{"gene":"CTNNA1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2025,"finding":"UBE2O, a hybrid E2/E3 ubiquitin enzyme, selectively interacts with and ubiquitylates cytosolic CTNNA1 in a phosphorylation-independent manner. Mass spectrometry-based interactome analysis showed that ubiquitylation of CTNNA1 diminishes its interaction with β-catenin while enabling its interaction with vinculin, promoting focal adhesion maturation and cell-to-ECM adhesion during cell spreading. Ubiquitylation thus acts as a molecular switch directing CTNNA1's function toward cell-to-ECM adhesions.","method":"Co-IP, mass spectrometry-based interactome analysis, ubiquitylation assay, functional cell spreading assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified by MS-based interactome plus functional readout in single lab; ubiquitylation established biochemically but full reconstitution not described in abstract","pmids":["40983751"],"is_preprint":false},{"year":2010,"finding":"PTEN–mTOR signaling acts upstream of C/EBPα to control the ratio of p42 to p30 C/EBPα isoforms. p30 C/EBPα binds the CTNNA1 proximal promoter and recruits Polycomb Repressive Complex 2 (PRC2), suppressing CTNNA1 transcription via H3K27me3; p42 C/EBPα binding at the same promoter relieves repression and promotes CTNNA1 expression via H3K4me3. Loss of Pten in mice and zebrafish reduces wild-type C/EBPα and α-catenin protein, inducing myelodysplasia. This defines a conserved PTEN–C/EBPα–CTNNA1 pathway controlling myeloid differentiation.","method":"Chromatin immunoprecipitation (ChIP), promoter-binding assays, genetic epistasis in mouse and zebrafish loss-of-function models, protein expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, genetic models in two organisms, protein analysis) in a single rigorous study establishing pathway position","pmids":["20371743"],"is_preprint":false},{"year":2006,"finding":"In HL-60 myeloid leukemia cells (which carry a 5q31 deletion), the retained CTNNA1 allele is epigenetically silenced by promoter methylation and histone deacetylation. Restoration of CTNNA1 expression in these cells resulted in reduced proliferation and apoptotic cell death, establishing a tumor-suppressor function in myeloid cells.","method":"Methylation analysis, chromatin/histone modification assays, CTNNA1 restoration (gain-of-function) with proliferation and apoptosis readouts in HL-60 cells","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal epigenetic methods plus functional rescue experiment; replicated mechanistically by subsequent studies (PMID:19826047, PMID:20371743)","pmids":["17159988"],"is_preprint":false},{"year":2009,"finding":"Progressive epigenetic inactivation of CTNNA1 in AML/MDS involves sequential acquisition of repressive histone marks (H3K27me3) at the promoter followed by DNA CpG methylation. The most repressive chromatin state correlates with DNA methylation and is found in advanced (AML) rather than low-risk MDS, indicating stepwise epigenetic silencing during leukemic transformation.","method":"ChIP for H3K27me3, methylation-specific PCR, gene expression analysis in primary leukemia cells and AML cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal epigenetic methods in primary patient samples and cell lines, single lab","pmids":["19826047"],"is_preprint":false},{"year":1999,"finding":"In the HCT-8 colon cancer cell family (identical to HCT-15, DLD-1, HRT-18), one CTNNA1 allele is constitutively mutated. Spontaneous invasive variants arising due to HMSH6/GTBP mismatch-repair defects carry a mutation or exon skipping in the second CTNNA1 allele, fulfilling Knudsen's two-hit model, establishing CTNNA1 as an invasion-suppressor gene.","method":"Sequencing of both alleles, genetic analysis of spontaneous invasive variants, mismatch-repair gene context","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic two-hit loss-of-function in cell panel with defined phenotypic readout (invasion), single lab","pmids":["10023666"],"is_preprint":false},{"year":2021,"finding":"CTNNA1/α-catenin functions as a negative regulator of YAP1–WWTR1/TAZ transcriptional co-factors and is itself an autophagy substrate. α-Catenin levels determine the direction of YAP1–WWTR1/TAZ signaling change after autophagy perturbation: cells with higher CTNNA1 show decreased YAP1–WWTR1/TAZ activity upon autophagy inhibition (because CTNNA1 accumulates and suppresses YAP1–WWTR1/TAZ), while cells with lower CTNNA1 show the opposite. A mathematical model integrating these feedback relationships was experimentally validated.","method":"Autophagy perturbation experiments, YAP1–WWTR1/TAZ activity assays, mathematical modeling with experimental validation in cell lines with varying CTNNA1 levels","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pathway placement with quantitative modeling and experimental validation; single lab","pmids":["34036899"],"is_preprint":false},{"year":2015,"finding":"Heterozygous missense mutations in CTNNA1 cause butterfly-shaped pigment dystrophy. A Ctnna1 missense mutation in the mouse mutant tvrm5 phenocopies the human disease: RPE cells show increased shedding, large multinucleated cells, pigmentary abnormalities and decreased light-activated responses, demonstrating that CTNNA1 is required for intercellular adhesion and cytokinesis in the retinal pigment epithelium.","method":"Identification of human missense mutations, chemically-induced mouse mutant characterization (morphological studies, electroretinography), RPE cell analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel human genetic and mouse functional data with multiple phenotypic readouts establishing RPE integrity role","pmids":["26691986"],"is_preprint":false},{"year":2011,"finding":"Bidirectional promoters shared between CTNNA1 and the antisense-oriented LRRTM2 gene drive alternative CTNNA1 transcripts whose translation produces N-terminally truncated CTNNA1 isoforms lacking the β-catenin interaction domain; these isoforms are expressed at high levels in the nervous system.","method":"Promoter mapping, RT-PCR, protein expression analysis, luciferase reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct characterization of alternative isoform production and promoter activity; functional consequence of lacking β-catenin domain inferred from domain knowledge, not directly tested","pmids":["21708131"],"is_preprint":false},{"year":2013,"finding":"A germline truncating allele of CTNNA1 co-segregates with hereditary diffuse gastric cancer in a CDH1-negative family; the remaining CTNNA1 allele is silenced in invasive tumors and signet ring cells (biallelic inactivation), placing CTNNA1 as a tumor suppressor in the same adherens junction complex as E-cadherin.","method":"Exome sequencing, Sanger validation, loss-of-heterozygosity analysis, promoter methylation analysis in tumor tissue","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exome sequencing plus molecular verification of second-hit silencing; single family, no functional rescue experiment","pmids":["23208944"],"is_preprint":false},{"year":2026,"finding":"CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD) in human gastric cancer cells, resulting in loss of αE-catenin protein. In a humanized Drosophila model, truncating CTNNA1 variants failed to rescue epithelial architecture or viability upon depletion of endogenous Drosophila α-catenin and were associated with increased apoptosis, confirming they are loss-of-function alleles. Non-truncating transcripts retained function. Missense variant p.Asn853Ser (in the M-fragment) showed partial functional loss.","method":"CRISPR/Cas9 CTNNA1-knockout in gastric cancer cells, NMD analysis (RT-PCR), humanized Drosophila complementation assay (tissue-specific RNAi + CRISPR/Cas9 depletion of endogenous Dα-cat + expression of human WT or mutant αE-catenin), apoptosis readout","journal":"Gut / European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo complementation model with mutagenesis panel plus NMD validation in human cells; multiple orthogonal methods across two papers from related teams","pmids":["40998418","41760782"],"is_preprint":false},{"year":2002,"finding":"Alternative splicing of CTNNA1 that was previously reported generates a frameshift rather than an in-frame insert, resulting in a truncated protein. Quantitative RT-PCR showed no relevant expression of this splice variant in any human tissue, cell line, or mouse developmental stage tested, indicating it is not a functionally significant isoform.","method":"RT-PCR, real-time quantitative RT-PCR across human tissues/cell lines and mouse developmental stages, genomic characterization","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental refutation of a previously proposed isoform using quantitative expression analysis across multiple tissues; negative result mechanistically informative","pmids":["11997091"],"is_preprint":false},{"year":2016,"finding":"The pseudogene CTNNAP1 competes with CTNNA1 for binding to microRNA-141 (miR-141), acting as a competing endogenous RNA (ceRNA). Overexpression of CTNNAP1 reduced miR-141-mediated suppression of CTNNA1, increasing CTNNA1 levels; overexpression of either CTNNAP1 or CTNNA1 inhibited cell proliferation and induced G0/G1 cell cycle arrest in vitro and suppressed tumor growth in vivo.","method":"ceRNA/miRNA competition assay, overexpression gain-of-function experiments, cell cycle analysis (flow cytometry), xenograft tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ceRNA mechanism established with gain-of-function and in vivo readout, single lab","pmids":["27487124"],"is_preprint":false},{"year":2020,"finding":"Overexpression of CTNNA1 in bladder cancer cell lines (T24, UMUC-2) inhibited cell proliferation, migration, invasion and EMT (increasing E-cadherin, decreasing N-cadherin, Snail, MMP2, MMP9) and promoted apoptosis. GSEA linked CTNNA1 to p53 and apoptosis pathways. CTNNA1 also suppressed tumor growth in a nude mouse xenograft model.","method":"Overexpression plasmid transfection, CCK-8 proliferation assay, flow cytometry apoptosis assay, wound healing, Transwell invasion, Western blot for EMT markers, GSEA, xenograft mouse model","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain-of-function in cell lines with phenotypic readouts but pathway placement (p53/apoptosis) based on GSEA inference, single lab","pmids":["33364826"],"is_preprint":false}],"current_model":"CTNNA1 encodes αE-catenin, a component of the E-cadherin/adherens junction complex that suppresses cell invasion and tumor growth; it is epigenetically silenced in myeloid malignancies via PRC2-mediated H3K27me3 followed by DNA methylation, driven by a PTEN–C/EBPα–CTNNA1 axis; in the cytosol, UBE2O ubiquitylates CTNNA1 to switch its binding from β-catenin to vinculin and direct it toward focal adhesion maturation and cell-to-ECM adhesion; CTNNA1 negatively regulates YAP1–WWTR1/TAZ signaling as an autophagy substrate; truncating germline variants cause loss of αE-catenin protein via nonsense-mediated mRNA decay and are confirmed loss-of-function alleles in a humanized Drosophila complementation model, predisposing to hereditary diffuse gastric cancer; and missense mutations in its M-fragment disrupt RPE intercellular adhesion and cytokinesis, causing macular dystrophy."},"narrative":{"mechanistic_narrative":"CTNNA1 encodes αE-catenin, a component of the E-cadherin adherens junction complex that functions as an invasion- and tumor-suppressor across epithelial and myeloid lineages [PMID:10023666, PMID:17159988]. In colon cancer cells, biallelic inactivation of CTNNA1 fulfills a two-hit model and drives spontaneous invasive conversion [PMID:10023666], and a germline truncating allele co-segregating with hereditary diffuse gastric cancer in a CDH1-negative family, together with silencing of the second allele in invasive tumor tissue, places αE-catenin in the same adherens-junction tumor-suppressor module as E-cadherin [PMID:23208944]. Truncating CTNNA1 transcripts are degraded by nonsense-mediated mRNA decay, eliminating αE-catenin protein, and a humanized Drosophila complementation assay confirms these variants are loss-of-function alleles that fail to rescue epithelial architecture and viability [PMID:40998418, PMID:41760782]. αE-catenin's activity is governed by multiple regulatory layers: in myeloid cells a PTEN–C/EBPα axis controls its transcription, where the p30 C/EBPα isoform binds the CTNNA1 promoter and recruits PRC2 to deposit H3K27me3, with stepwise progression to DNA CpG methylation silencing the locus during leukemic transformation [PMID:20371743, PMID:19826047], and restoration of CTNNA1 in silenced leukemia cells reduces proliferation and induces apoptosis [PMID:17159988]. Post-translationally, UBE2O ubiquitylates cytosolic CTNNA1 to switch its binding partner from β-catenin to vinculin, directing it toward focal adhesion maturation and cell-to-ECM adhesion [PMID:40983751], and CTNNA1 acts as an autophagy substrate that negatively regulates YAP1–WWTR1/TAZ transcriptional signaling [PMID:34036899]. Beyond its junctional role, αE-catenin is required for intercellular adhesion and cytokinesis in the retinal pigment epithelium, where heterozygous missense mutations cause butterfly-shaped pigment (macular) dystrophy [PMID:26691986].","teleology":[{"year":1999,"claim":"Established CTNNA1 as an invasion-suppressor gene by showing that biallelic inactivation accompanies acquisition of invasiveness, defining its loss-of-function role in epithelial cancer.","evidence":"Allele sequencing and genetic analysis of spontaneous invasive variants in a colon cancer cell family with mismatch-repair defects","pmids":["10023666"],"confidence":"Medium","gaps":["No reconstitution showing which junctional function is lost","Mechanism linking CTNNA1 loss to invasion not dissected at the molecular level"]},{"year":2006,"claim":"Demonstrated that the retained CTNNA1 allele is epigenetically silenced in myeloid leukemia and that its restoration is growth-suppressive, extending the tumor-suppressor role beyond epithelia.","evidence":"Promoter methylation/histone modification analysis and CTNNA1 restoration with proliferation/apoptosis readouts in HL-60 cells","pmids":["17159988"],"confidence":"High","gaps":["Did not define the upstream regulators recruiting the silencing machinery","Mechanism of growth suppression not resolved"]},{"year":2009,"claim":"Resolved the temporal order of epigenetic silencing, showing H3K27me3 precedes DNA CpG methylation and tracks with leukemic progression.","evidence":"ChIP for H3K27me3 and methylation-specific PCR in primary leukemia samples and AML cell lines","pmids":["19826047"],"confidence":"Medium","gaps":["Single lab","Did not identify the transcription factor directing PRC2 to the promoter"]},{"year":2010,"claim":"Placed CTNNA1 transcription downstream of a PTEN–C/EBPα axis, explaining how isoform balance of C/EBPα recruits PRC2 to silence the gene and links its loss to myelodysplasia.","evidence":"ChIP, promoter-binding assays, and genetic loss-of-function in mouse and zebrafish with protein expression analysis","pmids":["20371743"],"confidence":"High","gaps":["Did not establish whether the same axis operates in non-myeloid lineages","Direct PRC2 recruitment mechanism by p30 C/EBPα not structurally defined"]},{"year":2011,"claim":"Showed CTNNA1 shares bidirectional promoters with antisense LRRTM2, producing N-terminally truncated isoforms lacking the β-catenin domain enriched in nervous system.","evidence":"Promoter mapping, RT-PCR, luciferase reporter assays, protein expression analysis","pmids":["21708131"],"confidence":"Medium","gaps":["Functional consequence of the missing β-catenin domain inferred, not directly tested","Physiological role of neural isoforms unknown"]},{"year":2013,"claim":"Connected a germline CTNNA1 truncating allele to hereditary diffuse gastric cancer with second-hit silencing, placing αE-catenin alongside E-cadherin as a heritable gastric tumor suppressor.","evidence":"Exome sequencing, Sanger validation, loss-of-heterozygosity and promoter methylation analysis in a CDH1-negative family","pmids":["23208944"],"confidence":"Medium","gaps":["Single family","No functional rescue experiment to prove causality at the time"]},{"year":2015,"claim":"Defined a non-cancer role for αE-catenin in retinal pigment epithelium adhesion and cytokinesis, showing missense mutations cause butterfly-shaped pigment dystrophy.","evidence":"Human mutation identification plus characterization of a Ctnna1 missense mouse mutant with morphological and electroretinography readouts","pmids":["26691986"],"confidence":"High","gaps":["Molecular mechanism by which missense changes impair cytokinesis not resolved","Link between RPE adhesion defect and pigment phenotype incompletely defined"]},{"year":2016,"claim":"Identified a pseudogene-based ceRNA layer in which CTNNAP1 sponges miR-141 to elevate CTNNA1 and suppress proliferation, adding a post-transcriptional control mechanism.","evidence":"ceRNA/miRNA competition assays, overexpression, cell cycle flow cytometry, and xenograft model","pmids":["27487124"],"confidence":"Medium","gaps":["Single lab","Physiological relevance of the ceRNA axis in primary tissue not established"]},{"year":2021,"claim":"Positioned αE-catenin as an autophagy substrate and negative regulator of YAP1–WWTR1/TAZ, showing its abundance sets the direction of signaling change after autophagy perturbation.","evidence":"Autophagy perturbation, YAP1–TAZ activity assays, and a validated mathematical model in cells with varying CTNNA1 levels","pmids":["34036899"],"confidence":"Medium","gaps":["Single lab","Direct biochemical mechanism of YAP1–TAZ suppression not mapped"]},{"year":2025,"claim":"Revealed that UBE2O-mediated ubiquitylation acts as a switch redirecting cytosolic CTNNA1 from β-catenin to vinculin, coupling it to focal adhesion maturation and cell-to-ECM adhesion.","evidence":"Co-IP, MS-based interactome, ubiquitylation assay, and cell-spreading functional readout","pmids":["40983751"],"confidence":"Medium","gaps":["Full in vitro reconstitution of the ubiquitylation reaction not described","Ubiquitin site mapping and chain type not defined"]},{"year":2026,"claim":"Provided in vivo proof that truncating CTNNA1 variants are loss-of-function via NMD-driven protein loss, confirming causality for hereditary diffuse gastric cancer.","evidence":"CRISPR knockout and NMD analysis in gastric cancer cells plus a humanized Drosophila complementation assay with a mutagenesis panel","pmids":["40998418","41760782"],"confidence":"High","gaps":["Penetrance and clinical management implications not addressed","Mechanism of the partial-loss missense variant p.Asn853Ser not fully resolved"]},{"year":null,"claim":"How the distinct regulatory inputs on αE-catenin — transcriptional silencing, ceRNA control, ubiquitin switching, and autophagic turnover — are integrated to set its abundance and partner choice in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling abundance control to junction vs. focal-adhesion vs. YAP-regulatory functions","Tissue-specific dominance of each regulatory layer unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]}],"pathway":[],"complexes":["adherens junction (E-cadherin complex)"],"partners":["CTNNB1","VCL","UBE2O","CDH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35221","full_name":"Catenin alpha-1","aliases":["Alpha E-catenin","Cadherin-associated protein","Renal carcinoma antigen NY-REN-13"],"length_aa":906,"mass_kda":100.1,"function":"Associates with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Can associate with both E- and N-cadherins. Originally believed to be a stable component of E-cadherin/catenin adhesion complexes and to mediate the linkage of cadherins to the actin cytoskeleton at adherens junctions. In contrast, cortical actin was found to be much more dynamic than E-cadherin/catenin complexes and CTNNA1 was shown not to bind to F-actin when assembled in the complex suggesting a different linkage between actin and adherens junctions components. The homodimeric form may regulate actin filament assembly and inhibit actin branching by competing with the Arp2/3 complex for binding to actin filaments. Involved in the regulation of WWTR1/TAZ, YAP1 and TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). May play a crucial role in cell differentiation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P35221/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTNNA1","classification":"Not Classified","n_dependent_lines":116,"n_total_lines":1208,"dependency_fraction":0.09602649006622517},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDH2","stoichiometry":10.0},{"gene":"CTNNB1","stoichiometry":10.0},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2},{"gene":"VCL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CTNNA1","total_profiled":1310},"omim":[{"mim_id":"618361","title":"DUAL-SPECIFICITY PHOSPHATASE 23; DUSP23","url":"https://www.omim.org/entry/618361"},{"mim_id":"616432","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 18; ARHGEF18","url":"https://www.omim.org/entry/616432"},{"mim_id":"613573","title":"ECTODERMAL DYSPLASIA-SYNDACTYLY SYNDROME 1; EDSS1","url":"https://www.omim.org/entry/613573"},{"mim_id":"612686","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY A, MEMBER 7; PLEKHA7","url":"https://www.omim.org/entry/612686"},{"mim_id":"611731","title":"APC REGULATOR OF WNT SIGNALING PATHWAY; APC","url":"https://www.omim.org/entry/611731"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTNNA1"},"hgnc":{"alias_symbol":["CAP102"],"prev_symbol":[]},"alphafold":{"accession":"P35221","domains":[{"cath_id":"1.20.120.230","chopping":"12-42_57-145","consensus_level":"medium","plddt":84.2306,"start":12,"end":145},{"cath_id":"1.20.120.230","chopping":"170-265","consensus_level":"medium","plddt":90.7485,"start":170,"end":265},{"cath_id":"1.20.120","chopping":"278-383","consensus_level":"high","plddt":91.101,"start":278,"end":383},{"cath_id":"1.20.120.230","chopping":"397-505","consensus_level":"medium","plddt":93.2605,"start":397,"end":505},{"cath_id":"1.20.120.230","chopping":"507-637","consensus_level":"medium","plddt":90.6105,"start":507,"end":637},{"cath_id":"1.20.120.230","chopping":"668-845","consensus_level":"high","plddt":85.8863,"start":668,"end":845}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35221","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35221-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35221-F1-predicted_aligned_error_v6.png","plddt_mean":82.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTNNA1","jax_strain_url":"https://www.jax.org/strain/search?query=CTNNA1"},"sequence":{"accession":"P35221","fasta_url":"https://rest.uniprot.org/uniprotkb/P35221.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35221/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35221"}},"corpus_meta":[{"pmid":"23208944","id":"PMC_23208944","title":"An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23208944","citation_count":171,"is_preprint":false},{"pmid":"17159988","id":"PMC_17159988","title":"Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation.","date":"2006","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17159988","citation_count":154,"is_preprint":false},{"pmid":"10023666","id":"PMC_10023666","title":"The alphaE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10023666","citation_count":63,"is_preprint":false},{"pmid":"26691986","id":"PMC_26691986","title":"Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity.","date":"2015","source":"Nature 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mutations in a case of MDS with normal chromosome and FISH results.","date":"2014","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25177364","citation_count":9,"is_preprint":false},{"pmid":"34036899","id":"PMC_34036899","title":"Cell type-specific YAP1-WWTR1/TAZ transcriptional responses after autophagy perturbations are determined by levels of α-catenins (CTNNA1 and CTNNA3).","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34036899","citation_count":7,"is_preprint":false},{"pmid":"23399619","id":"PMC_23399619","title":"Genetic variations of the CTNNA1 and the CTNNB1 genes in sporadic colorectal cancer in Polish population.","date":"2012","source":"Polski przeglad chirurgiczny","url":"https://pubmed.ncbi.nlm.nih.gov/23399619","citation_count":7,"is_preprint":false},{"pmid":"40998418","id":"PMC_40998418","title":"Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and 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ubiquitylates cytosolic CTNNA1 in a phosphorylation-independent manner. Mass spectrometry-based interactome analysis showed that ubiquitylation of CTNNA1 diminishes its interaction with β-catenin while enabling its interaction with vinculin, promoting focal adhesion maturation and cell-to-ECM adhesion during cell spreading. Ubiquitylation thus acts as a molecular switch directing CTNNA1's function toward cell-to-ECM adhesions.\",\n      \"method\": \"Co-IP, mass spectrometry-based interactome analysis, ubiquitylation assay, functional cell spreading assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified by MS-based interactome plus functional readout in single lab; ubiquitylation established biochemically but full reconstitution not described in abstract\",\n      \"pmids\": [\"40983751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTEN–mTOR signaling acts upstream of C/EBPα to control the ratio of p42 to p30 C/EBPα isoforms. p30 C/EBPα binds the CTNNA1 proximal promoter and recruits Polycomb Repressive Complex 2 (PRC2), suppressing CTNNA1 transcription via H3K27me3; p42 C/EBPα binding at the same promoter relieves repression and promotes CTNNA1 expression via H3K4me3. Loss of Pten in mice and zebrafish reduces wild-type C/EBPα and α-catenin protein, inducing myelodysplasia. This defines a conserved PTEN–C/EBPα–CTNNA1 pathway controlling myeloid differentiation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter-binding assays, genetic epistasis in mouse and zebrafish loss-of-function models, protein expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, genetic models in two organisms, protein analysis) in a single rigorous study establishing pathway position\",\n      \"pmids\": [\"20371743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In HL-60 myeloid leukemia cells (which carry a 5q31 deletion), the retained CTNNA1 allele is epigenetically silenced by promoter methylation and histone deacetylation. Restoration of CTNNA1 expression in these cells resulted in reduced proliferation and apoptotic cell death, establishing a tumor-suppressor function in myeloid cells.\",\n      \"method\": \"Methylation analysis, chromatin/histone modification assays, CTNNA1 restoration (gain-of-function) with proliferation and apoptosis readouts in HL-60 cells\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal epigenetic methods plus functional rescue experiment; replicated mechanistically by subsequent studies (PMID:19826047, PMID:20371743)\",\n      \"pmids\": [\"17159988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Progressive epigenetic inactivation of CTNNA1 in AML/MDS involves sequential acquisition of repressive histone marks (H3K27me3) at the promoter followed by DNA CpG methylation. The most repressive chromatin state correlates with DNA methylation and is found in advanced (AML) rather than low-risk MDS, indicating stepwise epigenetic silencing during leukemic transformation.\",\n      \"method\": \"ChIP for H3K27me3, methylation-specific PCR, gene expression analysis in primary leukemia cells and AML cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal epigenetic methods in primary patient samples and cell lines, single lab\",\n      \"pmids\": [\"19826047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In the HCT-8 colon cancer cell family (identical to HCT-15, DLD-1, HRT-18), one CTNNA1 allele is constitutively mutated. Spontaneous invasive variants arising due to HMSH6/GTBP mismatch-repair defects carry a mutation or exon skipping in the second CTNNA1 allele, fulfilling Knudsen's two-hit model, establishing CTNNA1 as an invasion-suppressor gene.\",\n      \"method\": \"Sequencing of both alleles, genetic analysis of spontaneous invasive variants, mismatch-repair gene context\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic two-hit loss-of-function in cell panel with defined phenotypic readout (invasion), single lab\",\n      \"pmids\": [\"10023666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTNNA1/α-catenin functions as a negative regulator of YAP1–WWTR1/TAZ transcriptional co-factors and is itself an autophagy substrate. α-Catenin levels determine the direction of YAP1–WWTR1/TAZ signaling change after autophagy perturbation: cells with higher CTNNA1 show decreased YAP1–WWTR1/TAZ activity upon autophagy inhibition (because CTNNA1 accumulates and suppresses YAP1–WWTR1/TAZ), while cells with lower CTNNA1 show the opposite. A mathematical model integrating these feedback relationships was experimentally validated.\",\n      \"method\": \"Autophagy perturbation experiments, YAP1–WWTR1/TAZ activity assays, mathematical modeling with experimental validation in cell lines with varying CTNNA1 levels\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pathway placement with quantitative modeling and experimental validation; single lab\",\n      \"pmids\": [\"34036899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Heterozygous missense mutations in CTNNA1 cause butterfly-shaped pigment dystrophy. A Ctnna1 missense mutation in the mouse mutant tvrm5 phenocopies the human disease: RPE cells show increased shedding, large multinucleated cells, pigmentary abnormalities and decreased light-activated responses, demonstrating that CTNNA1 is required for intercellular adhesion and cytokinesis in the retinal pigment epithelium.\",\n      \"method\": \"Identification of human missense mutations, chemically-induced mouse mutant characterization (morphological studies, electroretinography), RPE cell analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel human genetic and mouse functional data with multiple phenotypic readouts establishing RPE integrity role\",\n      \"pmids\": [\"26691986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Bidirectional promoters shared between CTNNA1 and the antisense-oriented LRRTM2 gene drive alternative CTNNA1 transcripts whose translation produces N-terminally truncated CTNNA1 isoforms lacking the β-catenin interaction domain; these isoforms are expressed at high levels in the nervous system.\",\n      \"method\": \"Promoter mapping, RT-PCR, protein expression analysis, luciferase reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct characterization of alternative isoform production and promoter activity; functional consequence of lacking β-catenin domain inferred from domain knowledge, not directly tested\",\n      \"pmids\": [\"21708131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A germline truncating allele of CTNNA1 co-segregates with hereditary diffuse gastric cancer in a CDH1-negative family; the remaining CTNNA1 allele is silenced in invasive tumors and signet ring cells (biallelic inactivation), placing CTNNA1 as a tumor suppressor in the same adherens junction complex as E-cadherin.\",\n      \"method\": \"Exome sequencing, Sanger validation, loss-of-heterozygosity analysis, promoter methylation analysis in tumor tissue\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exome sequencing plus molecular verification of second-hit silencing; single family, no functional rescue experiment\",\n      \"pmids\": [\"23208944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD) in human gastric cancer cells, resulting in loss of αE-catenin protein. In a humanized Drosophila model, truncating CTNNA1 variants failed to rescue epithelial architecture or viability upon depletion of endogenous Drosophila α-catenin and were associated with increased apoptosis, confirming they are loss-of-function alleles. Non-truncating transcripts retained function. Missense variant p.Asn853Ser (in the M-fragment) showed partial functional loss.\",\n      \"method\": \"CRISPR/Cas9 CTNNA1-knockout in gastric cancer cells, NMD analysis (RT-PCR), humanized Drosophila complementation assay (tissue-specific RNAi + CRISPR/Cas9 depletion of endogenous Dα-cat + expression of human WT or mutant αE-catenin), apoptosis readout\",\n      \"journal\": \"Gut / European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo complementation model with mutagenesis panel plus NMD validation in human cells; multiple orthogonal methods across two papers from related teams\",\n      \"pmids\": [\"40998418\", \"41760782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Alternative splicing of CTNNA1 that was previously reported generates a frameshift rather than an in-frame insert, resulting in a truncated protein. Quantitative RT-PCR showed no relevant expression of this splice variant in any human tissue, cell line, or mouse developmental stage tested, indicating it is not a functionally significant isoform.\",\n      \"method\": \"RT-PCR, real-time quantitative RT-PCR across human tissues/cell lines and mouse developmental stages, genomic characterization\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental refutation of a previously proposed isoform using quantitative expression analysis across multiple tissues; negative result mechanistically informative\",\n      \"pmids\": [\"11997091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The pseudogene CTNNAP1 competes with CTNNA1 for binding to microRNA-141 (miR-141), acting as a competing endogenous RNA (ceRNA). Overexpression of CTNNAP1 reduced miR-141-mediated suppression of CTNNA1, increasing CTNNA1 levels; overexpression of either CTNNAP1 or CTNNA1 inhibited cell proliferation and induced G0/G1 cell cycle arrest in vitro and suppressed tumor growth in vivo.\",\n      \"method\": \"ceRNA/miRNA competition assay, overexpression gain-of-function experiments, cell cycle analysis (flow cytometry), xenograft tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ceRNA mechanism established with gain-of-function and in vivo readout, single lab\",\n      \"pmids\": [\"27487124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of CTNNA1 in bladder cancer cell lines (T24, UMUC-2) inhibited cell proliferation, migration, invasion and EMT (increasing E-cadherin, decreasing N-cadherin, Snail, MMP2, MMP9) and promoted apoptosis. GSEA linked CTNNA1 to p53 and apoptosis pathways. CTNNA1 also suppressed tumor growth in a nude mouse xenograft model.\",\n      \"method\": \"Overexpression plasmid transfection, CCK-8 proliferation assay, flow cytometry apoptosis assay, wound healing, Transwell invasion, Western blot for EMT markers, GSEA, xenograft mouse model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain-of-function in cell lines with phenotypic readouts but pathway placement (p53/apoptosis) based on GSEA inference, single lab\",\n      \"pmids\": [\"33364826\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTNNA1 encodes αE-catenin, a component of the E-cadherin/adherens junction complex that suppresses cell invasion and tumor growth; it is epigenetically silenced in myeloid malignancies via PRC2-mediated H3K27me3 followed by DNA methylation, driven by a PTEN–C/EBPα–CTNNA1 axis; in the cytosol, UBE2O ubiquitylates CTNNA1 to switch its binding from β-catenin to vinculin and direct it toward focal adhesion maturation and cell-to-ECM adhesion; CTNNA1 negatively regulates YAP1–WWTR1/TAZ signaling as an autophagy substrate; truncating germline variants cause loss of αE-catenin protein via nonsense-mediated mRNA decay and are confirmed loss-of-function alleles in a humanized Drosophila complementation model, predisposing to hereditary diffuse gastric cancer; and missense mutations in its M-fragment disrupt RPE intercellular adhesion and cytokinesis, causing macular dystrophy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTNNA1 encodes αE-catenin, a component of the E-cadherin adherens junction complex that functions as an invasion- and tumor-suppressor across epithelial and myeloid lineages [#4, #2]. In colon cancer cells, biallelic inactivation of CTNNA1 fulfills a two-hit model and drives spontaneous invasive conversion [#4], and a germline truncating allele co-segregating with hereditary diffuse gastric cancer in a CDH1-negative family, together with silencing of the second allele in invasive tumor tissue, places αE-catenin in the same adherens-junction tumor-suppressor module as E-cadherin [#8]. Truncating CTNNA1 transcripts are degraded by nonsense-mediated mRNA decay, eliminating αE-catenin protein, and a humanized Drosophila complementation assay confirms these variants are loss-of-function alleles that fail to rescue epithelial architecture and viability [#9]. αE-catenin's activity is governed by multiple regulatory layers: in myeloid cells a PTEN–C/EBPα axis controls its transcription, where the p30 C/EBPα isoform binds the CTNNA1 promoter and recruits PRC2 to deposit H3K27me3, with stepwise progression to DNA CpG methylation silencing the locus during leukemic transformation [#1, #3], and restoration of CTNNA1 in silenced leukemia cells reduces proliferation and induces apoptosis [#2]. Post-translationally, UBE2O ubiquitylates cytosolic CTNNA1 to switch its binding partner from β-catenin to vinculin, directing it toward focal adhesion maturation and cell-to-ECM adhesion [#0], and CTNNA1 acts as an autophagy substrate that negatively regulates YAP1–WWTR1/TAZ transcriptional signaling [#5]. Beyond its junctional role, αE-catenin is required for intercellular adhesion and cytokinesis in the retinal pigment epithelium, where heterozygous missense mutations cause butterfly-shaped pigment (macular) dystrophy [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established CTNNA1 as an invasion-suppressor gene by showing that biallelic inactivation accompanies acquisition of invasiveness, defining its loss-of-function role in epithelial cancer.\",\n      \"evidence\": \"Allele sequencing and genetic analysis of spontaneous invasive variants in a colon cancer cell family with mismatch-repair defects\",\n      \"pmids\": [\"10023666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution showing which junctional function is lost\", \"Mechanism linking CTNNA1 loss to invasion not dissected at the molecular level\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that the retained CTNNA1 allele is epigenetically silenced in myeloid leukemia and that its restoration is growth-suppressive, extending the tumor-suppressor role beyond epithelia.\",\n      \"evidence\": \"Promoter methylation/histone modification analysis and CTNNA1 restoration with proliferation/apoptosis readouts in HL-60 cells\",\n      \"pmids\": [\"17159988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the upstream regulators recruiting the silencing machinery\", \"Mechanism of growth suppression not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the temporal order of epigenetic silencing, showing H3K27me3 precedes DNA CpG methylation and tracks with leukemic progression.\",\n      \"evidence\": \"ChIP for H3K27me3 and methylation-specific PCR in primary leukemia samples and AML cell lines\",\n      \"pmids\": [\"19826047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not identify the transcription factor directing PRC2 to the promoter\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed CTNNA1 transcription downstream of a PTEN–C/EBPα axis, explaining how isoform balance of C/EBPα recruits PRC2 to silence the gene and links its loss to myelodysplasia.\",\n      \"evidence\": \"ChIP, promoter-binding assays, and genetic loss-of-function in mouse and zebrafish with protein expression analysis\",\n      \"pmids\": [\"20371743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether the same axis operates in non-myeloid lineages\", \"Direct PRC2 recruitment mechanism by p30 C/EBPα not structurally defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CTNNA1 shares bidirectional promoters with antisense LRRTM2, producing N-terminally truncated isoforms lacking the β-catenin domain enriched in nervous system.\",\n      \"evidence\": \"Promoter mapping, RT-PCR, luciferase reporter assays, protein expression analysis\",\n      \"pmids\": [\"21708131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the missing β-catenin domain inferred, not directly tested\", \"Physiological role of neural isoforms unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected a germline CTNNA1 truncating allele to hereditary diffuse gastric cancer with second-hit silencing, placing αE-catenin alongside E-cadherin as a heritable gastric tumor suppressor.\",\n      \"evidence\": \"Exome sequencing, Sanger validation, loss-of-heterozygosity and promoter methylation analysis in a CDH1-negative family\",\n      \"pmids\": [\"23208944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"No functional rescue experiment to prove causality at the time\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a non-cancer role for αE-catenin in retinal pigment epithelium adhesion and cytokinesis, showing missense mutations cause butterfly-shaped pigment dystrophy.\",\n      \"evidence\": \"Human mutation identification plus characterization of a Ctnna1 missense mouse mutant with morphological and electroretinography readouts\",\n      \"pmids\": [\"26691986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which missense changes impair cytokinesis not resolved\", \"Link between RPE adhesion defect and pigment phenotype incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a pseudogene-based ceRNA layer in which CTNNAP1 sponges miR-141 to elevate CTNNA1 and suppress proliferation, adding a post-transcriptional control mechanism.\",\n      \"evidence\": \"ceRNA/miRNA competition assays, overexpression, cell cycle flow cytometry, and xenograft model\",\n      \"pmids\": [\"27487124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological relevance of the ceRNA axis in primary tissue not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned αE-catenin as an autophagy substrate and negative regulator of YAP1–WWTR1/TAZ, showing its abundance sets the direction of signaling change after autophagy perturbation.\",\n      \"evidence\": \"Autophagy perturbation, YAP1–TAZ activity assays, and a validated mathematical model in cells with varying CTNNA1 levels\",\n      \"pmids\": [\"34036899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct biochemical mechanism of YAP1–TAZ suppression not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that UBE2O-mediated ubiquitylation acts as a switch redirecting cytosolic CTNNA1 from β-catenin to vinculin, coupling it to focal adhesion maturation and cell-to-ECM adhesion.\",\n      \"evidence\": \"Co-IP, MS-based interactome, ubiquitylation assay, and cell-spreading functional readout\",\n      \"pmids\": [\"40983751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full in vitro reconstitution of the ubiquitylation reaction not described\", \"Ubiquitin site mapping and chain type not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided in vivo proof that truncating CTNNA1 variants are loss-of-function via NMD-driven protein loss, confirming causality for hereditary diffuse gastric cancer.\",\n      \"evidence\": \"CRISPR knockout and NMD analysis in gastric cancer cells plus a humanized Drosophila complementation assay with a mutagenesis panel\",\n      \"pmids\": [\"40998418\", \"41760782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and clinical management implications not addressed\", \"Mechanism of the partial-loss missense variant p.Asn853Ser not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct regulatory inputs on αE-catenin — transcriptional silencing, ceRNA control, ubiquitin switching, and autophagic turnover — are integrated to set its abundance and partner choice in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling abundance control to junction vs. focal-adhesion vs. YAP-regulatory functions\", \"Tissue-specific dominance of each regulatory layer unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"adherens junction (E-cadherin complex)\"],\n    \"partners\": [\"CTNNB1\", \"VCL\", \"UBE2O\", \"CDH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}