{"gene":"CTNNA3","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2004,"finding":"GATA-4 and MEF2C transcription factors directly activate the CTNNA3 (alphaT-catenin) promoter; one GATA box is absolutely required for high promoter activity in cardiac HL-1 cells, and GATA-4 specifically binds and activates the CTNNA3 promoter in vivo. The isolated promoter region directs tissue-specific expression in transgenic mice concordant with endogenous alphaT-catenin expression.","method":"Co-transfection studies with wild-type and mutant promoter constructs in P19 and HL-1 cells; in vivo promoter analysis in transgenic mice with LacZ reporter; GATA-4 in vivo binding assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (promoter mutagenesis, in vivo binding, transgenic reporter), single lab but rigorous controls","pmids":["15302915"],"is_preprint":false},{"year":2004,"finding":"CTNNA3 is subject to genomic imprinting in placenta with preferential expression of the maternal allele in villus cytotrophoblast; expression in extravillous trophoblast is biallelic; expression is lost in villus syncytiotrophoblast and in extravillous trophoblast following epithelial-mesenchymal transition. This imprinting pattern mirrors that of p57KIP2, suggesting a shared conserved regulatory mechanism.","method":"Allele-specific RT-PCR using informative heterozygous samples; immunostaining for alphaT-catenin, p57KIP2, and low-molecular-weight cytokeratin","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific RT-PCR plus immunostaining, single lab, two orthogonal approaches","pmids":["15533819"],"is_preprint":false},{"year":2013,"finding":"CTNNA3 acts as a tumour suppressor in laryngeal carcinoma; cells producing mutated forms of CTNNA3 or cells where CTNNA3 is silenced show increased migration and invasive ability, establishing a direct role for CTNNA3 in suppressing cell migration and invasion.","method":"Functional studies with mutant CTNNA3 expression and siRNA-mediated silencing in head and neck squamous cell carcinoma cells; migration and invasion assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype, two approaches (mutant overexpression and silencing), single lab","pmids":["24100690"],"is_preprint":false},{"year":2016,"finding":"CTNNA3 inhibits proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cell lines by suppressing Akt signaling, decreasing PCNA and MMP-9, and increasing p21Cip1/Waf1. CTNNA3 is directly targeted and repressed by miR-425 binding to the 3′UTR of CTNNA3 mRNA. Both the tumour-suppressor function of CTNNA3 and the oncogenic function of miR-425 were confirmed in HCC xenografts in nude mice.","method":"CTNNA3 overexpression/knockdown in HCC cell lines; luciferase 3′UTR reporter assay for miR-425; Western blot for Akt, PCNA, MMP-9, p21; xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, in vitro functional assays, in vivo xenograft), single lab","pmids":["26882563"],"is_preprint":false},{"year":2016,"finding":"Knockdown of CTNNA3 (alphaT-catenin) in Schwann cells causes cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like changes, consistent with a role for CTNNA3 in maintaining cytoskeletal integrity and cell-cell adhesion in peripheral nerve sheath cells.","method":"Transient siRNA knockdown of CTNNA3 in cultured Schwann cells; cytoskeletal staining; E-cadherin immunostaining","journal":"The American journal of pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown experiment with limited mechanistic follow-up, phenotypic readout without full pathway placement","pmids":["27765635"],"is_preprint":false},{"year":2015,"finding":"Knockdown of CTNNA3 in mononuclear cells results in upregulation of CD63 and CD203c upon PMA stimulation, suggesting CTNNA3 plays a role in regulating allergen sensitization signaling.","method":"siRNA knockdown of CTNNA3 in mononuclear cells; flow cytometry for CD63 and CD203c after PMA stimulation","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment, single lab, limited pathway characterization","pmids":["26188062"],"is_preprint":false},{"year":2021,"finding":"CTNNA3 levels determine cell-type-specific YAP1-WWTR1/TAZ transcriptional responses to autophagy perturbations. CTNNA3 (like CTNNA1) acts as a negative regulator of YAP1-WWTR1/TAZ and is itself an autophagy substrate; this relationship was integrated into a mathematical model validated by experimental data.","method":"Experimental autophagy modulation in cells with varying CTNNA3 levels; YAP1/TAZ activity measurements; mathematical modeling validated against experimental observations","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — experimental perturbation of autophagy with functional readout on YAP1/TAZ, mathematical model validated experimentally, single lab","pmids":["34036899"],"is_preprint":false},{"year":2022,"finding":"SPATA33 physically interacts with CTNNA3 in TM4 Sertoli cells. This interaction inhibits the formation of the CDH1-CTNNB1-CTNNA3 adhesion complex, thereby weakening cell-cell adhesion and promoting cell migration. SPATA33 knockout disrupts F-actin formation, decreases G1-phase cells, and impairs cell migration.","method":"Co-immunoprecipitation (protein IP); CRISPR-Cas9 Spata33 knockout in TM4 cells; cell wound scratch assay; flow cytometry; phalloidin staining for F-actin","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional knockout with defined cellular phenotypes, single lab, multiple orthogonal methods","pmids":["35536443"],"is_preprint":false},{"year":2023,"finding":"CTNNA3 is hyperphosphorylated at specific residues in the intercalated disc (ICD) of cardiomyocytes in dilated cardiomyopathy (DCM). Phosphorylation at these residues is required for maintaining CTNNA3 protein localization at the cardiomyocyte ICD to regulate cell-cell conductance and adhesion, as demonstrated by ex vivo cardiomyocytes and in vivo AAV9-mediated overexpression of wild-type vs. phosphomutant CTNNA3 in mice.","method":"Mass spectrometry phosphoproteomics of human LV tissue; ex vivo cardiomyocyte experiments; in vivo AAV9-mediated overexpression of CTNNA3 phospho-variants in mouse heart; localization imaging and conductance/adhesion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphoproteomic discovery in human tissue validated by in vivo AAV9 mouse model with phospho-null/mimetic mutants, multiple orthogonal approaches","pmids":["37126683"],"is_preprint":false},{"year":2025,"finding":"Fortilin specifically binds CTNNA3 (but not CTNNA1, CTNNA2, or CTNNB1) via direct protein-protein interaction. Fortilin protects CTNNA3 against phosphorylation, subsequent ubiquitination, and proteasome-mediated degradation. Silencing of CTNNA3 causes apoptosis in 293T cells, identifying CTNNA3 as a pro-survival molecule. Absence of fortilin accelerates CTNNA3 phosphorylation and degradation.","method":"Co-immunoprecipitation western blot; proximity ligation assay; microscale thermophoresis; biolayer interferometry; siRNA silencing of fortilin and CTNNA3; phospho-null (5A) and phospho-mimetic (5D) CTNNA3 mutants; proteasome inhibitor experiments; apoptosis assays in 293T cells and fortilin-deficient THP1 cells","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Co-IP, PLA, MST, BLI) plus mutagenesis and functional rescue, single lab but exceptionally rigorous","pmids":["39747445"],"is_preprint":false},{"year":2025,"finding":"Ctnna3 deficiency in neonatal mice promotes cardiomyocyte proliferation and enhances heart regeneration after apex resection. The mechanism involves upregulation of YAP (Yes-associated protein) expression in Ctnna3-deficient P7 hearts.","method":"Ctnna3 knockout neonatal mouse model; heart apex resection; cardiomyocyte proliferation assays; YAP expression analysis","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined loss-of-function mouse model with specific in vivo phenotype and YAP pathway placement, single lab, single study","pmids":["40765350"],"is_preprint":false},{"year":2025,"finding":"UBD (ubiquitin D) promotes ubiquitination and proteasomal degradation of CTNNA3 in HCC cells, thereby reducing CTNNA3 protein levels. UBD knockdown restores CTNNA3 expression and suppresses HCC proliferation, migration, invasion, and EMT; CTNNA3 knockdown counteracts these inhibitory effects, placing CTNNA3 downstream of UBD in a UBD/CTNNA3 regulatory axis.","method":"In vitro ubiquitination assay; siRNA knockdown of UBD and CTNNA3 in HCC cells; CCK-8, colony formation, EdU, and transwell assays; Western blot for EMT markers","journal":"Cell journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination assay plus epistasis rescue experiment, multiple functional assays, single lab","pmids":["41076572"],"is_preprint":false},{"year":2026,"finding":"Fortilin specifically binds the N-terminal region (amino acids 1–85) of MEF2C (but not MEF2A, MEF2B, or MEF2D) via a binding interface involving aspartic acid 25 of fortilin (D25A mutation weakens binding). Fortilin protects MEF2C from ubiquitination and proteasomal degradation and promotes MEF2C serine 59 phosphorylation (required for transcriptional activity) in a binding-dependent manner. Loss of fortilin reduces MEF2C binding to nuclear DNA, decreases CTNNA3 promoter-driven luciferase activity in an MEF2C-dependent fashion, and lowers RNA polymerase II occupancy at the CTNNA3 locus, establishing fortilin as a transcriptional cofactor of MEF2C that drives CTNNA3 transcription.","method":"Microscale thermophoresis; proximity ligation assay; in vitro and in vivo co-immunoprecipitation western blot; molecular docking; site-directed mutagenesis (D25A); ubiquitination assays; CTNNA3 promoter-driven luciferase reporter; chromatin immunoprecipitation (RNA Pol II occupancy); fortilin loss-of-function","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-level biochemistry (MST, Co-IP), site-directed mutagenesis, promoter luciferase, ChIP, multiple orthogonal methods in single rigorous study","pmids":["41933733"],"is_preprint":false}],"current_model":"CTNNA3 (αT-catenin) is a cardiac and epithelial adherens junction protein that links cadherin-based adhesion complexes to the actin cytoskeleton; its expression is driven transcriptionally by GATA-4 and MEF2C (the latter stabilized and activated by fortilin), its protein stability is maintained by fortilin-mediated protection against phosphorylation-triggered ubiquitination and proteasomal degradation (counteracted by UBD), its phosphorylation state at ICD residues governs its localization and function in cardiomyocyte conductance and cell-cell adhesion, it acts as a negative regulator of YAP/TAZ signaling and cardiomyocyte proliferation, it suppresses cancer cell migration and invasion partly through Akt pathway inhibition, and it is subject to tissue-specific genomic imprinting in placenta with preferential maternal-allele expression in villous cytotrophoblast."},"narrative":{"mechanistic_narrative":"CTNNA3 (αT-catenin) is an adherens-junction catenin that links cadherin-based adhesion complexes to the actin cytoskeleton and constrains growth-promoting signaling across cardiac, epithelial, and tumor contexts [PMID:35536443, PMID:37126683]. Its expression is established transcriptionally by GATA-4 and MEF2C acting at the CTNNA3 promoter, with one GATA box absolutely required for high promoter activity in cardiac cells; the isolated promoter recapitulates tissue-specific αT-catenin expression in vivo [PMID:15302915]. MEF2C-driven CTNNA3 transcription is potentiated by fortilin, which binds the N-terminal region of MEF2C, protects it from ubiquitin-proteasome degradation, promotes its activating Ser59 phosphorylation, and thereby increases MEF2C occupancy and RNA Pol II loading at the CTNNA3 locus [PMID:41933733]. At the protein level, fortilin additionally binds CTNNA3 directly and shields it from phosphorylation-triggered ubiquitination and proteasomal turnover, defining CTNNA3 as a pro-survival molecule whose loss induces apoptosis [PMID:39747445]; this stabilizing influence is opposed by UBD, which drives CTNNA3 ubiquitination and degradation in hepatocellular carcinoma [PMID:41076572]. In the cardiomyocyte intercalated disc, site-specific phosphorylation of CTNNA3 governs its localization and its regulation of cell-cell conductance and adhesion, with hyperphosphorylation observed in dilated cardiomyopathy [PMID:37126683]. Functionally, CTNNA3 is a negative regulator of YAP/TAZ signaling and cardiomyocyte proliferation—its deficiency upregulates YAP and enhances neonatal heart regeneration [PMID:34036899, PMID:40765350]—and it acts as a tumor suppressor that restrains cell migration and invasion, in part through inhibition of Akt signaling, with its assembly into the CDH1-CTNNB1-CTNNA3 adhesion complex antagonized by SPATA33 [PMID:24100690, PMID:26882563, PMID:35536443]. CTNNA3 is also subject to placental genomic imprinting with preferential maternal-allele expression in villous cytotrophoblast [PMID:15533819].","teleology":[{"year":2004,"claim":"Established how CTNNA3 transcription is controlled and restricted to specific tissues, identifying GATA-4 and MEF2C as direct activators of its promoter.","evidence":"Promoter mutagenesis in P19/HL-1 cells, in vivo GATA-4 binding, and transgenic LacZ reporter mice","pmids":["15302915"],"confidence":"High","gaps":["Did not address cofactors required for MEF2C activity at the locus","No post-transcriptional or protein-level regulation defined"]},{"year":2004,"claim":"Showed CTNNA3 is epigenetically regulated, revealing tissue- and cell-type-specific genomic imprinting in placenta.","evidence":"Allele-specific RT-PCR on informative heterozygous samples with immunostaining of trophoblast subtypes","pmids":["15533819"],"confidence":"Medium","gaps":["Imprinting control region/mechanism not mapped","Functional consequence of monoallelic expression unknown"]},{"year":2013,"claim":"Provided the first direct functional evidence that CTNNA3 suppresses tumor cell behavior, framing it as a tumor suppressor.","evidence":"Mutant CTNNA3 expression and siRNA silencing with migration/invasion assays in head and neck squamous carcinoma cells","pmids":["24100690"],"confidence":"Medium","gaps":["Downstream effector pathway not defined","No in vivo validation in this study"]},{"year":2015,"claim":"Implicated CTNNA3 in immune/allergen sensitization signaling beyond its adhesion role.","evidence":"siRNA knockdown in mononuclear cells with flow cytometry for CD63/CD203c after PMA stimulation","pmids":["26188062"],"confidence":"Low","gaps":["Single knockdown experiment without pathway characterization","Mechanism linking CTNNA3 to basophil activation markers unknown"]},{"year":2016,"claim":"Connected CTNNA3 tumor suppression to a defined signaling axis (Akt) and to upstream microRNA control.","evidence":"Overexpression/knockdown in HCC lines, miR-425 3′UTR luciferase reporter, Western blots, and xenografts","pmids":["26882563"],"confidence":"Medium","gaps":["Direct biochemical link between CTNNA3 and Akt not resolved","Whether adhesion-complex assembly mediates the effect not tested"]},{"year":2016,"claim":"Tested whether CTNNA3 maintains cytoskeletal integrity and adhesion in a non-canonical (Schwann cell) context.","evidence":"Transient siRNA knockdown in cultured Schwann cells with cytoskeletal and E-cadherin staining","pmids":["27765635"],"confidence":"Low","gaps":["Single knockdown without rescue or pathway placement","Phenotype not validated in vivo"]},{"year":2021,"claim":"Positioned CTNNA3 as a negative regulator of YAP/TAZ and as an autophagy substrate, integrating its level into cell-type-specific transcriptional responses.","evidence":"Autophagy modulation in cells with varying CTNNA3, YAP/TAZ activity readouts, and a mathematical model validated experimentally","pmids":["34036899"],"confidence":"Medium","gaps":["Mechanism by which CTNNA3 sequesters/regulates YAP/TAZ not detailed","Autophagy receptor mediating CTNNA3 degradation not identified"]},{"year":2022,"claim":"Identified a direct binding partner (SPATA33) that controls CTNNA3 incorporation into the cadherin adhesion complex.","evidence":"Co-IP, CRISPR Spata33 knockout in TM4 Sertoli cells, scratch/migration assays, flow cytometry, and phalloidin F-actin staining","pmids":["35536443"],"confidence":"Medium","gaps":["Binding interface on CTNNA3 not mapped","Whether SPATA33 regulation operates in other tissues unknown"]},{"year":2023,"claim":"Defined how CTNNA3 phosphorylation governs its localization and function at the cardiomyocyte intercalated disc, linking it to dilated cardiomyopathy.","evidence":"Phosphoproteomics of human LV tissue plus ex vivo cardiomyocytes and in vivo AAV9 overexpression of phospho-variants in mice","pmids":["37126683"],"confidence":"High","gaps":["Kinase(s) responsible for ICD-specific phosphorylation not identified","Causal role of hyperphosphorylation in human DCM not established"]},{"year":2025,"claim":"Established CTNNA3 as a pro-survival protein and identified fortilin as a direct stabilizer protecting it from phosphorylation-dependent degradation.","evidence":"Co-IP, PLA, MST, BLI, fortilin/CTNNA3 silencing, phospho-null (5A)/mimetic (5D) mutants, proteasome inhibition, and apoptosis assays","pmids":["39747445"],"confidence":"High","gaps":["E3 ligase driving CTNNA3 ubiquitination not identified in this study","Kinase linking phosphorylation to degradation not defined"]},{"year":2025,"claim":"Demonstrated that CTNNA3 restrains cardiomyocyte proliferation in vivo and that its loss enhances neonatal heart regeneration via YAP.","evidence":"Ctnna3 knockout neonatal mouse apex-resection model with proliferation assays and YAP expression analysis","pmids":["40765350"],"confidence":"Medium","gaps":["Molecular link between CTNNA3 and YAP regulation not resolved","Whether effect persists into adult regeneration unknown"]},{"year":2025,"claim":"Identified UBD as a negative regulator that degrades CTNNA3, placing CTNNA3 downstream in a UBD/CTNNA3 axis controlling HCC malignancy.","evidence":"In vitro ubiquitination assay, UBD/CTNNA3 knockdown epistasis, proliferation/migration/invasion assays, and EMT marker Western blots","pmids":["41076572"],"confidence":"Medium","gaps":["Whether UBD acts directly as the degradation signal or recruits an E3 not defined","Relationship to fortilin-mediated stabilization not tested"]},{"year":2026,"claim":"Resolved the transcriptional arm of CTNNA3 regulation, showing fortilin acts as a MEF2C cofactor that stabilizes and activates MEF2C to drive CTNNA3 expression.","evidence":"MST, PLA, in vitro/in vivo Co-IP, docking, D25A mutagenesis, ubiquitination assays, CTNNA3 promoter luciferase, and RNA Pol II ChIP","pmids":["41933733"],"confidence":"High","gaps":["How fortilin partitions between MEF2C (nuclear) and CTNNA3 (junctional) regulation not addressed","Physiological contexts where this axis dominates not mapped"]},{"year":null,"claim":"The kinase and E3 ligase machinery that couples CTNNA3 phosphorylation to its ubiquitination and turnover remain unidentified, and the molecular basis of its YAP/TAZ regulation is undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No CTNNA3-directed kinase identified","Direct E3 ligase versus UBD adaptor role unresolved","Structural/biochemical mechanism of YAP/TAZ suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,12]}],"complexes":["CDH1-CTNNB1-CTNNA3 adhesion complex"],"partners":["TPT1","MEF2C","SPATA33","UBD","CDH1","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI47","full_name":"Catenin alpha-3","aliases":["Alpha T-catenin","Cadherin-associated protein"],"length_aa":895,"mass_kda":99.8,"function":"May be involved in formation of stretch-resistant cell-cell adhesion complexes","subcellular_location":"Cytoplasm, cytoskeleton; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/Q9UI47/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTNNA3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTNNA3","total_profiled":1310},"omim":[{"mim_id":"615616","title":"ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 13; ARVD13","url":"https://www.omim.org/entry/615616"},{"mim_id":"610869","title":"LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN 3; LRRTM3","url":"https://www.omim.org/entry/610869"},{"mim_id":"609397","title":"STORKHEAD BOX 1; STOX1","url":"https://www.omim.org/entry/609397"},{"mim_id":"607667","title":"CATENIN, ALPHA-3; CTNNA3","url":"https://www.omim.org/entry/607667"},{"mim_id":"605526","title":"ALZHEIMER DISEASE 6","url":"https://www.omim.org/entry/605526"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":13.7},{"tissue":"tongue","ntpm":14.0}],"url":"https://www.proteinatlas.org/search/CTNNA3"},"hgnc":{"alias_symbol":["VR22","MGC26194"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI47","domains":[{"cath_id":"1.20.120.230","chopping":"22-41_56-144","consensus_level":"medium","plddt":83.6039,"start":22,"end":144},{"cath_id":"1.20.120.230","chopping":"274-381","consensus_level":"high","plddt":87.8396,"start":274,"end":381},{"cath_id":"1.20.120.230","chopping":"503-639","consensus_level":"medium","plddt":85.7104,"start":503,"end":639},{"cath_id":"1.20.120.230","chopping":"658-851","consensus_level":"high","plddt":80.8712,"start":658,"end":851}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI47","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI47-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI47-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTNNA3","jax_strain_url":"https://www.jax.org/strain/search?query=CTNNA3"},"sequence":{"accession":"Q9UI47","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI47.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI47/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI47"}},"corpus_meta":[{"pmid":"19187332","id":"PMC_19187332","title":"Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis.","date":"2009","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19187332","citation_count":75,"is_preprint":false},{"pmid":"24100690","id":"PMC_24100690","title":"Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24100690","citation_count":71,"is_preprint":false},{"pmid":"17761686","id":"PMC_17761686","title":"Genetic association of CTNNA3 with late-onset Alzheimer's disease in females.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17761686","citation_count":59,"is_preprint":false},{"pmid":"26882563","id":"PMC_26882563","title":"CTNNA3 is a tumor suppressor in hepatocellular 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The isolated promoter region directs tissue-specific expression in transgenic mice concordant with endogenous alphaT-catenin expression.\",\n      \"method\": \"Co-transfection studies with wild-type and mutant promoter constructs in P19 and HL-1 cells; in vivo promoter analysis in transgenic mice with LacZ reporter; GATA-4 in vivo binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (promoter mutagenesis, in vivo binding, transgenic reporter), single lab but rigorous controls\",\n      \"pmids\": [\"15302915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CTNNA3 is subject to genomic imprinting in placenta with preferential expression of the maternal allele in villus cytotrophoblast; expression in extravillous trophoblast is biallelic; expression is lost in villus syncytiotrophoblast and in extravillous trophoblast following epithelial-mesenchymal transition. This imprinting pattern mirrors that of p57KIP2, suggesting a shared conserved regulatory mechanism.\",\n      \"method\": \"Allele-specific RT-PCR using informative heterozygous samples; immunostaining for alphaT-catenin, p57KIP2, and low-molecular-weight cytokeratin\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific RT-PCR plus immunostaining, single lab, two orthogonal approaches\",\n      \"pmids\": [\"15533819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CTNNA3 acts as a tumour suppressor in laryngeal carcinoma; cells producing mutated forms of CTNNA3 or cells where CTNNA3 is silenced show increased migration and invasive ability, establishing a direct role for CTNNA3 in suppressing cell migration and invasion.\",\n      \"method\": \"Functional studies with mutant CTNNA3 expression and siRNA-mediated silencing in head and neck squamous cell carcinoma cells; migration and invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype, two approaches (mutant overexpression and silencing), single lab\",\n      \"pmids\": [\"24100690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CTNNA3 inhibits proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cell lines by suppressing Akt signaling, decreasing PCNA and MMP-9, and increasing p21Cip1/Waf1. CTNNA3 is directly targeted and repressed by miR-425 binding to the 3′UTR of CTNNA3 mRNA. Both the tumour-suppressor function of CTNNA3 and the oncogenic function of miR-425 were confirmed in HCC xenografts in nude mice.\",\n      \"method\": \"CTNNA3 overexpression/knockdown in HCC cell lines; luciferase 3′UTR reporter assay for miR-425; Western blot for Akt, PCNA, MMP-9, p21; xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, in vitro functional assays, in vivo xenograft), single lab\",\n      \"pmids\": [\"26882563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of CTNNA3 (alphaT-catenin) in Schwann cells causes cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like changes, consistent with a role for CTNNA3 in maintaining cytoskeletal integrity and cell-cell adhesion in peripheral nerve sheath cells.\",\n      \"method\": \"Transient siRNA knockdown of CTNNA3 in cultured Schwann cells; cytoskeletal staining; E-cadherin immunostaining\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown experiment with limited mechanistic follow-up, phenotypic readout without full pathway placement\",\n      \"pmids\": [\"27765635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of CTNNA3 in mononuclear cells results in upregulation of CD63 and CD203c upon PMA stimulation, suggesting CTNNA3 plays a role in regulating allergen sensitization signaling.\",\n      \"method\": \"siRNA knockdown of CTNNA3 in mononuclear cells; flow cytometry for CD63 and CD203c after PMA stimulation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment, single lab, limited pathway characterization\",\n      \"pmids\": [\"26188062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTNNA3 levels determine cell-type-specific YAP1-WWTR1/TAZ transcriptional responses to autophagy perturbations. CTNNA3 (like CTNNA1) acts as a negative regulator of YAP1-WWTR1/TAZ and is itself an autophagy substrate; this relationship was integrated into a mathematical model validated by experimental data.\",\n      \"method\": \"Experimental autophagy modulation in cells with varying CTNNA3 levels; YAP1/TAZ activity measurements; mathematical modeling validated against experimental observations\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — experimental perturbation of autophagy with functional readout on YAP1/TAZ, mathematical model validated experimentally, single lab\",\n      \"pmids\": [\"34036899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPATA33 physically interacts with CTNNA3 in TM4 Sertoli cells. This interaction inhibits the formation of the CDH1-CTNNB1-CTNNA3 adhesion complex, thereby weakening cell-cell adhesion and promoting cell migration. SPATA33 knockout disrupts F-actin formation, decreases G1-phase cells, and impairs cell migration.\",\n      \"method\": \"Co-immunoprecipitation (protein IP); CRISPR-Cas9 Spata33 knockout in TM4 cells; cell wound scratch assay; flow cytometry; phalloidin staining for F-actin\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional knockout with defined cellular phenotypes, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35536443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CTNNA3 is hyperphosphorylated at specific residues in the intercalated disc (ICD) of cardiomyocytes in dilated cardiomyopathy (DCM). Phosphorylation at these residues is required for maintaining CTNNA3 protein localization at the cardiomyocyte ICD to regulate cell-cell conductance and adhesion, as demonstrated by ex vivo cardiomyocytes and in vivo AAV9-mediated overexpression of wild-type vs. phosphomutant CTNNA3 in mice.\",\n      \"method\": \"Mass spectrometry phosphoproteomics of human LV tissue; ex vivo cardiomyocyte experiments; in vivo AAV9-mediated overexpression of CTNNA3 phospho-variants in mouse heart; localization imaging and conductance/adhesion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphoproteomic discovery in human tissue validated by in vivo AAV9 mouse model with phospho-null/mimetic mutants, multiple orthogonal approaches\",\n      \"pmids\": [\"37126683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fortilin specifically binds CTNNA3 (but not CTNNA1, CTNNA2, or CTNNB1) via direct protein-protein interaction. Fortilin protects CTNNA3 against phosphorylation, subsequent ubiquitination, and proteasome-mediated degradation. Silencing of CTNNA3 causes apoptosis in 293T cells, identifying CTNNA3 as a pro-survival molecule. Absence of fortilin accelerates CTNNA3 phosphorylation and degradation.\",\n      \"method\": \"Co-immunoprecipitation western blot; proximity ligation assay; microscale thermophoresis; biolayer interferometry; siRNA silencing of fortilin and CTNNA3; phospho-null (5A) and phospho-mimetic (5D) CTNNA3 mutants; proteasome inhibitor experiments; apoptosis assays in 293T cells and fortilin-deficient THP1 cells\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (Co-IP, PLA, MST, BLI) plus mutagenesis and functional rescue, single lab but exceptionally rigorous\",\n      \"pmids\": [\"39747445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ctnna3 deficiency in neonatal mice promotes cardiomyocyte proliferation and enhances heart regeneration after apex resection. The mechanism involves upregulation of YAP (Yes-associated protein) expression in Ctnna3-deficient P7 hearts.\",\n      \"method\": \"Ctnna3 knockout neonatal mouse model; heart apex resection; cardiomyocyte proliferation assays; YAP expression analysis\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined loss-of-function mouse model with specific in vivo phenotype and YAP pathway placement, single lab, single study\",\n      \"pmids\": [\"40765350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBD (ubiquitin D) promotes ubiquitination and proteasomal degradation of CTNNA3 in HCC cells, thereby reducing CTNNA3 protein levels. UBD knockdown restores CTNNA3 expression and suppresses HCC proliferation, migration, invasion, and EMT; CTNNA3 knockdown counteracts these inhibitory effects, placing CTNNA3 downstream of UBD in a UBD/CTNNA3 regulatory axis.\",\n      \"method\": \"In vitro ubiquitination assay; siRNA knockdown of UBD and CTNNA3 in HCC cells; CCK-8, colony formation, EdU, and transwell assays; Western blot for EMT markers\",\n      \"journal\": \"Cell journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination assay plus epistasis rescue experiment, multiple functional assays, single lab\",\n      \"pmids\": [\"41076572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Fortilin specifically binds the N-terminal region (amino acids 1–85) of MEF2C (but not MEF2A, MEF2B, or MEF2D) via a binding interface involving aspartic acid 25 of fortilin (D25A mutation weakens binding). Fortilin protects MEF2C from ubiquitination and proteasomal degradation and promotes MEF2C serine 59 phosphorylation (required for transcriptional activity) in a binding-dependent manner. Loss of fortilin reduces MEF2C binding to nuclear DNA, decreases CTNNA3 promoter-driven luciferase activity in an MEF2C-dependent fashion, and lowers RNA polymerase II occupancy at the CTNNA3 locus, establishing fortilin as a transcriptional cofactor of MEF2C that drives CTNNA3 transcription.\",\n      \"method\": \"Microscale thermophoresis; proximity ligation assay; in vitro and in vivo co-immunoprecipitation western blot; molecular docking; site-directed mutagenesis (D25A); ubiquitination assays; CTNNA3 promoter-driven luciferase reporter; chromatin immunoprecipitation (RNA Pol II occupancy); fortilin loss-of-function\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-level biochemistry (MST, Co-IP), site-directed mutagenesis, promoter luciferase, ChIP, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41933733\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTNNA3 (αT-catenin) is a cardiac and epithelial adherens junction protein that links cadherin-based adhesion complexes to the actin cytoskeleton; its expression is driven transcriptionally by GATA-4 and MEF2C (the latter stabilized and activated by fortilin), its protein stability is maintained by fortilin-mediated protection against phosphorylation-triggered ubiquitination and proteasomal degradation (counteracted by UBD), its phosphorylation state at ICD residues governs its localization and function in cardiomyocyte conductance and cell-cell adhesion, it acts as a negative regulator of YAP/TAZ signaling and cardiomyocyte proliferation, it suppresses cancer cell migration and invasion partly through Akt pathway inhibition, and it is subject to tissue-specific genomic imprinting in placenta with preferential maternal-allele expression in villous cytotrophoblast.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTNNA3 (αT-catenin) is an adherens-junction catenin that links cadherin-based adhesion complexes to the actin cytoskeleton and constrains growth-promoting signaling across cardiac, epithelial, and tumor contexts [#7, #8]. Its expression is established transcriptionally by GATA-4 and MEF2C acting at the CTNNA3 promoter, with one GATA box absolutely required for high promoter activity in cardiac cells; the isolated promoter recapitulates tissue-specific αT-catenin expression in vivo [#0]. MEF2C-driven CTNNA3 transcription is potentiated by fortilin, which binds the N-terminal region of MEF2C, protects it from ubiquitin-proteasome degradation, promotes its activating Ser59 phosphorylation, and thereby increases MEF2C occupancy and RNA Pol II loading at the CTNNA3 locus [#12]. At the protein level, fortilin additionally binds CTNNA3 directly and shields it from phosphorylation-triggered ubiquitination and proteasomal turnover, defining CTNNA3 as a pro-survival molecule whose loss induces apoptosis [#9]; this stabilizing influence is opposed by UBD, which drives CTNNA3 ubiquitination and degradation in hepatocellular carcinoma [#11]. In the cardiomyocyte intercalated disc, site-specific phosphorylation of CTNNA3 governs its localization and its regulation of cell-cell conductance and adhesion, with hyperphosphorylation observed in dilated cardiomyopathy [#8]. Functionally, CTNNA3 is a negative regulator of YAP/TAZ signaling and cardiomyocyte proliferation—its deficiency upregulates YAP and enhances neonatal heart regeneration [#6, #10]—and it acts as a tumor suppressor that restrains cell migration and invasion, in part through inhibition of Akt signaling, with its assembly into the CDH1-CTNNB1-CTNNA3 adhesion complex antagonized by SPATA33 [#2, #3, #7]. CTNNA3 is also subject to placental genomic imprinting with preferential maternal-allele expression in villous cytotrophoblast [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established how CTNNA3 transcription is controlled and restricted to specific tissues, identifying GATA-4 and MEF2C as direct activators of its promoter.\",\n      \"evidence\": \"Promoter mutagenesis in P19/HL-1 cells, in vivo GATA-4 binding, and transgenic LacZ reporter mice\",\n      \"pmids\": [\"15302915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address cofactors required for MEF2C activity at the locus\", \"No post-transcriptional or protein-level regulation defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CTNNA3 is epigenetically regulated, revealing tissue- and cell-type-specific genomic imprinting in placenta.\",\n      \"evidence\": \"Allele-specific RT-PCR on informative heterozygous samples with immunostaining of trophoblast subtypes\",\n      \"pmids\": [\"15533819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Imprinting control region/mechanism not mapped\", \"Functional consequence of monoallelic expression unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the first direct functional evidence that CTNNA3 suppresses tumor cell behavior, framing it as a tumor suppressor.\",\n      \"evidence\": \"Mutant CTNNA3 expression and siRNA silencing with migration/invasion assays in head and neck squamous carcinoma cells\",\n      \"pmids\": [\"24100690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway not defined\", \"No in vivo validation in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated CTNNA3 in immune/allergen sensitization signaling beyond its adhesion role.\",\n      \"evidence\": \"siRNA knockdown in mononuclear cells with flow cytometry for CD63/CD203c after PMA stimulation\",\n      \"pmids\": [\"26188062\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown experiment without pathway characterization\", \"Mechanism linking CTNNA3 to basophil activation markers unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CTNNA3 tumor suppression to a defined signaling axis (Akt) and to upstream microRNA control.\",\n      \"evidence\": \"Overexpression/knockdown in HCC lines, miR-425 3′UTR luciferase reporter, Western blots, and xenografts\",\n      \"pmids\": [\"26882563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between CTNNA3 and Akt not resolved\", \"Whether adhesion-complex assembly mediates the effect not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Tested whether CTNNA3 maintains cytoskeletal integrity and adhesion in a non-canonical (Schwann cell) context.\",\n      \"evidence\": \"Transient siRNA knockdown in cultured Schwann cells with cytoskeletal and E-cadherin staining\",\n      \"pmids\": [\"27765635\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown without rescue or pathway placement\", \"Phenotype not validated in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned CTNNA3 as a negative regulator of YAP/TAZ and as an autophagy substrate, integrating its level into cell-type-specific transcriptional responses.\",\n      \"evidence\": \"Autophagy modulation in cells with varying CTNNA3, YAP/TAZ activity readouts, and a mathematical model validated experimentally\",\n      \"pmids\": [\"34036899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CTNNA3 sequesters/regulates YAP/TAZ not detailed\", \"Autophagy receptor mediating CTNNA3 degradation not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a direct binding partner (SPATA33) that controls CTNNA3 incorporation into the cadherin adhesion complex.\",\n      \"evidence\": \"Co-IP, CRISPR Spata33 knockout in TM4 Sertoli cells, scratch/migration assays, flow cytometry, and phalloidin F-actin staining\",\n      \"pmids\": [\"35536443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on CTNNA3 not mapped\", \"Whether SPATA33 regulation operates in other tissues unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined how CTNNA3 phosphorylation governs its localization and function at the cardiomyocyte intercalated disc, linking it to dilated cardiomyopathy.\",\n      \"evidence\": \"Phosphoproteomics of human LV tissue plus ex vivo cardiomyocytes and in vivo AAV9 overexpression of phospho-variants in mice\",\n      \"pmids\": [\"37126683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for ICD-specific phosphorylation not identified\", \"Causal role of hyperphosphorylation in human DCM not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CTNNA3 as a pro-survival protein and identified fortilin as a direct stabilizer protecting it from phosphorylation-dependent degradation.\",\n      \"evidence\": \"Co-IP, PLA, MST, BLI, fortilin/CTNNA3 silencing, phospho-null (5A)/mimetic (5D) mutants, proteasome inhibition, and apoptosis assays\",\n      \"pmids\": [\"39747445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase driving CTNNA3 ubiquitination not identified in this study\", \"Kinase linking phosphorylation to degradation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that CTNNA3 restrains cardiomyocyte proliferation in vivo and that its loss enhances neonatal heart regeneration via YAP.\",\n      \"evidence\": \"Ctnna3 knockout neonatal mouse apex-resection model with proliferation assays and YAP expression analysis\",\n      \"pmids\": [\"40765350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between CTNNA3 and YAP regulation not resolved\", \"Whether effect persists into adult regeneration unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified UBD as a negative regulator that degrades CTNNA3, placing CTNNA3 downstream in a UBD/CTNNA3 axis controlling HCC malignancy.\",\n      \"evidence\": \"In vitro ubiquitination assay, UBD/CTNNA3 knockdown epistasis, proliferation/migration/invasion assays, and EMT marker Western blots\",\n      \"pmids\": [\"41076572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UBD acts directly as the degradation signal or recruits an E3 not defined\", \"Relationship to fortilin-mediated stabilization not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the transcriptional arm of CTNNA3 regulation, showing fortilin acts as a MEF2C cofactor that stabilizes and activates MEF2C to drive CTNNA3 expression.\",\n      \"evidence\": \"MST, PLA, in vitro/in vivo Co-IP, docking, D25A mutagenesis, ubiquitination assays, CTNNA3 promoter luciferase, and RNA Pol II ChIP\",\n      \"pmids\": [\"41933733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fortilin partitions between MEF2C (nuclear) and CTNNA3 (junctional) regulation not addressed\", \"Physiological contexts where this axis dominates not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The kinase and E3 ligase machinery that couples CTNNA3 phosphorylation to its ubiquitination and turnover remain unidentified, and the molecular basis of its YAP/TAZ regulation is undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No CTNNA3-directed kinase identified\", \"Direct E3 ligase versus UBD adaptor role unresolved\", \"Structural/biochemical mechanism of YAP/TAZ suppression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"complexes\": [\"CDH1-CTNNB1-CTNNA3 adhesion complex\"],\n    \"partners\": [\"TPT1\", \"MEF2C\", \"SPATA33\", \"UBD\", \"CDH1\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}