Fgfr4 transcriptional pathway required for muscle regeneration.","method":"Co-transfection/promoter-reporter assay, site-directed mutagenesis of M-CAT, chromatin immunoprecipitation (ChIP), immunostaining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for direct binding, promoter reporter with mutagenesis, and in vivo Fgfr4 null mouse regeneration phenotype","pmids":["16267055"],"is_preprint":false},{"year":2007,"finding":"Inactivation of the Tead2 gene in mice significantly increased the risk of exencephaly (defect in neural tube closure). This role in neural tube closure was found to be independent of Pax3 regulation, as Pax3 expression was normal in E11.5 Tead2 nullizygous embryos. The risk of exencephaly was greatest with Tead2 nullizygous females and could be suppressed by folic acid or pifithrin-alpha, revealing a maternal genetic contribution.","method":"Mouse knockout, phenotypic analysis, pharmacological rescue (folic acid, pifithrin-alpha)","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined phenotype, pharmacological rescue, but mechanistic pathway only partially characterized","pmids":["17868131"],"is_preprint":false},{"year":1989,"finding":"Transcription factor ETF (TEAD2) specifically stimulates transcription from promoters lacking a TATA box. ETF recognizes GC-rich sequences including GC boxes and TATA boxes (with lower affinity). ETF-binding sites only functionally activated transcription when placed upstream of TATA-less promoters; introduction of a TATA box into the EGFR promoter abolished ETF responsiveness.","method":"In vitro transcription assay, DNA binding (gel-shift), promoter-reporter analysis with TATA box substitution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transcription reconstitution with mutagenesis and multiple promoter variants tested","pmids":["2768275"],"is_preprint":false},{"year":1999,"finding":"ETF (TEAD2) binds to three upstream and one downstream site in the mouse p53 promoter, and adenovirus E1a proteins stimulate this binding to transcriptionally activate the p53 gene. The ETF site downstream of the transcription start site was identified as the key element conferring E1a responsiveness. Both major E1a proteins (243R and 289R) were required for complete activation.","method":"Promoter-reporter assay, electrophoretic mobility shift assay (EMSA), deletion/mutation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and functional reporter assays in a single lab with multiple binding site variants","pmids":["10446138"],"is_preprint":false},{"year":2022,"finding":"TEAD2 (together with E2A) transcriptionally represses all six acetyl-CoA biosynthesis pathways in hepatocellular carcinoma, leading to decreased acetyl-CoA levels and hypo-acetylation of non-histone proteins. Knockdown of TEAD2 restored acetyl-CoA levels and inhibited tumor growth in a mouse HCC model.","method":"RNA sequencing, mouse HCC model, siRNA knockdown, metabolic measurements of acetyl-CoA levels and protein acetylation","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined metabolic phenotype in mouse model, single lab","pmids":["36400009"],"is_preprint":false},{"year":2023,"finding":"In hepatocellular carcinoma, TAZ-driven tumor growth specifically requires TEAD2 (and to a lesser extent TEAD4). TAZ and TEAD2 promote HCC proliferation via transcriptional upregulation of ANLN and KIF23, as confirmed by chromatin immunoprecipitation and CRISPRi screen. TAZ expression in HCC is regulated by cholesterol synthesis upstream of TEAD2.","method":"AAV-mediated knockout in floxed mice, RNA-seq, ChIP, CRISPRi screen, TAZ-S89A overexpression HCC model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, CRISPRi, genetic knockout, overexpression) in both mouse and human HCC","pmids":["36894036"],"is_preprint":false},{"year":2023,"finding":"In basal-like pancreatic ductal adenocarcinoma (PDA) cells, TEAD2 drives a proangiogenic enhancer landscape. Genetic and pharmacologic inhibition of TEAD2 impairs proangiogenic phenotypes in vitro and cancer progression in vivo. CD109 was identified as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells.","method":"Epigenome analysis (ATAC-seq/ChIP-seq), transcriptome analysis, loss-of-function (genetic and pharmacologic), in vivo tumor models","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenomic and transcriptomic plus in vivo loss-of-function, single lab","pmids":["36907523"],"is_preprint":false},{"year":2024,"finding":"TEAD2 binds to the TAK1 promoter and transcriptionally activates TAK1 expression, thereby mediating sorafenib resistance in hepatocellular carcinoma. Functional assays showed that TEAD2 promotes HCC progression and drug resistance, and TAK1 inhibitors reversed TEAD2-induced sorafenib resistance.","method":"Accessibility sequencing (ATAC-seq), chromatin immunoprecipitation for TAK1 promoter, functional cell-based assays, TAK1 inhibitor treatment","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding plus functional rescue, single lab","pmids":["39106149"],"is_preprint":false},{"year":2024,"finding":"TEAD2 exhibits increased chromatin binding in ground-state (2i/LIF) mouse embryonic stem cells, targeting active chromatin regions to regulate 2i-specific gene expression. TEAD2 mediates enhancer-promoter looping interactions during the serum/LIF to 2i/LIF transition. Deletion of Tead2 reduces a specific set of enhancer-promoter interactions without significantly affecting CTCF or YY1 binding.","method":"ChIP-seq, ATAC-seq, Hi-C/chromatin interaction assays, Tead2 knockout ESCs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genomics methods (ChIP-seq, ATAC-seq, chromatin looping) combined with genetic deletion","pmids":["38605224"],"is_preprint":false},{"year":2019,"finding":"TEAD2 mRNA is a direct target of miR-608 in NSCLC cells, as confirmed by dual-luciferase reporter assay. miR-608 overexpression negatively regulated TEAD2 protein levels and decreased expression of Hippo-YAP pathway target genes. Restoration of TEAD2 reversed the increased cisplatin sensitivity induced by miR-608, placing TEAD2 downstream of miR-608 in mediating drug sensitivity.","method":"Dual-luciferase reporter assay, western blot, siRNA/overexpression rescue experiments","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter confirming direct 3'UTR targeting plus rescue experiments, single lab","pmids":["31485614"],"is_preprint":false},{"year":2019,"finding":"Pax3 cooperates with Six4 and Tead2 at chromatin to specify the skeletal myogenic lineage. ChIP-seq and ATAC-seq in Pax3-induced embryonic stem cells and Pax3-null E9.5 mouse embryos showed that Pax3 binding increases chromatin accessibility and that Tead2 co-occupies Pax3-bound elements in the context of myogenic specification.","method":"ChIP-seq, ATAC-seq, RNA-seq, Pax3-null mouse embryo analysis, ES cell differentiation platform","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomics methods, but Tead2 functional contribution to myogenesis is inferred from co-occupancy rather than Tead2-specific loss-of-function","pmids":["30807574"],"is_preprint":false},{"year":2001,"finding":"A 117-bp enhancer in the first intron of the mouse ETF/Tead2 gene is required for cell-specific transcriptional activation. This enhancer contains a GC box and two GA elements. Sp1 acts as an activator by competing with an unknown repressor (GA element-binding factor) for binding to the GC box and GA elements to achieve full enhancer activity.","method":"Transient transfection assays, electrophoretic mobility shift assays (EMSA), deletion and point mutation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple deletion/mutation constructs with EMSA and functional reporter, single lab","pmids":["11741291"],"is_preprint":false},{"year":2024,"finding":"In vemurafenib-resistant melanoma cells, EGFR signaling activates YAP1 nuclear localization, which in turn cooperates with TEAD2 to upregulate STIM1 expression. EGF and EGFR levels are increased in resistant cells, and this pathway drives STIM1-dependent calcium entry associated with drug resistance.","method":"Pathway inhibitor experiments, YAP1 nuclear localization assays, gene knockdown, reporter/expression analysis","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily knockdown and expression analyses with limited mechanistic dissection of the TEAD2-specific step","pmids":["39298503"],"is_preprint":false},{"year":1998,"finding":"ETF (TEAD2/mETF) encodes a full-length protein with a TEA/ATTS DNA-binding domain. Gel mobility shift assays confirmed that ETF binds M-CAT/GT-IIC elements, and GAL4-fusion protein analysis demonstrated that ETF contains a transcriptional activation domain.","method":"cDNA cloning, gel mobility shift assay, GAL4 fusion transcription activation assay","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and activation domain assays, single lab","pmids":["9502435"],"is_preprint":false},{"year":2025,"finding":"A peptide inhibitor (TEAi) derived from Drosophila Nerfin-1 directly binds the TEA DNA-binding domain of TEAD2 and inhibits its DNA-binding capacity without direct DNA interaction, thereby abolishing promoter recruitment of the TEAD-YAP complex. TEAi also induced nuclear export and cytoplasmic accumulation of TEAD2, suggesting a non-canonical mechanism. TEAi suppressed TEAD-YAP-driven transcriptional activity (CTGF, CYR61) and tumor growth in vivo.","method":"Luciferase reporter assay, qPCR, DNA-binding assay, nuclear/cytoplasmic fractionation, in vivo tumor model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanism of DNA-binding inhibition and nuclear export inferred from functional assays without structural validation","pmids":["bio_10.1101_2025.08.31.672803"],"is_preprint":true},{"year":2024,"finding":"TEAD1/2 have both YAP/TAZ-dependent and YAP/TAZ-independent functions during ventral telencephalon development in mice. Whereas YAP/TAZ loss depletes early progenitors, TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote neural progenitor lineage progression. TEAD1/2 do so in part by inhibiting Notch signaling and cooperating with INSM1.","method":"Mouse conditional double knockout (TEAD1/2 and YAP/TAZ), histological and molecular analysis, epistasis experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, rigorous genetic approach but single lab and mechanism of TEAD-INSM1 cooperation not biochemically characterized","pmids":["bio_10.1101_2024.12.19.629472"],"is_preprint":true},{"year":2025,"finding":"lnc81 physically interacts with TEAD2 in ovarian granulosa cells, as shown by RNA immunoprecipitation (RIP), and is predominantly nuclear. lnc81 knockdown upregulates CCN1/CCN2 protein levels without affecting TEAD2 protein expression, suggesting lnc81 modulates TEAD2 transcriptional activity rather than its stability.","method":"RNA immunoprecipitation (RIP), subcellular fractionation, siRNA knockdown, western blot","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay for interaction, functional consequence inferred indirectly; single lab, single method","pmids":["40928008"],"is_preprint":false},{"year":2026,"finding":"MEOX1 promotes TEAD2 transcription by binding to the -988 to -982 nt region of the TEAD2 promoter, as demonstrated by molecular docking and site-specific mutation experiments, establishing MEOX1 as a direct transcriptional activator of TEAD2. Knockdown of MEOX1 decreased TEAD2 expression and reduced Hippo pathway target transcription and hepatic stellate cell activation.","method":"Promoter binding assay with site-specific mutation, CETSA, surface plasmon resonance, siRNA knockdown, in vivo CCl4 fibrosis model","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding with mutation, multiple orthogonal methods (SPR, CETSA), but regulation of TEAD2 by MEOX1 is single lab","pmids":["42116734"],"is_preprint":false}],"current_model":"TEAD2 is a TEA-domain transcription factor that lacks an intrinsic activation domain and requires co-activators (primarily YAP, and also TAZ) to drive transcription; its YAP-binding domain adopts an immunoglobulin-like fold that presents a conserved surface for YAP docking, while its TEA domain mediates sequence-specific binding to MCAT/GT-IIC elements and GC-rich TATA-less promoters; it functions downstream of the Hippo pathway (and upstream via Yes kinase phosphorylation of YAP) to regulate organ size, embryonic development (notochord, neural tube closure, neural progenitor lineage), ES cell pluripotency through chromatin looping at 2i-specific loci, and—when aberrantly activated—promotes tumorigenesis by upregulating proliferative targets (ANLN, KIF23, FGFR4, TAK1) and repressing acetyl-CoA biosynthesis in HCC."},"narrative":{"mechanistic_narrative":"TEAD2 (originally identified as the transcription factor ETF) is a TEA/ATTS-domain DNA-binding transcription factor that partners with Hippo-pathway co-activators to control proliferation, embryonic development, stem cell state, and tumorigenesis [PMID:9502435, PMID:18332127, PMID:38605224]. Its DNA-binding TEA domain recognizes M-CAT/GT-IIC elements and preferentially activates GC-rich, TATA-less promoters [PMID:9502435, PMID:2768275], while a separate immunoglobulin-like YAP-binding domain presents an extensive conserved surface that docks the natively unfolded TEAD-binding region of YAP [PMID:20368466]. Because TEAD2 relies on recruited co-activators, transcriptional output is set by YAP/TAZ engagement: in mouse ES cells a Yes-kinase–YAP–TEAD2 axis drives Oct-3/4 and Nanog promoter activity to sustain self-renewal [PMID:21385842], and TEAD1/TEAD2 use YAP as their major coactivator in vivo, with double-knockout embryos dying at E9.5 with growth failure, loss of notochord maintenance, and reduced proliferation [PMID:18332127]. In development TEAD2 activates lineage enhancers, directly binding a Pax3 neural-crest enhancer and the Fgfr4 promoter through an M-CAT motif [PMID:14736747, PMID:16267055], and is independently required for neural tube closure [PMID:17868131]. In ES cells TEAD2 reorganizes the genome, gaining chromatin occupancy in the ground state and mediating enhancer–promoter looping at 2i-specific loci independently of CTCF and YY1 [PMID:38605224]. When aberrantly activated TEAD2 is oncogenic: it cooperates with TAZ to upregulate ANLN and KIF23 in hepatocellular carcinoma [PMID:36894036], activates the TAK1 promoter to drive sorafenib resistance [PMID:39106149], represses acetyl-CoA biosynthesis pathways in HCC [PMID:36400009], and establishes a proangiogenic enhancer landscape via CD109 in basal-like pancreatic cancer [PMID:36907523].","teleology":[{"year":1989,"claim":"Established the founding biochemical activity of TEAD2/ETF as a transcription factor with a defined promoter preference, answering what kind of promoters it acts on.","evidence":"In vitro transcription and gel-shift assays with TATA-box substitution across promoter variants","pmids":["2768275"],"confidence":"High","gaps":["Did not identify the co-activator requirement","Physiological target genes not defined"]},{"year":1998,"claim":"Cloned full-length ETF/TEAD2 and assigned its TEA/ATTS DNA-binding domain and a transcriptional activation capacity, defining the protein architecture.","evidence":"cDNA cloning, gel mobility shift on M-CAT/GT-IIC elements, GAL4-fusion activation assay","pmids":["9502435"],"confidence":"Medium","gaps":["GAL4-fusion activation does not establish intrinsic activation in native context","Co-activator dependence not addressed"]},{"year":2004,"claim":"Connected TEAD2 to a specific developmental enhancer, showing it directly activates Pax3 in the dorsal neural tube and identifying YAP65 as a co-expressed partner.","evidence":"Transgenic mouse reporters, binding-site mutagenesis, dominant-negative Tead2-Engrailed fusion","pmids":["14736747"],"confidence":"High","gaps":["Direct biochemical TEAD2-YAP interaction not shown here","Whether YAP is the functional coactivator at this enhancer untested"]},{"year":2005,"claim":"Placed TEAD2 in a defined transcriptional cascade by showing it activates Fgfr4 through an M-CAT motif while being itself a MyoD target, linking it to muscle regeneration.","evidence":"ChIP, promoter reporters with M-CAT mutagenesis, Fgfr4-null regeneration phenotype","pmids":["16267055"],"confidence":"High","gaps":["Co-activator at the Fgfr4 promoter not identified","TEAD2-specific loss-of-function in muscle not tested"]},{"year":2007,"claim":"Revealed a developmental role distinct from its enhancer targets, showing Tead2 loss causes neural tube closure defects independent of Pax3 regulation.","evidence":"Mouse knockout phenotyping with folic acid and pifithrin-alpha rescue","pmids":["17868131"],"confidence":"Medium","gaps":["Molecular pathway for exencephaly not defined","Maternal genetic contribution mechanism unresolved"]},{"year":2008,"claim":"Demonstrated in vivo that TEAD1 and TEAD2 are functionally redundant and depend on YAP as coactivator, establishing the genetic logic of the TEAD-YAP module in embryogenesis.","evidence":"Tead1/Tead2 double knockout with Yap genetic epistasis, histology","pmids":["18332127"],"confidence":"High","gaps":["Does not separate TEAD2-specific from TEAD1 functions","Direct target genes driving lethality not enumerated"]},{"year":2010,"claim":"Provided the structural basis for co-activator dependence by solving the TEAD2 YAP-binding domain fold and mapping the YAP docking surface.","evidence":"X-ray crystallography of YBD, NMR of YAP, in vitro and in vivo binding assays","pmids":["20368466"],"confidence":"High","gaps":["Structure of the full TEAD2-YAP-DNA complex not determined","TAZ binding mode not addressed"]},{"year":2011,"claim":"Defined an upstream signaling input, showing Yes kinase phosphorylates YAP to activate YAP-TEAD2 transcription required for ES cell self-renewal downstream of LIF.","evidence":"Co-IP, kinase assay, promoter reporters, siRNA, chromatin association at Oct-3/4 promoter","pmids":["21385842"],"confidence":"High","gaps":["Genome-wide TEAD2 targets in ESCs not mapped here","Relative contribution of other TEAD paralogs not resolved"]},{"year":2019,"claim":"Extended TEAD2's chromatin role to lineage specification and identified post-transcriptional regulation, showing Tead2 co-occupies Pax3-bound myogenic elements and is repressed by miR-608 to set drug sensitivity.","evidence":"ChIP-seq/ATAC-seq in Pax3-induced ESCs and embryos; dual-luciferase 3'UTR reporter and rescue in NSCLC","pmids":["30807574","31485614"],"confidence":"Medium","gaps":["Tead2 functional contribution to myogenesis inferred from co-occupancy, not loss-of-function","miR-608 finding from a single lab"]},{"year":2022,"claim":"Uncovered a repressive metabolic function, showing TEAD2 with E2A represses acetyl-CoA biosynthesis to drive HCC growth.","evidence":"RNA-seq, siRNA knockdown, acetyl-CoA and acetylation measurements, mouse HCC model","pmids":["36400009"],"confidence":"Medium","gaps":["Direct promoter occupancy at acetyl-CoA genes not fully mapped","Co-activator/co-repressor identity for repression unclear"]},{"year":2023,"claim":"Identified TEAD2 as the selectively required TEAD paralog for TAZ-driven tumors and defined its proliferative and angiogenic target programs across cancer types.","evidence":"AAV knockout in floxed mice, ChIP, CRISPRi screen, ATAC/ChIP-seq, in vivo HCC and PDA models","pmids":["36894036","36907523"],"confidence":"High","gaps":["Mechanism of TEAD2 paralog selectivity for TAZ not defined","PDA findings from a single lab"]},{"year":2024,"claim":"Established TEAD2 as a genome organizer in pluripotency and a driver of therapy resistance, linking it to enhancer-promoter looping in ground-state ESCs and to TAK1-mediated sorafenib resistance.","evidence":"ChIP-seq/ATAC-seq/Hi-C with Tead2 knockout ESCs; ATAC-seq and ChIP at the TAK1 promoter with inhibitor rescue","pmids":["38605224","39106149"],"confidence":"Medium","gaps":["How TEAD2 mediates looping independent of CTCF/YY1 mechanistically unresolved","TAK1 resistance study single lab"]},{"year":2024,"claim":"Probed YAP/TAZ-independent TEAD2 functions and additional regulators, indicating TEAD1/2 promote neural progenitor lineage progression and cooperate with EGFR-YAP signaling in drug-resistant melanoma.","evidence":"Conditional double knockouts and epistasis (preprint); EGFR/YAP1 inhibitor and knockdown experiments in melanoma","pmids":["bio_10.1101_2024.12.19.629472","39298503"],"confidence":"Low","gaps":["TEAD-INSM1 cooperation not biochemically characterized","TEAD2-specific step in melanoma resistance not dissected","Neural progenitor work is a preprint"]},{"year":2025,"claim":"Expanded the regulatory and pharmacological landscape, identifying a peptide inhibitor of the TEA domain and an lncRNA modulator of TEAD2 activity.","evidence":"DNA-binding and reporter assays with TEAi peptide and tumor model (preprint); RNA immunoprecipitation and knockdown for lnc81 in granulosa cells","pmids":["bio_10.1101_2025.08.31.672803","40928008"],"confidence":"Low","gaps":["TEAi mechanism of DNA-binding inhibition and nuclear export lacks structural validation","lnc81 interaction from single RIP assay without reciprocal validation"]},{"year":2026,"claim":"Identified an upstream transcriptional activator of TEAD2, showing MEOX1 directly binds the TEAD2 promoter to drive its expression in hepatic fibrosis.","evidence":"Promoter binding with site-specific mutation, CETSA, SPR, knockdown, CCl4 fibrosis model","pmids":["42116734"],"confidence":"Medium","gaps":["MEOX1-TEAD2 regulation from a single lab","Whether this axis operates outside hepatic stellate cells untested"]},{"year":null,"claim":"How TEAD2 achieves paralog-selective requirement for TAZ-driven and lineage-specific programs, and how it directs CTCF/YY1-independent enhancer-promoter looping, remain unresolved at the mechanistic level.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TEAD2 engaging chromatin loops","Determinants of TEAD2 vs TEAD1/4 functional selectivity unknown","Co-repressor identity for TEAD2-mediated metabolic gene repression not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,17,4,0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,17,1,9,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,12,18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,17,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,5,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,10,11]}],"complexes":["TEAD-YAP complex","TEAD-TAZ complex"],"partners":["YAP1","TAZ","PAX3","SIX4","MEOX1","LNC81","E2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15562","full_name":"Transcriptional enhancer factor TEF-4","aliases":["TEA domain family member 2","TEAD-2"],"length_aa":447,"mass_kda":49.2,"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 the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. 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NMR studies showed that the TEAD-binding domain of YAP is natively unfolded and undergoes localized conformational changes upon TEAD2 binding. In vitro binding and in vivo functional assays defined an extensive conserved surface of TEAD2 YBD as the YAP-binding site.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, in vitro binding assays, in vivo functional assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with NMR and functional validation in a single rigorous study\",\n      \"pmids\": [\"20368466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEAD2 and its transcriptional co-activator YAP cooperate in a signaling pathway downstream of the tyrosine kinase Yes in mouse embryonic stem cells. Kinase-active Yes binds and phosphorylates YAP, activates YAP-TEAD2-dependent transcription, and this pathway is required downstream of LIF for ES cell self-renewal. TEAD2 was shown to associate directly with the Oct-3/4 promoter, and activation of the Yes-YAP-TEAD2 pathway induced Oct-3/4 and Nanog promoter activity.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, promoter-reporter assays, siRNA knockdown, chromatin association assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase assay, reporter assays, and siRNA knockdown with defined cellular phenotype in a single study\",\n      \"pmids\": [\"21385842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tead1 and Tead2 are functionally redundant in mouse embryonic development. Tead1−/−;Tead2−/− double-knockout embryos die at E9.5 with severe growth defects, lack of notochord maintenance, and defects in yolk sac vasculature. Genetic interaction experiments demonstrated that Tead1 and Tead2 use YAP as a major coactivator in vivo. Double-knockout embryos showed reduced cell proliferation and increased apoptosis.\",\n      \"method\": \"Mouse knockout genetics, genetic epistasis with Yap mutants, histological and molecular analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double knockout plus genetic epistasis with YAP mutants, replicated across developmental stages\",\n      \"pmids\": [\"18332127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tead2 binds to a neural crest enhancer element in the Pax3 genomic locus and activates Pax3 expression. Mutation of the Tead2 binding site in Pax3 transgenic constructs abolished neural expression. A Tead2-Engrailed repressor fusion suppressed Pax3 expression in P19 cells and in vivo. Tead2 and its co-activator YAP65 are co-expressed with Pax3 in the dorsal neural tube.\",\n      \"method\": \"Transgenic mouse reporter assays, co-transfection, dominant-negative Tead2-Engrailed fusion, site-directed mutagenesis of binding site\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic enhancer assays with binding site mutation and dominant-negative, replicated in cell culture\",\n      \"pmids\": [\"14736747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Tead2 directly activates the Fgfr4 promoter through an M-CAT motif (5'-CATTCCT-3'). Mutation of this M-CAT motif abolished Tead2-driven Fgfr4 promoter activity in co-transfection assays. MyoD directly bound two E-boxes in the first intron of Tead2 (by ChIP), and co-transfection of MyoD activated Tead2 intronic reporter activity in a dose-dependent manner, establishing a MyoD-Tead2-Fgfr4 transcriptional pathway required for muscle regeneration.\",\n      \"method\": \"Co-transfection/promoter-reporter assay, site-directed mutagenesis of M-CAT, chromatin immunoprecipitation (ChIP), immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for direct binding, promoter reporter with mutagenesis, and in vivo Fgfr4 null mouse regeneration phenotype\",\n      \"pmids\": [\"16267055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Inactivation of the Tead2 gene in mice significantly increased the risk of exencephaly (defect in neural tube closure). This role in neural tube closure was found to be independent of Pax3 regulation, as Pax3 expression was normal in E11.5 Tead2 nullizygous embryos. The risk of exencephaly was greatest with Tead2 nullizygous females and could be suppressed by folic acid or pifithrin-alpha, revealing a maternal genetic contribution.\",\n      \"method\": \"Mouse knockout, phenotypic analysis, pharmacological rescue (folic acid, pifithrin-alpha)\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined phenotype, pharmacological rescue, but mechanistic pathway only partially characterized\",\n      \"pmids\": [\"17868131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Transcription factor ETF (TEAD2) specifically stimulates transcription from promoters lacking a TATA box. ETF recognizes GC-rich sequences including GC boxes and TATA boxes (with lower affinity). ETF-binding sites only functionally activated transcription when placed upstream of TATA-less promoters; introduction of a TATA box into the EGFR promoter abolished ETF responsiveness.\",\n      \"method\": \"In vitro transcription assay, DNA binding (gel-shift), promoter-reporter analysis with TATA box substitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transcription reconstitution with mutagenesis and multiple promoter variants tested\",\n      \"pmids\": [\"2768275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ETF (TEAD2) binds to three upstream and one downstream site in the mouse p53 promoter, and adenovirus E1a proteins stimulate this binding to transcriptionally activate the p53 gene. The ETF site downstream of the transcription start site was identified as the key element conferring E1a responsiveness. Both major E1a proteins (243R and 289R) were required for complete activation.\",\n      \"method\": \"Promoter-reporter assay, electrophoretic mobility shift assay (EMSA), deletion/mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and functional reporter assays in a single lab with multiple binding site variants\",\n      \"pmids\": [\"10446138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD2 (together with E2A) transcriptionally represses all six acetyl-CoA biosynthesis pathways in hepatocellular carcinoma, leading to decreased acetyl-CoA levels and hypo-acetylation of non-histone proteins. Knockdown of TEAD2 restored acetyl-CoA levels and inhibited tumor growth in a mouse HCC model.\",\n      \"method\": \"RNA sequencing, mouse HCC model, siRNA knockdown, metabolic measurements of acetyl-CoA levels and protein acetylation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined metabolic phenotype in mouse model, single lab\",\n      \"pmids\": [\"36400009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatocellular carcinoma, TAZ-driven tumor growth specifically requires TEAD2 (and to a lesser extent TEAD4). TAZ and TEAD2 promote HCC proliferation via transcriptional upregulation of ANLN and KIF23, as confirmed by chromatin immunoprecipitation and CRISPRi screen. TAZ expression in HCC is regulated by cholesterol synthesis upstream of TEAD2.\",\n      \"method\": \"AAV-mediated knockout in floxed mice, RNA-seq, ChIP, CRISPRi screen, TAZ-S89A overexpression HCC model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, CRISPRi, genetic knockout, overexpression) in both mouse and human HCC\",\n      \"pmids\": [\"36894036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In basal-like pancreatic ductal adenocarcinoma (PDA) cells, TEAD2 drives a proangiogenic enhancer landscape. Genetic and pharmacologic inhibition of TEAD2 impairs proangiogenic phenotypes in vitro and cancer progression in vivo. CD109 was identified as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells.\",\n      \"method\": \"Epigenome analysis (ATAC-seq/ChIP-seq), transcriptome analysis, loss-of-function (genetic and pharmacologic), in vivo tumor models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenomic and transcriptomic plus in vivo loss-of-function, single lab\",\n      \"pmids\": [\"36907523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD2 binds to the TAK1 promoter and transcriptionally activates TAK1 expression, thereby mediating sorafenib resistance in hepatocellular carcinoma. Functional assays showed that TEAD2 promotes HCC progression and drug resistance, and TAK1 inhibitors reversed TEAD2-induced sorafenib resistance.\",\n      \"method\": \"Accessibility sequencing (ATAC-seq), chromatin immunoprecipitation for TAK1 promoter, functional cell-based assays, TAK1 inhibitor treatment\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding plus functional rescue, single lab\",\n      \"pmids\": [\"39106149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD2 exhibits increased chromatin binding in ground-state (2i/LIF) mouse embryonic stem cells, targeting active chromatin regions to regulate 2i-specific gene expression. TEAD2 mediates enhancer-promoter looping interactions during the serum/LIF to 2i/LIF transition. Deletion of Tead2 reduces a specific set of enhancer-promoter interactions without significantly affecting CTCF or YY1 binding.\",\n      \"method\": \"ChIP-seq, ATAC-seq, Hi-C/chromatin interaction assays, Tead2 knockout ESCs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genomics methods (ChIP-seq, ATAC-seq, chromatin looping) combined with genetic deletion\",\n      \"pmids\": [\"38605224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEAD2 mRNA is a direct target of miR-608 in NSCLC cells, as confirmed by dual-luciferase reporter assay. miR-608 overexpression negatively regulated TEAD2 protein levels and decreased expression of Hippo-YAP pathway target genes. Restoration of TEAD2 reversed the increased cisplatin sensitivity induced by miR-608, placing TEAD2 downstream of miR-608 in mediating drug sensitivity.\",\n      \"method\": \"Dual-luciferase reporter assay, western blot, siRNA/overexpression rescue experiments\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter confirming direct 3'UTR targeting plus rescue experiments, single lab\",\n      \"pmids\": [\"31485614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pax3 cooperates with Six4 and Tead2 at chromatin to specify the skeletal myogenic lineage. ChIP-seq and ATAC-seq in Pax3-induced embryonic stem cells and Pax3-null E9.5 mouse embryos showed that Pax3 binding increases chromatin accessibility and that Tead2 co-occupies Pax3-bound elements in the context of myogenic specification.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq, Pax3-null mouse embryo analysis, ES cell differentiation platform\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomics methods, but Tead2 functional contribution to myogenesis is inferred from co-occupancy rather than Tead2-specific loss-of-function\",\n      \"pmids\": [\"30807574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A 117-bp enhancer in the first intron of the mouse ETF/Tead2 gene is required for cell-specific transcriptional activation. This enhancer contains a GC box and two GA elements. Sp1 acts as an activator by competing with an unknown repressor (GA element-binding factor) for binding to the GC box and GA elements to achieve full enhancer activity.\",\n      \"method\": \"Transient transfection assays, electrophoretic mobility shift assays (EMSA), deletion and point mutation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple deletion/mutation constructs with EMSA and functional reporter, single lab\",\n      \"pmids\": [\"11741291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vemurafenib-resistant melanoma cells, EGFR signaling activates YAP1 nuclear localization, which in turn cooperates with TEAD2 to upregulate STIM1 expression. EGF and EGFR levels are increased in resistant cells, and this pathway drives STIM1-dependent calcium entry associated with drug resistance.\",\n      \"method\": \"Pathway inhibitor experiments, YAP1 nuclear localization assays, gene knockdown, reporter/expression analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily knockdown and expression analyses with limited mechanistic dissection of the TEAD2-specific step\",\n      \"pmids\": [\"39298503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ETF (TEAD2/mETF) encodes a full-length protein with a TEA/ATTS DNA-binding domain. Gel mobility shift assays confirmed that ETF binds M-CAT/GT-IIC elements, and GAL4-fusion protein analysis demonstrated that ETF contains a transcriptional activation domain.\",\n      \"method\": \"cDNA cloning, gel mobility shift assay, GAL4 fusion transcription activation assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and activation domain assays, single lab\",\n      \"pmids\": [\"9502435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A peptide inhibitor (TEAi) derived from Drosophila Nerfin-1 directly binds the TEA DNA-binding domain of TEAD2 and inhibits its DNA-binding capacity without direct DNA interaction, thereby abolishing promoter recruitment of the TEAD-YAP complex. TEAi also induced nuclear export and cytoplasmic accumulation of TEAD2, suggesting a non-canonical mechanism. TEAi suppressed TEAD-YAP-driven transcriptional activity (CTGF, CYR61) and tumor growth in vivo.\",\n      \"method\": \"Luciferase reporter assay, qPCR, DNA-binding assay, nuclear/cytoplasmic fractionation, in vivo tumor model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanism of DNA-binding inhibition and nuclear export inferred from functional assays without structural validation\",\n      \"pmids\": [\"bio_10.1101_2025.08.31.672803\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1/2 have both YAP/TAZ-dependent and YAP/TAZ-independent functions during ventral telencephalon development in mice. Whereas YAP/TAZ loss depletes early progenitors, TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote neural progenitor lineage progression. TEAD1/2 do so in part by inhibiting Notch signaling and cooperating with INSM1.\",\n      \"method\": \"Mouse conditional double knockout (TEAD1/2 and YAP/TAZ), histological and molecular analysis, epistasis experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, rigorous genetic approach but single lab and mechanism of TEAD-INSM1 cooperation not biochemically characterized\",\n      \"pmids\": [\"bio_10.1101_2024.12.19.629472\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lnc81 physically interacts with TEAD2 in ovarian granulosa cells, as shown by RNA immunoprecipitation (RIP), and is predominantly nuclear. lnc81 knockdown upregulates CCN1/CCN2 protein levels without affecting TEAD2 protein expression, suggesting lnc81 modulates TEAD2 transcriptional activity rather than its stability.\",\n      \"method\": \"RNA immunoprecipitation (RIP), subcellular fractionation, siRNA knockdown, western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay for interaction, functional consequence inferred indirectly; single lab, single method\",\n      \"pmids\": [\"40928008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEOX1 promotes TEAD2 transcription by binding to the -988 to -982 nt region of the TEAD2 promoter, as demonstrated by molecular docking and site-specific mutation experiments, establishing MEOX1 as a direct transcriptional activator of TEAD2. Knockdown of MEOX1 decreased TEAD2 expression and reduced Hippo pathway target transcription and hepatic stellate cell activation.\",\n      \"method\": \"Promoter binding assay with site-specific mutation, CETSA, surface plasmon resonance, siRNA knockdown, in vivo CCl4 fibrosis model\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding with mutation, multiple orthogonal methods (SPR, CETSA), but regulation of TEAD2 by MEOX1 is single lab\",\n      \"pmids\": [\"42116734\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD2 is a TEA-domain transcription factor that lacks an intrinsic activation domain and requires co-activators (primarily YAP, and also TAZ) to drive transcription; its YAP-binding domain adopts an immunoglobulin-like fold that presents a conserved surface for YAP docking, while its TEA domain mediates sequence-specific binding to MCAT/GT-IIC elements and GC-rich TATA-less promoters; it functions downstream of the Hippo pathway (and upstream via Yes kinase phosphorylation of YAP) to regulate organ size, embryonic development (notochord, neural tube closure, neural progenitor lineage), ES cell pluripotency through chromatin looping at 2i-specific loci, and—when aberrantly activated—promotes tumorigenesis by upregulating proliferative targets (ANLN, KIF23, FGFR4, TAK1) and repressing acetyl-CoA biosynthesis in HCC.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEAD2 (originally identified as the transcription factor ETF) is a TEA/ATTS-domain DNA-binding transcription factor that partners with Hippo-pathway co-activators to control proliferation, embryonic development, stem cell state, and tumorigenesis [#17, #2, #12]. Its DNA-binding TEA domain recognizes M-CAT/GT-IIC elements and preferentially activates GC-rich, TATA-less promoters [#17, #6], while a separate immunoglobulin-like YAP-binding domain presents an extensive conserved surface that docks the natively unfolded TEAD-binding region of YAP [#0]. Because TEAD2 relies on recruited co-activators, transcriptional output is set by YAP/TAZ engagement: in mouse ES cells a Yes-kinase–YAP–TEAD2 axis drives Oct-3/4 and Nanog promoter activity to sustain self-renewal [#1], and TEAD1/TEAD2 use YAP as their major coactivator in vivo, with double-knockout embryos dying at E9.5 with growth failure, loss of notochord maintenance, and reduced proliferation [#2]. In development TEAD2 activates lineage enhancers, directly binding a Pax3 neural-crest enhancer and the Fgfr4 promoter through an M-CAT motif [#3, #4], and is independently required for neural tube closure [#5]. In ES cells TEAD2 reorganizes the genome, gaining chromatin occupancy in the ground state and mediating enhancer–promoter looping at 2i-specific loci independently of CTCF and YY1 [#12]. When aberrantly activated TEAD2 is oncogenic: it cooperates with TAZ to upregulate ANLN and KIF23 in hepatocellular carcinoma [#9], activates the TAK1 promoter to drive sorafenib resistance [#11], represses acetyl-CoA biosynthesis pathways in HCC [#8], and establishes a proangiogenic enhancer landscape via CD109 in basal-like pancreatic cancer [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established the founding biochemical activity of TEAD2/ETF as a transcription factor with a defined promoter preference, answering what kind of promoters it acts on.\",\n      \"evidence\": \"In vitro transcription and gel-shift assays with TATA-box substitution across promoter variants\",\n      \"pmids\": [\"2768275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the co-activator requirement\", \"Physiological target genes not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloned full-length ETF/TEAD2 and assigned its TEA/ATTS DNA-binding domain and a transcriptional activation capacity, defining the protein architecture.\",\n      \"evidence\": \"cDNA cloning, gel mobility shift on M-CAT/GT-IIC elements, GAL4-fusion activation assay\",\n      \"pmids\": [\"9502435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GAL4-fusion activation does not establish intrinsic activation in native context\", \"Co-activator dependence not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected TEAD2 to a specific developmental enhancer, showing it directly activates Pax3 in the dorsal neural tube and identifying YAP65 as a co-expressed partner.\",\n      \"evidence\": \"Transgenic mouse reporters, binding-site mutagenesis, dominant-negative Tead2-Engrailed fusion\",\n      \"pmids\": [\"14736747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical TEAD2-YAP interaction not shown here\", \"Whether YAP is the functional coactivator at this enhancer untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed TEAD2 in a defined transcriptional cascade by showing it activates Fgfr4 through an M-CAT motif while being itself a MyoD target, linking it to muscle regeneration.\",\n      \"evidence\": \"ChIP, promoter reporters with M-CAT mutagenesis, Fgfr4-null regeneration phenotype\",\n      \"pmids\": [\"16267055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-activator at the Fgfr4 promoter not identified\", \"TEAD2-specific loss-of-function in muscle not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a developmental role distinct from its enhancer targets, showing Tead2 loss causes neural tube closure defects independent of Pax3 regulation.\",\n      \"evidence\": \"Mouse knockout phenotyping with folic acid and pifithrin-alpha rescue\",\n      \"pmids\": [\"17868131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway for exencephaly not defined\", \"Maternal genetic contribution mechanism unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated in vivo that TEAD1 and TEAD2 are functionally redundant and depend on YAP as coactivator, establishing the genetic logic of the TEAD-YAP module in embryogenesis.\",\n      \"evidence\": \"Tead1/Tead2 double knockout with Yap genetic epistasis, histology\",\n      \"pmids\": [\"18332127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate TEAD2-specific from TEAD1 functions\", \"Direct target genes driving lethality not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis for co-activator dependence by solving the TEAD2 YAP-binding domain fold and mapping the YAP docking surface.\",\n      \"evidence\": \"X-ray crystallography of YBD, NMR of YAP, in vitro and in vivo binding assays\",\n      \"pmids\": [\"20368466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full TEAD2-YAP-DNA complex not determined\", \"TAZ binding mode not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined an upstream signaling input, showing Yes kinase phosphorylates YAP to activate YAP-TEAD2 transcription required for ES cell self-renewal downstream of LIF.\",\n      \"evidence\": \"Co-IP, kinase assay, promoter reporters, siRNA, chromatin association at Oct-3/4 promoter\",\n      \"pmids\": [\"21385842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide TEAD2 targets in ESCs not mapped here\", \"Relative contribution of other TEAD paralogs not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TEAD2's chromatin role to lineage specification and identified post-transcriptional regulation, showing Tead2 co-occupies Pax3-bound myogenic elements and is repressed by miR-608 to set drug sensitivity.\",\n      \"evidence\": \"ChIP-seq/ATAC-seq in Pax3-induced ESCs and embryos; dual-luciferase 3'UTR reporter and rescue in NSCLC\",\n      \"pmids\": [\"30807574\", \"31485614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tead2 functional contribution to myogenesis inferred from co-occupancy, not loss-of-function\", \"miR-608 finding from a single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a repressive metabolic function, showing TEAD2 with E2A represses acetyl-CoA biosynthesis to drive HCC growth.\",\n      \"evidence\": \"RNA-seq, siRNA knockdown, acetyl-CoA and acetylation measurements, mouse HCC model\",\n      \"pmids\": [\"36400009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy at acetyl-CoA genes not fully mapped\", \"Co-activator/co-repressor identity for repression unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TEAD2 as the selectively required TEAD paralog for TAZ-driven tumors and defined its proliferative and angiogenic target programs across cancer types.\",\n      \"evidence\": \"AAV knockout in floxed mice, ChIP, CRISPRi screen, ATAC/ChIP-seq, in vivo HCC and PDA models\",\n      \"pmids\": [\"36894036\", \"36907523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TEAD2 paralog selectivity for TAZ not defined\", \"PDA findings from a single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TEAD2 as a genome organizer in pluripotency and a driver of therapy resistance, linking it to enhancer-promoter looping in ground-state ESCs and to TAK1-mediated sorafenib resistance.\",\n      \"evidence\": \"ChIP-seq/ATAC-seq/Hi-C with Tead2 knockout ESCs; ATAC-seq and ChIP at the TAK1 promoter with inhibitor rescue\",\n      \"pmids\": [\"38605224\", \"39106149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TEAD2 mediates looping independent of CTCF/YY1 mechanistically unresolved\", \"TAK1 resistance study single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Probed YAP/TAZ-independent TEAD2 functions and additional regulators, indicating TEAD1/2 promote neural progenitor lineage progression and cooperate with EGFR-YAP signaling in drug-resistant melanoma.\",\n      \"evidence\": \"Conditional double knockouts and epistasis (preprint); EGFR/YAP1 inhibitor and knockdown experiments in melanoma\",\n      \"pmids\": [\"bio_10.1101_2024.12.19.629472\", \"39298503\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TEAD-INSM1 cooperation not biochemically characterized\", \"TEAD2-specific step in melanoma resistance not dissected\", \"Neural progenitor work is a preprint\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the regulatory and pharmacological landscape, identifying a peptide inhibitor of the TEA domain and an lncRNA modulator of TEAD2 activity.\",\n      \"evidence\": \"DNA-binding and reporter assays with TEAi peptide and tumor model (preprint); RNA immunoprecipitation and knockdown for lnc81 in granulosa cells\",\n      \"pmids\": [\"bio_10.1101_2025.08.31.672803\", \"40928008\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TEAi mechanism of DNA-binding inhibition and nuclear export lacks structural validation\", \"lnc81 interaction from single RIP assay without reciprocal validation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an upstream transcriptional activator of TEAD2, showing MEOX1 directly binds the TEAD2 promoter to drive its expression in hepatic fibrosis.\",\n      \"evidence\": \"Promoter binding with site-specific mutation, CETSA, SPR, knockdown, CCl4 fibrosis model\",\n      \"pmids\": [\"42116734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MEOX1-TEAD2 regulation from a single lab\", \"Whether this axis operates outside hepatic stellate cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEAD2 achieves paralog-selective requirement for TAZ-driven and lineage-specific programs, and how it directs CTCF/YY1-independent enhancer-promoter looping, remain unresolved at the mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TEAD2 engaging chromatin loops\", \"Determinants of TEAD2 vs TEAD1/4 functional selectivity unknown\", \"Co-repressor identity for TEAD2-mediated metabolic gene repression not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 17, 4, 0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 17, 1, 9, 8]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 12, 18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 17, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 5, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 10, 11]}\n    ],\n    \"complexes\": [\"TEAD-YAP complex\", \"TEAD-TAZ complex\"],\n    \"partners\": [\"YAP1\", \"TAZ\", \"Pax3\", \"Six4\", \"MEOX1\", \"lnc81\", \"E2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}