{"gene":"DACT2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2003,"finding":"Human DACT2 (DAPPER2) was identified as containing seven conserved DAPH domains including a leucine zipper (DAPH2), serine-rich region (DAPH3), and C-terminal PDZ-binding motif (DAPH7), establishing it as a DVL-binding protein homolog involved in WNT signaling.","method":"Bioinformatics/in silico characterization with evolutionary analysis","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no direct experimental validation of binding or function","pmids":["12632086"],"is_preprint":false},{"year":2006,"finding":"Mouse Dact2 (mDpr2) overexpression inhibited TGF-β-induced Smad-responsive reporter activity and targeted TGF-β type I receptor ALK5 for lysosomal degradation in mammalian cells, demonstrating evolutionarily conserved negative regulation of TGF-β/Nodal signaling.","method":"Overexpression in mammalian cells with Smad-reporter assays, receptor degradation assays, and zebrafish embryo overexpression","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, receptor degradation, in vivo zebrafish), single lab","pmids":["17197390"],"is_preprint":false},{"year":2010,"finding":"Dact2 is specifically expressed in ureteric bud/collecting duct epithelium of the developing mouse kidney; siRNA knockdown in collecting duct cells resulted in constitutive phospho-Smad2, elevated TGF-β-induced phospho-Smad2, defective actomyosin cable assembly at the leading edge during wound healing, and abnormal cyst/tubule morphology in 3D culture, placing Dact2 as a negative regulator of TGF-β signaling controlling collecting duct morphogenesis.","method":"siRNA knockdown, phospho-Smad2 immunoblotting, monolayer wound-healing assay, 3D culture morphology, immunofluorescence","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts (signaling, migration, morphology), single lab","pmids":["20685821"],"is_preprint":false},{"year":2013,"finding":"DACT2 suppresses canonical Wnt signaling in lung cancer cells by inhibiting TCF/LEF transcriptional activity; its expression is silenced by promoter CpG hypermethylation, and restoration of DACT2 reduces β-catenin expression and inhibits tumor proliferation in vitro and in xenograft models.","method":"Methylation-specific PCR, western blotting, siRNA knockdown, TCF/LEF reporter assay, xenograft mouse model","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (reporter assay, protein expression, in vivo xenograft), single lab","pmids":["22806826"],"is_preprint":false},{"year":2013,"finding":"Dact2 inhibits the canonical Wnt signaling pathway in odontogenesis by physically interacting with the transcription factor PITX2, repressing PITX2-driven activation of downstream targets (Dlx2 and amelogenin promoters) and attenuating PITX2-mediated Topflash Wnt reporter activity; Pitx2 in turn endogenously activates Dact2 expression forming a feedback loop.","method":"Co-immunoprecipitation, transient transfection, Topflash reporter assay, loss-of-function/gain-of-function studies, immunohistochemistry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays and physical interaction (Co-IP), single lab, multiple orthogonal methods","pmids":["23349981"],"is_preprint":false},{"year":2013,"finding":"DACT2 suppresses hepatocellular carcinoma by inhibiting Wnt signaling: re-expression suppressed TCF-4 transcriptional activity and Wnt downstream gene expression, induced G2-M arrest, and inhibited xenograft tumor growth; depletion of DACT2 reactivated TCF-4 activity.","method":"TCF-4 reporter assay, flow cytometry, siRNA knockdown, xenograft nude mice, western blotting","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, cell cycle, in vivo), single lab","pmids":["23449122"],"is_preprint":false},{"year":2014,"finding":"DACT2 restoration in papillary thyroid cancer cells (TPC-1) decreased β-catenin, c-Myc, cyclinD1, and MMP-9 and increased phospho-β-catenin, inhibited TCF/LEF activity in wild-type or mutant β-catenin contexts, and suppressed proliferation, invasion, and migration; co-transfection of DACT2 with Dvl2 increased TCF/LEF activity, indicating Dact2 modulates β-catenin phosphorylation and acts upstream of the TCF/LEF complex.","method":"TCF/LEF reporter assay, western blotting, siRNA knockdown, co-transfection, migration/invasion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including reporter assay and protein phosphorylation analysis, single lab","pmids":["25375359"],"is_preprint":false},{"year":2014,"finding":"DACT2 inhibits both canonical and noncanonical WNT signaling in gastric cancer cells (SGC7901) and suppresses gastric cancer xenograft growth; restoration of DACT2 expression also inhibited cell proliferation, migration, and invasion.","method":"siRNA, colony formation assay, flow cytometry, immunofluorescence, xenograft mouse model, WNT reporter assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional and signaling assays, in vivo xenograft, single lab","pmids":["25520862"],"is_preprint":false},{"year":2016,"finding":"DACT2 inhibits esophageal cancer growth by suppressing Wnt signaling; its expression is silenced by promoter hypermethylation, and restoration suppressed colony formation, migration, invasion, and xenograft tumor growth.","method":"MSP, 5-aza treatment, colony formation, migration/invasion assays, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays plus in vivo xenograft, single lab","pmids":["26919254"],"is_preprint":false},{"year":2016,"finding":"DACT2 ectopic expression in breast cancer cells induced apoptosis, inhibited proliferation and migration, suppressed EMT, and acted through antagonizing both Wnt/β-catenin and Akt/GSK-3 signaling pathways.","method":"Ectopic expression, apoptosis assays, migration assays, western blotting for pathway components, EMT marker analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway readouts (Wnt and Akt/GSK-3), multiple functional assays, single lab","pmids":["27708215"],"is_preprint":false},{"year":2017,"finding":"DACT2 overexpression in glioma cells suppressed proliferation and induced apoptosis by increasing phospho-YAP and phospho-β-catenin, preventing YAP nuclear translocation and sequestering it in the cytoplasm for degradation, placing DACT2 upstream of the YAP pathway via Wnt/β-catenin signaling.","method":"Overexpression and knockdown, flow cytometry, western blotting, nuclear/cytoplasmic fractionation, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including fractionation and in vivo, single lab","pmids":["28796248"],"is_preprint":false},{"year":2018,"finding":"DACT2 ectopic expression in NPC cells induced G2/M arrest by directly suppressing β-catenin/Cdc25c signaling, which sensitized cells to paclitaxel and 5-FU but not cisplatin; DACT2 also suppressed proliferation, migration, and invasion through downregulation of matrix metalloproteinases.","method":"Flow cytometric analysis, immunofluorescence, western blotting, dual-luciferase reporter assay, colony formation, chemosensitivity assay","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including reporter assay and cell cycle analysis, single lab","pmids":["30359298"],"is_preprint":false},{"year":2018,"finding":"TET1, a 5-methylcytosine dioxygenase, promotes demethylation of the DACT2 promoter in NPC cells, restoring DACT2 expression and thereby antagonizing Wnt/β-catenin signaling as part of TET1's tumor suppressor mechanism.","method":"Ectopic TET1 expression, MSP, RT-PCR, western blotting for nuclear β-catenin and downstream targets","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter demethylation linked to expression restoration and downstream signaling, single lab, multiple methods","pmids":["30075814"],"is_preprint":false},{"year":2019,"finding":"The DACT2 promoter SNP rs9364433 modulates DACT2 expression through allele-specific binding of transcription factor TFAP2A; the G allele reduces TFAP2A binding and decreases DACT2 expression in NSCLC cells, establishing TFAP2A as a transcriptional activator of DACT2.","method":"Luciferase reporter gene assay, EMSA (Electrophoretic Mobility Shift Assay), genotyping, in vitro and in vivo DACT2 expression analysis","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter assay provide orthogonal evidence for allele-specific TF binding, single lab","pmids":["31866302"],"is_preprint":false},{"year":2020,"finding":"DACT2 knockout in zebrafish (10-bp deletion via CRISPR-Cas9) enhanced expression of MMP2, MMP9, Snail, VEGF, and ZEB (EMT-related genes), caused gastrointestinal epithelial hyperplasia, pancreatic/hepatic fibrosis, and accelerated wound healing via EMT, establishing Dact2 as a negative regulator of EMT-related gene expression in vivo.","method":"CRISPR-Cas9 knockout zebrafish, RT-PCR, histology, wound healing assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with multiple phenotypic readouts, single lab","pmids":["31983425"],"is_preprint":false},{"year":2020,"finding":"DACT2 overexpression in HL-1 cardiac cells facilitated β-catenin accumulation by reducing its phosphorylation at Thr41/Ser45, and inhibited TGF-β signaling in primary atrial fibroblasts, reducing collagen I and III expression and regulating ion channel gene expression (increased KCNE5, decreased KCNH2 and SCN5A).","method":"Western blotting, RT-PCR, overexpression in HL-1 cells and primary atrial fibroblasts","journal":"Journal of thoracic disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach with western blot readouts, limited mechanistic depth","pmids":["32642106"],"is_preprint":false},{"year":2021,"finding":"miR-181a targets MLL3, a histone methyltransferase, downregulating it in PTC cells; this leads to decreased DACT2 expression and upregulation of YAP and VEGF, promoting angiogenesis, placing DACT2 downstream of MLL3 in an exosomal miR-181a/MLL3/DACT2/YAP-VEGF axis.","method":"miRNA mimic/inhibitor transfection, siRNA knockdown of MLL3, exosome extraction and treatment, in vitro tube formation and proliferation assays, in vivo tumor growth","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway ordering confirmed by rescue experiments and multiple functional assays, single lab","pmids":["33898109"],"is_preprint":false},{"year":2022,"finding":"DACT2 overexpression in lung myofibroblasts inhibited TGF-β-induced myofibroblast differentiation by promoting lysosome-mediated degradation of LDHA, thereby suppressing glycolysis (reduced glucose uptake, extracellular acidification rate, lactate, and ATP); AAV6-mediated DACT2 overexpression attenuated experimental pulmonary fibrosis in vivo.","method":"AAV6 overexpression in vivo, TGF-β-induced differentiation assays, LDHA degradation rate monitoring, lysosome colocalization, metabolic flux assays (ECAR, OCR, ATP, lactate)","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal metabolic and mechanistic assays plus in vivo AAV model, single lab","pmids":["36481337"],"is_preprint":false},{"year":2022,"finding":"DACT2 inhibits liver fibrosis by suppressing TGF-β/Smad signaling and Wnt/β-catenin signaling in HSC-T6 cells; lentiviral overexpression of DACT2 reduced α-SMA, TGF-β1, Smad3, β-catenin, and CyclinD1 protein levels, and decreased MMP-2 and TIMP-1 expression, while also attenuating CCl4-induced liver fibrosis in vivo.","method":"Lentiviral overexpression, western blotting (α-SMA, TGF-β1, Smad3, Smad7, β-catenin, CyclinD1), RT-PCR (MMP-2, TIMP-1), CCl4 liver fibrosis mouse model, histology","journal":"Cellular and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic resolution from abstract, lentiviral overexpression with western blot","pmids":["35818217"],"is_preprint":false},{"year":2023,"finding":"Dact2 knockout mice show elevated Igf1 expression (a Wnt target gene) with β-catenin directly binding and regulating Igf1 transcription; cisplatin-induced nephrotoxicity was alleviated in Dact2 KO mice through reduced apoptosis and downregulation of proapoptotic MAPK signaling, establishing a Dact2/Wnt/β-catenin/Igf1-MAPK axis in kidney injury response.","method":"Dact2 KO mouse model, RNA sequencing, western blotting, ChIP/β-catenin binding to Igf1 locus, Igf1 knockdown, Wnt agonist CHIR-99021 treatment","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with RNA-seq, direct β-catenin/Igf1 binding confirmed, rescue experiments with Wnt agonist, single lab","pmids":["37603122"],"is_preprint":false}],"current_model":"DACT2 is a cytoplasmic scaffold protein that functions as a negative regulator of both Wnt/β-catenin and TGF-β/Nodal signaling: it targets TGF-β type I receptor ALK5 and LDHA for lysosomal degradation, physically interacts with the transcription factor PITX2 to repress Wnt target gene activation, reduces β-catenin phosphorylation status to modulate TCF/LEF transcriptional activity, and suppresses YAP nuclear translocation downstream of Wnt/β-catenin; its expression is positively regulated by the TET1 demethylase (via promoter demethylation) and by the transcription factor TFAP2A, and it is frequently silenced by promoter CpG hypermethylation in multiple cancer types, leading to de-repression of Wnt and TGF-β pathways."},"narrative":{"mechanistic_narrative":"DACT2 is a cytoplasmic negative regulator of developmental signaling that restrains both the Wnt/β-catenin and TGF-β/Nodal pathways, with consequences for epithelial morphogenesis, fibrosis, and tumor suppression [PMID:17197390, PMID:22806826]. It dampens TGF-β signaling by targeting the type I receptor ALK5 for lysosomal degradation, limiting Smad2 phosphorylation, and these activities control collecting duct morphogenesis and oppose fibrotic differentiation [PMID:17197390, PMID:20685821, PMID:36481337, PMID:35818217]. On the Wnt axis DACT2 suppresses TCF/LEF transcriptional output by promoting β-catenin phosphorylation and reducing β-catenin levels, and it physically interacts with the transcription factor PITX2 to repress PITX2-driven Wnt target activation within a reciprocal feedback loop [PMID:23349981, PMID:25375359, PMID:30359298]. Downstream of Wnt/β-catenin it also blocks YAP nuclear translocation, sequestering YAP in the cytoplasm for degradation [PMID:28796248]. DACT2 expression is positively controlled by promoter demethylation through the dioxygenase TET1 and by allele-specific binding of the transcription factor TFAP2A, and it is frequently silenced by promoter CpG hypermethylation across lung, liver, thyroid, gastric, esophageal, and nasopharyngeal cancers, where its restoration suppresses proliferation, migration, invasion, EMT, and xenograft growth [PMID:22806826, PMID:23449122, PMID:30075814, PMID:31866302]. In vivo loss of Dact2 de-represses EMT-related genes and a β-catenin/Igf1-MAPK axis, confirming its physiological role as a brake on these pathways [PMID:31983425, PMID:37603122].","teleology":[{"year":2003,"claim":"Established DACT2 as a DVL-binding family member structurally equipped to participate in Wnt signaling, framing the protein's candidate function before any direct assay.","evidence":"Bioinformatic/evolutionary characterization identifying conserved DAPH domains including a leucine zipper and PDZ-binding motif","pmids":["12632086"],"confidence":"Low","gaps":["Computational prediction only, no experimental validation of DVL binding or function","No demonstration of endogenous activity"]},{"year":2006,"claim":"Answered how DACT2 acts on TGF-β signaling by showing it drives lysosomal degradation of the ALK5 receptor, defining a conserved receptor-level mechanism of pathway antagonism.","evidence":"Mouse Dact2 overexpression with Smad-reporter assays, receptor degradation assays, and zebrafish embryo overexpression","pmids":["17197390"],"confidence":"Medium","gaps":["Mechanism of how DACT2 recruits ALK5 to lysosomes not defined","Based on overexpression, not endogenous loss-of-function"]},{"year":2010,"claim":"Placed Dact2 in a developmental context by showing endogenous loss elevates phospho-Smad2 and disrupts collecting duct morphogenesis, demonstrating a physiological TGF-β brake.","evidence":"siRNA knockdown in collecting duct cells with phospho-Smad2 immunoblot, wound-healing, 3D morphology and immunofluorescence","pmids":["20685821"],"confidence":"Medium","gaps":["Connection to ALK5 degradation in this tissue not directly tested","No in vivo genetic confirmation in kidney"]},{"year":2013,"claim":"Defined DACT2 as an epigenetically silenced Wnt-pathway tumor suppressor and established its mechanism of repressing TCF/LEF activity and β-catenin in cancer.","evidence":"Methylation-specific PCR, TCF/LEF and TCF-4 reporter assays, siRNA, cell cycle analysis and xenografts in lung and hepatocellular carcinoma","pmids":["22806826","23449122"],"confidence":"Medium","gaps":["Direct molecular target on the Wnt axis not pinned down","Each cancer characterized by single lab"]},{"year":2013,"claim":"Identified a direct physical partner, showing DACT2 binds PITX2 to repress PITX2-driven Wnt target transcription within a feedback loop, giving a transcription-factor-level mechanism.","evidence":"Co-immunoprecipitation, Topflash reporter, loss/gain-of-function and immunohistochemistry in odontogenesis","pmids":["23349981"],"confidence":"Medium","gaps":["Interaction domain mapping absent","Generality of PITX2 repression beyond tooth development untested"]},{"year":2014,"claim":"Clarified where in the Wnt cascade DACT2 acts by showing it increases β-catenin phosphorylation and functions upstream of the TCF/LEF complex, with effects reversed by Dvl2.","evidence":"TCF/LEF reporter, western blot for phospho-β-catenin, co-transfection with Dvl2 and invasion assays in thyroid and gastric cancer","pmids":["25375359","25520862"],"confidence":"Medium","gaps":["Kinase responsible for β-catenin phosphorylation not identified","Noncanonical Wnt mechanism not resolved"]},{"year":2016,"claim":"Broadened DACT2's antagonism to additional pathways, showing it opposes Akt/GSK-3 and EMT alongside Wnt, linking it to apoptosis and metastatic phenotypes.","evidence":"Ectopic expression, apoptosis/migration assays, EMT marker and pathway western blots plus xenografts in breast and esophageal cancer","pmids":["27708215","26919254"],"confidence":"Medium","gaps":["Direct interaction with Akt/GSK-3 components not shown","EMT regulation mechanism downstream of which pathway unclear"]},{"year":2017,"claim":"Extended DACT2 downstream output to the Hippo effector YAP, showing it blocks YAP nuclear translocation and promotes its cytoplasmic degradation via Wnt/β-catenin.","evidence":"Overexpression/knockdown, nuclear/cytoplasmic fractionation, western blot and xenograft in glioma","pmids":["28796248"],"confidence":"Medium","gaps":["Direct versus indirect control of YAP not distinguished","Link between β-catenin phosphorylation and YAP retention unresolved"]},{"year":2018,"claim":"Identified upstream regulators of DACT2, establishing that TET1-mediated promoter demethylation restores its expression to antagonize Wnt, and that it enforces G2/M arrest via β-catenin/Cdc25c.","evidence":"Ectopic TET1 expression with MSP, RT-PCR, reporter assays and chemosensitivity testing in nasopharyngeal carcinoma","pmids":["30075814","30359298"],"confidence":"Medium","gaps":["Whether TET1 acts directly at the DACT2 locus not shown by ChIP","Cdc25c regulation mechanism downstream of β-catenin incomplete"]},{"year":2019,"claim":"Defined transcriptional activation of DACT2 by showing allele-specific TFAP2A binding at a promoter SNP controls its expression level.","evidence":"Luciferase reporter, EMSA and genotyping with expression analysis in NSCLC","pmids":["31866302"],"confidence":"Medium","gaps":["In vivo relevance of the SNP for cancer risk not established","Interplay between TFAP2A activation and methylation silencing untested"]},{"year":2020,"claim":"Provided in vivo genetic confirmation that Dact2 restrains EMT-related gene expression and tissue homeostasis, and explored its role in cardiac β-catenin and TGF-β regulation.","evidence":"CRISPR-Cas9 knockout zebrafish with EMT gene RT-PCR and histology; overexpression in cardiac cells and atrial fibroblasts","pmids":["31983425","32642106"],"confidence":"Medium","gaps":["Cardiac findings rest on single overexpression approach (Low confidence)","Direct targets driving EMT phenotype not identified"]},{"year":2022,"claim":"Revealed a metabolic dimension of DACT2's TGF-β antagonism by showing it directs lysosomal degradation of LDHA to suppress glycolysis and myofibroblast differentiation, and inhibits liver fibrosis.","evidence":"AAV6 overexpression in vivo, LDHA degradation and lysosome colocalization, metabolic flux assays in lung fibrosis; lentiviral overexpression in CCl4 liver fibrosis model","pmids":["36481337","35818217"],"confidence":"Medium","gaps":["How DACT2 selectively targets LDHA to lysosomes not defined","Liver fibrosis data limited to overexpression with western blot (Low confidence)"]},{"year":2023,"claim":"Connected Dact2 loss to a defined transcriptional output in vivo, showing β-catenin directly binds and activates Igf1 in the absence of Dact2, driving a MAPK-dependent injury response.","evidence":"Dact2 KO mouse with RNA-seq, ChIP/β-catenin binding to Igf1, Igf1 knockdown and Wnt agonist rescue in cisplatin nephrotoxicity","pmids":["37603122"],"confidence":"Medium","gaps":["How Dact2 mechanistically gates β-catenin occupancy at Igf1 not shown","Generality of the Igf1-MAPK axis beyond kidney injury untested"]},{"year":null,"claim":"The biochemical mechanism by which DACT2 selects and routes its targets (ALK5, LDHA) to lysosomes, and the identity of the kinase/complex through which it promotes β-catenin phosphorylation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of DACT2 in complex with any partner","Degradation adaptor machinery linking DACT2 to lysosomes unidentified","Direct biochemical demonstration of DACT2-induced β-catenin phosphorylation absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,7,8]}],"complexes":[],"partners":["PITX2","ALK5","LDHA","DVL2","YAP","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5SW24","full_name":"Dapper homolog 2","aliases":["Dapper antagonist of catenin 2"],"length_aa":774,"mass_kda":82.7,"function":"Involved in regulation of intracellular signaling pathways during development. Negatively regulates the Nodal signaling pathway, possibly by promoting the lysosomal degradation of Nodal receptors, such as TGFBR1. May be involved in control of the morphogenetic behavior of kidney ureteric bud cells by keeping cells epithelial and restraining their mesenchymal character. May play an inhibitory role in the re-epithelialization of skin wounds by attenuating TGF-beta signaling (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5SW24/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DACT2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DACT2","total_profiled":1310},"omim":[{"mim_id":"611112","title":"DAPPER, ANTAGONIST OF BETA-CATENIN, 3; DACT3","url":"https://www.omim.org/entry/611112"},{"mim_id":"608966","title":"DAPPER, ANTAGONIST OF BETA-CATENIN, 2; DACT2","url":"https://www.omim.org/entry/608966"},{"mim_id":"607861","title":"DAPPER, ANTAGONIST OF BETA-CATENIN, 1; DACT1","url":"https://www.omim.org/entry/607861"},{"mim_id":"604002","title":"RHO-ASSOCIATED COILED-COIL-CONTAINING PROTEIN KINASE 2; ROCK2","url":"https://www.omim.org/entry/604002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":19.2},{"tissue":"placenta","ntpm":12.1}],"url":"https://www.proteinatlas.org/search/DACT2"},"hgnc":{"alias_symbol":["bA503C24.7","DAPPER2"],"prev_symbol":["C6orf116"]},"alphafold":{"accession":"Q5SW24","domains":[{"cath_id":"-","chopping":"15-44_258-292","consensus_level":"medium","plddt":84.8597,"start":15,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SW24","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SW24-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SW24-F1-predicted_aligned_error_v6.png","plddt_mean":50.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DACT2","jax_strain_url":"https://www.jax.org/strain/search?query=DACT2"},"sequence":{"accession":"Q5SW24","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5SW24.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5SW24/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SW24"}},"corpus_meta":[{"pmid":"12632086","id":"PMC_12632086","title":"Identification and characterization of human DAPPER1 and DAPPER2 genes in silico.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12632086","citation_count":141,"is_preprint":false},{"pmid":"17197390","id":"PMC_17197390","title":"The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling.","date":"2006","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17197390","citation_count":57,"is_preprint":false},{"pmid":"22806826","id":"PMC_22806826","title":"Epigenetic regulation of DACT2, a key component of the Wnt signalling pathway in human lung cancer.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22806826","citation_count":54,"is_preprint":false},{"pmid":"30359298","id":"PMC_30359298","title":"The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via β-catenin/Cdc25c signaling and G2/M arrest.","date":"2018","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/30359298","citation_count":38,"is_preprint":false},{"pmid":"25520862","id":"PMC_25520862","title":"DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling.","date":"2014","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25520862","citation_count":36,"is_preprint":false},{"pmid":"33898109","id":"PMC_33898109","title":"miR-181a, delivered by hypoxic PTC-secreted exosomes, inhibits DACT2 by downregulating MLL3, leading to YAP-VEGF-mediated angiogenesis.","date":"2021","source":"Molecular therapy. 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Promoter Methylation and its Clinicopathological Significance in Prostate Cancer.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31205531","citation_count":5,"is_preprint":false},{"pmid":"33440955","id":"PMC_33440955","title":"Diagnostic value of DACT-2 methylation in serum of prostate cancer patients.","date":"2021","source":"Annals of palliative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33440955","citation_count":5,"is_preprint":false},{"pmid":"29745077","id":"PMC_29745077","title":"Association between promoter hypermethylation of the DACT2 gene and tumor stages in breast cancer.","date":"2018","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29745077","citation_count":4,"is_preprint":false},{"pmid":"35818217","id":"PMC_35818217","title":"Mechanism of dact2 gene inhibiting the occurrence and development of liver fibrosis.","date":"2022","source":"Cellular and molecular 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  \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no direct experimental validation of binding or function\",\n      \"pmids\": [\"12632086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mouse Dact2 (mDpr2) overexpression inhibited TGF-β-induced Smad-responsive reporter activity and targeted TGF-β type I receptor ALK5 for lysosomal degradation in mammalian cells, demonstrating evolutionarily conserved negative regulation of TGF-β/Nodal signaling.\",\n      \"method\": \"Overexpression in mammalian cells with Smad-reporter assays, receptor degradation assays, and zebrafish embryo overexpression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, receptor degradation, in vivo zebrafish), single lab\",\n      \"pmids\": [\"17197390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dact2 is specifically expressed in ureteric bud/collecting duct epithelium of the developing mouse kidney; siRNA knockdown in collecting duct cells resulted in constitutive phospho-Smad2, elevated TGF-β-induced phospho-Smad2, defective actomyosin cable assembly at the leading edge during wound healing, and abnormal cyst/tubule morphology in 3D culture, placing Dact2 as a negative regulator of TGF-β signaling controlling collecting duct morphogenesis.\",\n      \"method\": \"siRNA knockdown, phospho-Smad2 immunoblotting, monolayer wound-healing assay, 3D culture morphology, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts (signaling, migration, morphology), single lab\",\n      \"pmids\": [\"20685821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DACT2 suppresses canonical Wnt signaling in lung cancer cells by inhibiting TCF/LEF transcriptional activity; its expression is silenced by promoter CpG hypermethylation, and restoration of DACT2 reduces β-catenin expression and inhibits tumor proliferation in vitro and in xenograft models.\",\n      \"method\": \"Methylation-specific PCR, western blotting, siRNA knockdown, TCF/LEF reporter assay, xenograft mouse model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (reporter assay, protein expression, in vivo xenograft), single lab\",\n      \"pmids\": [\"22806826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dact2 inhibits the canonical Wnt signaling pathway in odontogenesis by physically interacting with the transcription factor PITX2, repressing PITX2-driven activation of downstream targets (Dlx2 and amelogenin promoters) and attenuating PITX2-mediated Topflash Wnt reporter activity; Pitx2 in turn endogenously activates Dact2 expression forming a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, transient transfection, Topflash reporter assay, loss-of-function/gain-of-function studies, immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays and physical interaction (Co-IP), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23349981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DACT2 suppresses hepatocellular carcinoma by inhibiting Wnt signaling: re-expression suppressed TCF-4 transcriptional activity and Wnt downstream gene expression, induced G2-M arrest, and inhibited xenograft tumor growth; depletion of DACT2 reactivated TCF-4 activity.\",\n      \"method\": \"TCF-4 reporter assay, flow cytometry, siRNA knockdown, xenograft nude mice, western blotting\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, cell cycle, in vivo), single lab\",\n      \"pmids\": [\"23449122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DACT2 restoration in papillary thyroid cancer cells (TPC-1) decreased β-catenin, c-Myc, cyclinD1, and MMP-9 and increased phospho-β-catenin, inhibited TCF/LEF activity in wild-type or mutant β-catenin contexts, and suppressed proliferation, invasion, and migration; co-transfection of DACT2 with Dvl2 increased TCF/LEF activity, indicating Dact2 modulates β-catenin phosphorylation and acts upstream of the TCF/LEF complex.\",\n      \"method\": \"TCF/LEF reporter assay, western blotting, siRNA knockdown, co-transfection, migration/invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including reporter assay and protein phosphorylation analysis, single lab\",\n      \"pmids\": [\"25375359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DACT2 inhibits both canonical and noncanonical WNT signaling in gastric cancer cells (SGC7901) and suppresses gastric cancer xenograft growth; restoration of DACT2 expression also inhibited cell proliferation, migration, and invasion.\",\n      \"method\": \"siRNA, colony formation assay, flow cytometry, immunofluorescence, xenograft mouse model, WNT reporter assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional and signaling assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"25520862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DACT2 inhibits esophageal cancer growth by suppressing Wnt signaling; its expression is silenced by promoter hypermethylation, and restoration suppressed colony formation, migration, invasion, and xenograft tumor growth.\",\n      \"method\": \"MSP, 5-aza treatment, colony formation, migration/invasion assays, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays plus in vivo xenograft, single lab\",\n      \"pmids\": [\"26919254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DACT2 ectopic expression in breast cancer cells induced apoptosis, inhibited proliferation and migration, suppressed EMT, and acted through antagonizing both Wnt/β-catenin and Akt/GSK-3 signaling pathways.\",\n      \"method\": \"Ectopic expression, apoptosis assays, migration assays, western blotting for pathway components, EMT marker analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway readouts (Wnt and Akt/GSK-3), multiple functional assays, single lab\",\n      \"pmids\": [\"27708215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DACT2 overexpression in glioma cells suppressed proliferation and induced apoptosis by increasing phospho-YAP and phospho-β-catenin, preventing YAP nuclear translocation and sequestering it in the cytoplasm for degradation, placing DACT2 upstream of the YAP pathway via Wnt/β-catenin signaling.\",\n      \"method\": \"Overexpression and knockdown, flow cytometry, western blotting, nuclear/cytoplasmic fractionation, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including fractionation and in vivo, single lab\",\n      \"pmids\": [\"28796248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DACT2 ectopic expression in NPC cells induced G2/M arrest by directly suppressing β-catenin/Cdc25c signaling, which sensitized cells to paclitaxel and 5-FU but not cisplatin; DACT2 also suppressed proliferation, migration, and invasion through downregulation of matrix metalloproteinases.\",\n      \"method\": \"Flow cytometric analysis, immunofluorescence, western blotting, dual-luciferase reporter assay, colony formation, chemosensitivity assay\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including reporter assay and cell cycle analysis, single lab\",\n      \"pmids\": [\"30359298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TET1, a 5-methylcytosine dioxygenase, promotes demethylation of the DACT2 promoter in NPC cells, restoring DACT2 expression and thereby antagonizing Wnt/β-catenin signaling as part of TET1's tumor suppressor mechanism.\",\n      \"method\": \"Ectopic TET1 expression, MSP, RT-PCR, western blotting for nuclear β-catenin and downstream targets\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter demethylation linked to expression restoration and downstream signaling, single lab, multiple methods\",\n      \"pmids\": [\"30075814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The DACT2 promoter SNP rs9364433 modulates DACT2 expression through allele-specific binding of transcription factor TFAP2A; the G allele reduces TFAP2A binding and decreases DACT2 expression in NSCLC cells, establishing TFAP2A as a transcriptional activator of DACT2.\",\n      \"method\": \"Luciferase reporter gene assay, EMSA (Electrophoretic Mobility Shift Assay), genotyping, in vitro and in vivo DACT2 expression analysis\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter assay provide orthogonal evidence for allele-specific TF binding, single lab\",\n      \"pmids\": [\"31866302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DACT2 knockout in zebrafish (10-bp deletion via CRISPR-Cas9) enhanced expression of MMP2, MMP9, Snail, VEGF, and ZEB (EMT-related genes), caused gastrointestinal epithelial hyperplasia, pancreatic/hepatic fibrosis, and accelerated wound healing via EMT, establishing Dact2 as a negative regulator of EMT-related gene expression in vivo.\",\n      \"method\": \"CRISPR-Cas9 knockout zebrafish, RT-PCR, histology, wound healing assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"31983425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DACT2 overexpression in HL-1 cardiac cells facilitated β-catenin accumulation by reducing its phosphorylation at Thr41/Ser45, and inhibited TGF-β signaling in primary atrial fibroblasts, reducing collagen I and III expression and regulating ion channel gene expression (increased KCNE5, decreased KCNH2 and SCN5A).\",\n      \"method\": \"Western blotting, RT-PCR, overexpression in HL-1 cells and primary atrial fibroblasts\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach with western blot readouts, limited mechanistic depth\",\n      \"pmids\": [\"32642106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-181a targets MLL3, a histone methyltransferase, downregulating it in PTC cells; this leads to decreased DACT2 expression and upregulation of YAP and VEGF, promoting angiogenesis, placing DACT2 downstream of MLL3 in an exosomal miR-181a/MLL3/DACT2/YAP-VEGF axis.\",\n      \"method\": \"miRNA mimic/inhibitor transfection, siRNA knockdown of MLL3, exosome extraction and treatment, in vitro tube formation and proliferation assays, in vivo tumor growth\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway ordering confirmed by rescue experiments and multiple functional assays, single lab\",\n      \"pmids\": [\"33898109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DACT2 overexpression in lung myofibroblasts inhibited TGF-β-induced myofibroblast differentiation by promoting lysosome-mediated degradation of LDHA, thereby suppressing glycolysis (reduced glucose uptake, extracellular acidification rate, lactate, and ATP); AAV6-mediated DACT2 overexpression attenuated experimental pulmonary fibrosis in vivo.\",\n      \"method\": \"AAV6 overexpression in vivo, TGF-β-induced differentiation assays, LDHA degradation rate monitoring, lysosome colocalization, metabolic flux assays (ECAR, OCR, ATP, lactate)\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal metabolic and mechanistic assays plus in vivo AAV model, single lab\",\n      \"pmids\": [\"36481337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DACT2 inhibits liver fibrosis by suppressing TGF-β/Smad signaling and Wnt/β-catenin signaling in HSC-T6 cells; lentiviral overexpression of DACT2 reduced α-SMA, TGF-β1, Smad3, β-catenin, and CyclinD1 protein levels, and decreased MMP-2 and TIMP-1 expression, while also attenuating CCl4-induced liver fibrosis in vivo.\",\n      \"method\": \"Lentiviral overexpression, western blotting (α-SMA, TGF-β1, Smad3, Smad7, β-catenin, CyclinD1), RT-PCR (MMP-2, TIMP-1), CCl4 liver fibrosis mouse model, histology\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic resolution from abstract, lentiviral overexpression with western blot\",\n      \"pmids\": [\"35818217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dact2 knockout mice show elevated Igf1 expression (a Wnt target gene) with β-catenin directly binding and regulating Igf1 transcription; cisplatin-induced nephrotoxicity was alleviated in Dact2 KO mice through reduced apoptosis and downregulation of proapoptotic MAPK signaling, establishing a Dact2/Wnt/β-catenin/Igf1-MAPK axis in kidney injury response.\",\n      \"method\": \"Dact2 KO mouse model, RNA sequencing, western blotting, ChIP/β-catenin binding to Igf1 locus, Igf1 knockdown, Wnt agonist CHIR-99021 treatment\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with RNA-seq, direct β-catenin/Igf1 binding confirmed, rescue experiments with Wnt agonist, single lab\",\n      \"pmids\": [\"37603122\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DACT2 is a cytoplasmic scaffold protein that functions as a negative regulator of both Wnt/β-catenin and TGF-β/Nodal signaling: it targets TGF-β type I receptor ALK5 and LDHA for lysosomal degradation, physically interacts with the transcription factor PITX2 to repress Wnt target gene activation, reduces β-catenin phosphorylation status to modulate TCF/LEF transcriptional activity, and suppresses YAP nuclear translocation downstream of Wnt/β-catenin; its expression is positively regulated by the TET1 demethylase (via promoter demethylation) and by the transcription factor TFAP2A, and it is frequently silenced by promoter CpG hypermethylation in multiple cancer types, leading to de-repression of Wnt and TGF-β pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DACT2 is a cytoplasmic negative regulator of developmental signaling that restrains both the Wnt/\\u03b2-catenin and TGF-\\u03b2/Nodal pathways, with consequences for epithelial morphogenesis, fibrosis, and tumor suppression [#1, #3]. It dampens TGF-\\u03b2 signaling by targeting the type I receptor ALK5 for lysosomal degradation, limiting Smad2 phosphorylation, and these activities control collecting duct morphogenesis and oppose fibrotic differentiation [#1, #2, #17, #18]. On the Wnt axis DACT2 suppresses TCF/LEF transcriptional output by promoting \\u03b2-catenin phosphorylation and reducing \\u03b2-catenin levels, and it physically interacts with the transcription factor PITX2 to repress PITX2-driven Wnt target activation within a reciprocal feedback loop [#4, #6, #11]. Downstream of Wnt/\\u03b2-catenin it also blocks YAP nuclear translocation, sequestering YAP in the cytoplasm for degradation [#10]. DACT2 expression is positively controlled by promoter demethylation through the dioxygenase TET1 and by allele-specific binding of the transcription factor TFAP2A, and it is frequently silenced by promoter CpG hypermethylation across lung, liver, thyroid, gastric, esophageal, and nasopharyngeal cancers, where its restoration suppresses proliferation, migration, invasion, EMT, and xenograft growth [#3, #5, #12, #13]. In vivo loss of Dact2 de-represses EMT-related genes and a \\u03b2-catenin/Igf1-MAPK axis, confirming its physiological role as a brake on these pathways [#14, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established DACT2 as a DVL-binding family member structurally equipped to participate in Wnt signaling, framing the protein's candidate function before any direct assay.\",\n      \"evidence\": \"Bioinformatic/evolutionary characterization identifying conserved DAPH domains including a leucine zipper and PDZ-binding motif\",\n      \"pmids\": [\"12632086\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no experimental validation of DVL binding or function\", \"No demonstration of endogenous activity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Answered how DACT2 acts on TGF-\\u03b2 signaling by showing it drives lysosomal degradation of the ALK5 receptor, defining a conserved receptor-level mechanism of pathway antagonism.\",\n      \"evidence\": \"Mouse Dact2 overexpression with Smad-reporter assays, receptor degradation assays, and zebrafish embryo overexpression\",\n      \"pmids\": [\"17197390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of how DACT2 recruits ALK5 to lysosomes not defined\", \"Based on overexpression, not endogenous loss-of-function\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed Dact2 in a developmental context by showing endogenous loss elevates phospho-Smad2 and disrupts collecting duct morphogenesis, demonstrating a physiological TGF-\\u03b2 brake.\",\n      \"evidence\": \"siRNA knockdown in collecting duct cells with phospho-Smad2 immunoblot, wound-healing, 3D morphology and immunofluorescence\",\n      \"pmids\": [\"20685821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection to ALK5 degradation in this tissue not directly tested\", \"No in vivo genetic confirmation in kidney\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined DACT2 as an epigenetically silenced Wnt-pathway tumor suppressor and established its mechanism of repressing TCF/LEF activity and \\u03b2-catenin in cancer.\",\n      \"evidence\": \"Methylation-specific PCR, TCF/LEF and TCF-4 reporter assays, siRNA, cell cycle analysis and xenografts in lung and hepatocellular carcinoma\",\n      \"pmids\": [\"22806826\", \"23449122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target on the Wnt axis not pinned down\", \"Each cancer characterized by single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a direct physical partner, showing DACT2 binds PITX2 to repress PITX2-driven Wnt target transcription within a feedback loop, giving a transcription-factor-level mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, Topflash reporter, loss/gain-of-function and immunohistochemistry in odontogenesis\",\n      \"pmids\": [\"23349981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction domain mapping absent\", \"Generality of PITX2 repression beyond tooth development untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Clarified where in the Wnt cascade DACT2 acts by showing it increases \\u03b2-catenin phosphorylation and functions upstream of the TCF/LEF complex, with effects reversed by Dvl2.\",\n      \"evidence\": \"TCF/LEF reporter, western blot for phospho-\\u03b2-catenin, co-transfection with Dvl2 and invasion assays in thyroid and gastric cancer\",\n      \"pmids\": [\"25375359\", \"25520862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for \\u03b2-catenin phosphorylation not identified\", \"Noncanonical Wnt mechanism not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened DACT2's antagonism to additional pathways, showing it opposes Akt/GSK-3 and EMT alongside Wnt, linking it to apoptosis and metastatic phenotypes.\",\n      \"evidence\": \"Ectopic expression, apoptosis/migration assays, EMT marker and pathway western blots plus xenografts in breast and esophageal cancer\",\n      \"pmids\": [\"27708215\", \"26919254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with Akt/GSK-3 components not shown\", \"EMT regulation mechanism downstream of which pathway unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended DACT2 downstream output to the Hippo effector YAP, showing it blocks YAP nuclear translocation and promotes its cytoplasmic degradation via Wnt/\\u03b2-catenin.\",\n      \"evidence\": \"Overexpression/knockdown, nuclear/cytoplasmic fractionation, western blot and xenograft in glioma\",\n      \"pmids\": [\"28796248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect control of YAP not distinguished\", \"Link between \\u03b2-catenin phosphorylation and YAP retention unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified upstream regulators of DACT2, establishing that TET1-mediated promoter demethylation restores its expression to antagonize Wnt, and that it enforces G2/M arrest via \\u03b2-catenin/Cdc25c.\",\n      \"evidence\": \"Ectopic TET1 expression with MSP, RT-PCR, reporter assays and chemosensitivity testing in nasopharyngeal carcinoma\",\n      \"pmids\": [\"30075814\", \"30359298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TET1 acts directly at the DACT2 locus not shown by ChIP\", \"Cdc25c regulation mechanism downstream of \\u03b2-catenin incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined transcriptional activation of DACT2 by showing allele-specific TFAP2A binding at a promoter SNP controls its expression level.\",\n      \"evidence\": \"Luciferase reporter, EMSA and genotyping with expression analysis in NSCLC\",\n      \"pmids\": [\"31866302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the SNP for cancer risk not established\", \"Interplay between TFAP2A activation and methylation silencing untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided in vivo genetic confirmation that Dact2 restrains EMT-related gene expression and tissue homeostasis, and explored its role in cardiac \\u03b2-catenin and TGF-\\u03b2 regulation.\",\n      \"evidence\": \"CRISPR-Cas9 knockout zebrafish with EMT gene RT-PCR and histology; overexpression in cardiac cells and atrial fibroblasts\",\n      \"pmids\": [\"31983425\", \"32642106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiac findings rest on single overexpression approach (Low confidence)\", \"Direct targets driving EMT phenotype not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a metabolic dimension of DACT2's TGF-\\u03b2 antagonism by showing it directs lysosomal degradation of LDHA to suppress glycolysis and myofibroblast differentiation, and inhibits liver fibrosis.\",\n      \"evidence\": \"AAV6 overexpression in vivo, LDHA degradation and lysosome colocalization, metabolic flux assays in lung fibrosis; lentiviral overexpression in CCl4 liver fibrosis model\",\n      \"pmids\": [\"36481337\", \"35818217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DACT2 selectively targets LDHA to lysosomes not defined\", \"Liver fibrosis data limited to overexpression with western blot (Low confidence)\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected Dact2 loss to a defined transcriptional output in vivo, showing \\u03b2-catenin directly binds and activates Igf1 in the absence of Dact2, driving a MAPK-dependent injury response.\",\n      \"evidence\": \"Dact2 KO mouse with RNA-seq, ChIP/\\u03b2-catenin binding to Igf1, Igf1 knockdown and Wnt agonist rescue in cisplatin nephrotoxicity\",\n      \"pmids\": [\"37603122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Dact2 mechanistically gates \\u03b2-catenin occupancy at Igf1 not shown\", \"Generality of the Igf1-MAPK axis beyond kidney injury untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which DACT2 selects and routes its targets (ALK5, LDHA) to lysosomes, and the identity of the kinase/complex through which it promotes \\u03b2-catenin phosphorylation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of DACT2 in complex with any partner\", \"Degradation adaptor machinery linking DACT2 to lysosomes unidentified\", \"Direct biochemical demonstration of DACT2-induced \\u03b2-catenin phosphorylation absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PITX2\", \"ALK5\", \"LDHA\", \"DVL2\", \"YAP\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}