{"gene":"CDH1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1987,"finding":"The extracellular domain of uvomorulin (E-cadherin/CDH1) contains three internally repeated domains of ~112 residues, each with putative Ca2+-binding sites located in external loops, and a single membrane-spanning region followed by a cytoplasmic domain; sequence comparison revealed extensive homology to chicken L-CAM, establishing the conserved cadherin architecture.","method":"Protein sequencing and amino acid sequence analysis; secondary structure prediction; sequence comparison","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — direct protein sequencing with structural analysis; foundational structural characterization","pmids":["3501370"],"is_preprint":false},{"year":1985,"finding":"A 26 kDa extracellular fragment of uvomorulin (E-cadherin/CDH1), recognized by function-blocking monoclonal antibodies, was identified as the cell adhesion domain; anti-uvomorulin antibodies that block this fragment disrupt MDCK monolayers and inhibit embryo compaction.","method":"Protease digestion of uvomorulin to generate fragments; functional blocking with monoclonal antibody DECMA-1; embryo compaction assay; MDCK monolayer disruption assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct functional mapping using antibody blocking and proteolytic fragment identification, replicated across cell systems","pmids":["2419126"],"is_preprint":false},{"year":1988,"finding":"Uvomorulin (E-cadherin/CDH1) mediates an early, Ca2+-dependent adhesion event between MDCK epithelial cells that is a prerequisite for assembly of all junctional complex elements including the zonula adherens, zonula occludens, and desmosomes, as demonstrated using blocking antibodies in a Ca2+-switch assay.","method":"Ca2+-switch assay for de novo junction assembly; function-blocking antibody treatment; fluorescence staining for ZO-1, actin, and desmoplakin; transepithelial resistance measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal readouts in a controlled Ca2+-switch assay; foundational study replicated widely","pmids":["3049625"],"is_preprint":false},{"year":1989,"finding":"The cytoplasmic domain of uvomorulin (E-cadherin/CDH1) associates with three independent proteins of 102, 88, and 80 kDa (named catenin α, β, and γ, respectively) that are structurally conserved across species; this complex links E-cadherin to cytoskeletal structures.","method":"Transfection of uvomorulin cDNA into uvomorulin-negative cells; co-immunoprecipitation with anti-uvomorulin antibodies; cDNA deletion constructs mapping the binding domain; peptide pattern analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP with deletion mapping in multiple cell lines/species; foundational discovery of catenin complex, replicated across labs","pmids":["2788574"],"is_preprint":false},{"year":1990,"finding":"Catenin association with uvomorulin (E-cadherin/CDH1) is mediated by a specific 72-amino-acid domain in the cytoplasmic region (largely encoded by a single exon); β-catenin binds more directly to E-cadherin, while α-catenin links the complex to actin filaments; adhesive function requires catenin association.","method":"Expression of mutant uvomorulin polypeptides and H-2Kd chimeric constructs in L cells; co-immunoprecipitation; cell aggregation assay; biochemical association with actin bundles","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with chimeric proteins, functional aggregation assay, and biochemical fractionation; highly cited foundational work","pmids":["2349235"],"is_preprint":false},{"year":1990,"finding":"Correct proteolytic cleavage of the uvomorulin (E-cadherin/CDH1) precursor is required for its adhesive function; unprocessed mutant E-cadherin can reach the cell surface and associate with catenins but is non-functional; precise cleavage of the 129-residue prodomain, not merely its removal, is required for activation.","method":"Site-directed mutagenesis of protease recognition sites; expression of mutant uvomorulin in L cells; cell aggregation assay; treatment with specific proteases (Factor Xa, trypsin)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with mutagenesis and rescue by specific proteases; multiple controls","pmids":["2211831"],"is_preprint":false},{"year":1990,"finding":"Expression of uvomorulin (E-cadherin/CDH1) in transfected fibroblasts is sufficient to induce redistribution of Na+,K+-ATPase to sites of cell-cell contact, inducing cell surface polarity in the absence of tight junctions, coincident with reorganization of the membrane cytoskeleton.","method":"Transfection of uvomorulin cDNA into fibroblasts; immunofluorescence for Na+/K+-ATPase distribution; Ca2+-switch assay; comparison with polarized epithelial cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function experiment in fibroblasts with defined molecular readout; highly cited","pmids":["2164888"],"is_preprint":false},{"year":1991,"finding":"Alpha-catenin is a vinculin homologue that complexes with multiple cadherins (uvomorulin, N-cadherin, P-cadherin); in cadherin-negative cells alpha-catenin is cytoplasmic, but E-cadherin expression recruits it to membrane contact sites, suggesting α-catenin links the cadherin-catenin complex to the actin cytoskeleton.","method":"Molecular cloning and sequencing of murine alpha-catenin; co-immunoprecipitation with multiple cadherins; immunofluorescence; transfection of E-cadherin into cadherin-negative Ltk- cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — sequence analysis plus co-IP with multiple cadherins and transfection-based localization; foundational structural and functional characterization","pmids":["1924379"],"is_preprint":false},{"year":1991,"finding":"The uvomorulin-catenin complex consists of one molecule of E-cadherin, one or two molecules of β-catenin, and one molecule of α-catenin; β-catenin associates with the precursor form of E-cadherin co-translationally, while α-catenin joins the complex only around the time of endoproteolytic processing.","method":"Biochemical co-immunoprecipitation; pulse-chase labeling; analysis of complex stoichiometry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — pulse-chase with stoichiometric biochemical analysis; defines temporal assembly order","pmids":["1734027"],"is_preprint":false},{"year":1991,"finding":"E-cadherin (uvomorulin/CDH1)-mediated cell-cell contacts inhibit invasive migration of L cells into 3D collagen gels in a cell-density-dependent manner (contact inhibition of movement); this invasion suppression is reversible by anti-E-cadherin antibodies.","method":"Stable transfection of E-cadherin into L cells; 3D collagen gel invasion assay; function-blocking antibody treatment; time-lapse videoscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function with clean genetic controls and antibody rescue; multiple readouts","pmids":["1649199"],"is_preprint":false},{"year":1992,"finding":"Uvomorulin (E-cadherin/CDH1) is synthesized as a 135 kDa precursor that is core glycosylated in the ER, processed to the 120 kDa mature form in the late Golgi after complex glycosylation but before cell-surface delivery; glycosylation is not required for processing or transport. At the cell surface, E-cadherin has a half-life of ~5 h and is rapidly localized to cell-cell contacts upon Ca2+-induced adhesion, coinciding with Triton X-100 insolubility.","method":"Pulse-chase metabolic labeling; subcellular fractionation; Triton X-100 extraction; glycosylation inhibitor studies; immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — detailed biosynthetic analysis with multiple biochemical methods","pmids":["1918074"],"is_preprint":false},{"year":1990,"finding":"The membrane-proximal region of uvomorulin (E-cadherin/CDH1) containing a cluster of cysteine residues is involved in cell adhesion; reduction of disulfide bonds by DTT blocks close cell-cell contacts and cell flattening (but not aggregation) and increases susceptibility to trypsin digestion in the membrane-proximal domain, suggesting this region mediates a second adhesive mechanism.","method":"DTT treatment of cells; cell aggregation and morphology assays; limited trypsin digestion; epitope mapping with DECMA-1 antibody","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological perturbation with functional readout; single lab","pmids":["1710917"],"is_preprint":false},{"year":1994,"finding":"E-cadherin and APC directly compete for binding to the arm repeat region of β-catenin; the N-terminal domain of β-catenin mediates interaction with α-catenin and cytoskeletal anchorage for both the E-cadherin and APC complexes; plakoglobin mediates identical interactions.","method":"Direct competition binding assays; co-immunoprecipitation; domain mapping with deletion constructs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct competition binding assay with domain mapping; foundational mechanistic study","pmids":["7806582"],"is_preprint":false},{"year":1994,"finding":"E-cadherin/catenin complex assembly occurs in two stages: β-catenin or plakoglobin bind E-cadherin immediately after synthesis in the ER (TX-100 soluble), and α-catenin is recruited later, coincident with plasma membrane delivery and entry into the TX-100-insoluble fraction; cadherin-independent pools of catenins also exist.","method":"Pulse-chase metabolic labeling; sucrose density gradient fractionation; chemical cross-linking; sequential immunoprecipitation with catenin-specific antibodies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — pulse-chase with chemical cross-linking and sequential IP; defines temporal assembly","pmids":["8207061"],"is_preprint":false},{"year":1995,"finding":"Silencing of E-cadherin (CDH1) expression in human carcinoma cell lines is caused by CpG hypermethylation of the promoter region; treatment with demethylating agent 5-azacytidine restores E-cadherin expression and reverts cells to an epithelial morphology with homophilic adhesion.","method":"Methylation-sensitive restriction enzyme digestion (HpaII); 5-azacytidine demethylation; RT-PCR; immunohistochemistry; morphological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct demonstration of methylation-dependent silencing with pharmacological rescue; foundational epigenetic mechanism","pmids":["7543680"],"is_preprint":false},{"year":1995,"finding":"E-cadherin (CDH1) functions as a tumour/invasion suppressor gene; protein-truncating mutations (nonsense and frameshift) in the extracellular domain combined with loss of heterozygosity at 16q22.1 cause complete loss of E-cadherin expression in human infiltrative lobular breast carcinomas.","method":"PCR/SSCP mutation screening; LOH analysis; immunohistochemistry for E-cadherin expression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic identification of biallelic inactivation mechanism in human tumors; foundational tumor suppressor characterization","pmids":["8557030"],"is_preprint":false},{"year":1997,"finding":"ZO-1 directly binds α-catenin (Kd ~0.5 nM) through its N-terminal half (dlg-like domain) and actin filaments (Kd ~10 nM) through its C-terminal half, acting as a cross-linker between the E-cadherin/catenin complex and the actin cytoskeleton; ZO-1 expression suppresses cadherin-dependent intercellular motility.","method":"Transfection of truncated ZO-1 constructs into E-cadherin-expressing L cells; co-immunoprecipitation; GST pull-down with recombinant proteins from Sf9 insect cells; in vitro actin co-sedimentation; cell aggregation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of direct protein-protein interactions with defined Kd values plus functional validation","pmids":["9214391"],"is_preprint":false},{"year":1998,"finding":"E-cadherin (CDH1) germline mutations (nonsense, frameshift, splice-site causing in-frame exon deletions) are frequently identified in diffuse gastric cancers and lobular breast cancers; the predominant defects in diffuse gastric tumors are exon skippings causing in-frame deletions, while lobular breast cancers show out-of-frame mutations; in most cases mutations occur with LOH of the wild-type allele.","method":"PCR/SSCP mutation analysis; sequencing; LOH analysis; compilation of 69 somatic mutations","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — comprehensive mutation analysis defining biallelic inactivation pattern and tumor-type specificity","pmids":["9744472"],"is_preprint":false},{"year":2001,"finding":"Crystal structure of the β-catenin arm repeat region complexed with the E-cadherin cytoplasmic domain revealed that the interaction spans all 12 arm repeats, involves quasi-independent binding regions including helices at both ends of the arm repeat domain and an extended 14-residue stretch. Phosphorylation of E-cadherin creates interactions with a hydrophobic patch of β-catenin mimicking an amphipathic XTcf-3 helix, and APC contains homologous sequences suggesting similar binding mode.","method":"X-ray crystallography of unphosphorylated and phosphorylated E-cadherin cytoplasmic domain/β-catenin arm repeat complex","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional implications for phosphorylation-dependent binding","pmids":["11348595"],"is_preprint":false},{"year":2002,"finding":"Hakai, a c-Cbl-like E3 ubiquitin ligase, binds E-cadherin in a tyrosine phosphorylation-dependent manner via its SH2 domain, induces ubiquitination of the E-cadherin complex, and promotes endocytosis of E-cadherin; Hakai expression in epithelial cells disrupts cell-cell contacts and enhances cell motility.","method":"Modified yeast two-hybrid screen; co-immunoprecipitation; ubiquitination assay; endocytosis assay; domain analysis (SH2, RING); transfection and cell morphology/motility assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — identified E3 ligase with mechanistic ubiquitination assay and functional cellular readouts","pmids":["11836526"],"is_preprint":false},{"year":2002,"finding":"Presenilin-1 (PS1)/γ-secretase cleaves E-cadherin between residues Leu731 and Arg732 (membrane-cytoplasm interface), stimulated by apoptosis or calcium influx; this cleavage dissociates E-cadherin, β-catenin and α-catenin from the cytoskeleton, promoting adherens junction disassembly and releasing cytoplasmic β-catenin.","method":"Mapping of PS1/γ-secretase cleavage site by sequencing; pharmacological inhibition; apoptosis induction; calcium influx experiments; cytoskeletal fractionation; co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — precise cleavage site mapping with mechanistic dissection of complex disassembly consequences","pmids":["11953314"],"is_preprint":false},{"year":2002,"finding":"SLUG (SNAI2) zinc-finger transcription factor directly binds E-box elements in the E-cadherin (CDH1) proximal promoter and represses E-cadherin transcription; SLUG expression strongly correlates with loss of E-cadherin in breast cancer cell lines.","method":"Reporter gene assays with E-box mutant promoter constructs; endogenous E-cadherin expression analysis; RT-PCR; co-transfection of SLUG/SNAIL expression constructs","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — promoter reporter assays with E-box mutagenesis plus endogenous gene regulation; foundational EMT transcriptional repressor study","pmids":["11912130"],"is_preprint":false},{"year":2003,"finding":"Snail directly represses transcription of claudin and occludin genes by binding E-boxes in their promoters during EMT; Snail-induced EMT involves simultaneous transcriptional repression of E-cadherin and tight junction proteins, establishing a coordinated program of epithelial junction loss.","method":"Snail overexpression in epithelial cells; promoter reporter assays; electrophoretic mobility shift assay; RT-PCR and immunoblot for junction proteins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding demonstrated by EMSA with functional reporter assays","pmids":["12668723"],"is_preprint":false},{"year":2005,"finding":"ADAM10 metalloprotease is responsible for both constitutive and regulated ectodomain shedding of E-cadherin; ADAM10 deficiency abolishes C-terminal fragment generation in vivo; ADAM10-mediated E-cadherin shedding affects cell-cell adhesion, migration, and β-catenin subcellular localization/downstream signaling including cyclin D1 induction.","method":"ADAM10-deficient fibroblast analysis; metalloprotease inhibitors; RNA interference; ADAM10-deficient mouse embryo analysis; β-catenin transcriptional reporter; cell adhesion and migration assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO mouse, RNAi, and inhibitor studies with multiple orthogonal readouts; in vivo validation","pmids":["15958533"],"is_preprint":false},{"year":2005,"finding":"DeltaEF1 (ZEB1) directly binds the E-cadherin promoter via E-box elements and functions as a transcriptional repressor; ectopic DeltaEF1 is sufficient to downregulate E-cadherin and induce EMT; RNAi-mediated DeltaEF1 knockdown in cancer cells derepresses E-cadherin and restores cell-cell adhesion.","method":"Chromatin immunoprecipitation; promoter reporter assays; DeltaEF1 overexpression and RNAi; E-cadherin expression analysis; cell morphology","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus gain- and loss-of-function with defined molecular and cellular readouts","pmids":["15674322"],"is_preprint":false},{"year":2006,"finding":"VEGF promotes vascular permeability by inducing beta-arrestin2-dependent endocytosis of VE-cadherin (not E-cadherin/CDH1); this is mediated through Src-dependent Vav2 activation, Rac/PAK, and serine phosphorylation of VE-cadherin's intracellular tail, recruiting beta-arrestin2.","method":"Phosphorylation mapping; beta-arrestin2 co-IP; endocytosis assays; clathrin coated vesicle analysis; RNAi","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistically detailed but concerns VE-cadherin not E-cadherin; EXCLUDE from E-cadherin findings","pmids":["17060906"],"is_preprint":false},{"year":2008,"finding":"Loss of E-cadherin (CDH1) protein promotes metastasis not simply by disrupting cell-cell contacts but by inducing an EMT program including invasiveness and anoikis resistance; β-catenin is necessary but not sufficient for these phenotypes; E-cadherin loss induces multiple transcription factors including Twist, which is required for E-cadherin loss-induced metastasis.","method":"Two methods to inhibit E-cadherin function distinguishing adhesion vs. signaling; gene expression profiling; Twist knockdown; in vivo metastasis assays; anoikis resistance assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of adhesion vs. signaling using multiple genetic and functional approaches with in vivo validation","pmids":["18483246"],"is_preprint":false},{"year":2008,"finding":"miR-200 family members (two genomic clusters) directly target ZEB1 and ZEB2 mRNAs, repressing their translation; loss of miR-200 during TGF-β-induced EMT leads to ZEB1/ZEB2-mediated E-cadherin repression; ectopic miR-200 restores E-cadherin expression and inhibits cell motility in mesenchymal carcinoma cells.","method":"TGF-β EMT assay; miRNA overexpression; luciferase reporter with ZEB1/ZEB2 3'UTR; E-cadherin western blot; cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct target validation with 3'UTR reporter plus functional cell migration readout","pmids":["18411277"],"is_preprint":false},{"year":2010,"finding":"miR-9, activated by MYC/MYCN, directly targets the CDH1 (E-cadherin) mRNA 3'UTR, reducing E-cadherin protein levels; this leads to β-catenin nuclear signaling, increased VEGF expression, and enhanced tumour angiogenesis; miR-9 overexpression enables pulmonary micrometastasis formation in mice.","method":"miR-9 overexpression and 'sponge' inhibition; luciferase reporter with CDH1 3'UTR; β-catenin signaling assays; VEGF measurement; in vivo mouse metastasis model; MYC/MYCN promoter binding at mir-9-3 locus","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct 3'UTR reporter validation plus in vivo metastasis assay with mechanistic downstream pathway","pmids":["20173740"],"is_preprint":false},{"year":2011,"finding":"E-cadherin (CDH1) homophilic binding at the cell surface mediates contact inhibition of proliferation through the Hippo signaling pathway; E-cadherin/catenin complex functions as an upstream regulator of LATS/YAP in mammalian cells; β-catenin depletion (depleting E-cadherin-bound β-catenin) reduces YAP phosphorylation and increases nuclear YAP.","method":"Hippo component knockdown; YAP overexpression; E-cadherin expression in MDA-MB-231 cells; β-catenin RNAi in confluent MCF10A cells; YAP phosphorylation and nuclear localization assays; cell proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — epistasis analysis with multiple genetic perturbations and defined pathway placement","pmids":["21730131"],"is_preprint":false},{"year":2013,"finding":"Fusobacterium nucleatum FadA adhesin binds directly to E-cadherin (CDH1); the FadA binding site on E-cadherin was mapped to an 11-amino-acid region; FadA-E-cadherin binding activates β-catenin signaling and induces oncogenic and inflammatory responses in colorectal cancer cells; a synthetic peptide from the FadA-binding region of E-cadherin abolishes these effects.","method":"Direct binding/invasion assays; E-cadherin binding site mapping with peptides; β-catenin reporter; gene expression analysis; synthetic peptide inhibition","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding site mapping with peptide inhibition and defined downstream signaling; highly cited","pmids":["23954158"],"is_preprint":false},{"year":2014,"finding":"HMGA2 epigenetically silences the Cdh1 (E-cadherin) promoter during EMT by recruiting the de novo DNA methyltransferase DNMT3A to the Cdh1 promoter, causing hypermethylation; E-cadherin expression can be restored by the demethylating agent 5-aza-2'-deoxycytidine; this mechanism acts downstream of HMGA2-mediated induction of EMT transcription factors.","method":"Constitutive HMGA2 expression in NMuMG mammary epithelial cells; bisulfite sequencing; ChIP for DNMT3A binding to Cdh1 promoter; 5-aza-2'-deoxycytidine treatment; cell motility and invasion assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating direct DNMT3A recruitment with pharmacological rescue; multiple orthogonal methods","pmids":["25492890"],"is_preprint":false},{"year":2015,"finding":"ABCG2 localizes to the nucleus in lung cancer cells where it binds to the E-box of the CDH1 (E-cadherin) promoter and upregulates CDH1 transcription; increased ABCG2 increases E-cadherin and attenuates cell migration, while ABCG2 knockdown downregulates E-cadherin and enhances cell motility.","method":"Nuclear fractionation; chromatin immunoprecipitation at CDH1 E-box; ABCG2 overexpression and RNAi knockdown; cell migration assays; mouse xenograft metastasis model","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP with functional gain/loss-of-function; single lab","pmids":["25810011"],"is_preprint":false},{"year":2015,"finding":"Rab7 regulates E-cadherin (CDH1) endocytosis in thyroid FRT cells; Rab7 overexpression strongly reduces CDH1 endocytosis and promotes circular dorsal ruffle (CDR) formation co-localizing with cortactin and F-actin; cAMP stimulation induces Rab7 expression and blocks CDH1 endocytosis.","method":"Rab7 overexpression and RNAi in FRT cells; CDH1 endocytosis assay; co-localization by immunofluorescence; PAK1 phosphorylation as Rac1 activity readout; cAMP stimulation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression and RNAi with functional endocytosis assay; single lab, one cell type","pmids":["26599499"],"is_preprint":false},{"year":2017,"finding":"Cancer-associated fibroblasts (CAFs) exert physical force on cancer cells through a mechanically active heterotypic E-cadherin (cancer cell)/N-cadherin (CAF) adhesion; this adhesion triggers β-catenin recruitment and reinforcement dependent on α-catenin/vinculin interaction under force; E-cadherin/N-cadherin adhesion is required for CAF-guided collective invasion.","method":"Traction force microscopy; FRET-based tension sensor; blocking antibodies; α-catenin/vinculin domain mutants; co-culture invasion assay; patient-derived material analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical force measurement combined with molecular perturbation and patient validation; highly cited","pmids":["28218910"],"is_preprint":false},{"year":1996,"finding":"Prevention of compaction in mouse embryos by low Ca2+ reduces overall uvomorulin (E-cadherin) phosphorylation and perturbs its localization to cell-cell contact regions in 8-cell embryos; phosphorylation of E-cadherin correlates with its redistribution during compaction but does not directly regulate adhesive function.","method":"Ca2+ depletion to prevent compaction; radioactive phosphorylation analysis; immunocytochemistry for uvomorulin localization","journal":"Molecular reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 — correlative phosphorylation analysis; cannot establish direct causation","pmids":["8722695"],"is_preprint":false}],"current_model":"E-cadherin (CDH1) is a transmembrane Ca2+-dependent cell adhesion molecule whose extracellular domain mediates homophilic binding and whose cytoplasmic domain recruits β-catenin directly and then α-catenin (a vinculin homologue) to form the cadherin–catenin complex that links E-cadherin to the actin cytoskeleton; this complex is essential for E-cadherin's adhesive function, formation of the epithelial junctional complex, and induction of cell surface polarity. E-cadherin undergoes sequential biosynthetic processing (ER glycosylation → late Golgi cleavage of a 129-residue prodomain → cell surface delivery), regulated ectodomain shedding by ADAM10, γ-secretase/PS1 intramembrane cleavage releasing β-catenin, tyrosine-phosphorylation-dependent ubiquitination by the E3 ligase Hakai leading to endocytosis, and promoter silencing by CpG methylation or transcriptional repressors (Snail/SLUG/ZEB1/DeltaEF1) that bind E-box elements. As a signaling hub, E-cadherin competes with APC for β-catenin binding, activates the Hippo–YAP pathway to mediate contact inhibition of proliferation, and is directly targeted by bacterial FadA adhesin to drive β-catenin oncogenic signaling; its loss promotes EMT, metastasis, and β-catenin nuclear signaling via multiple transcriptional programs."},"narrative":{"teleology":[{"year":1985,"claim":"Identifying the adhesion-mediating extracellular domain of E-cadherin established that a discrete proteolytic fragment is both necessary and sufficient for Ca²⁺-dependent cell–cell binding and embryo compaction.","evidence":"Protease digestion of uvomorulin and functional blocking with DECMA-1 antibody in MDCK cells and mouse embryos","pmids":["2419126"],"confidence":"High","gaps":["Structural basis of the adhesion domain unresolved","No information on cytoplasmic partners"]},{"year":1987,"claim":"Sequencing revealed the conserved cadherin architecture — three ~112-residue extracellular repeats with Ca²⁺-binding sites, a single transmembrane pass, and a cytoplasmic domain — establishing the molecular template for the cadherin superfamily.","evidence":"Protein sequencing, secondary structure prediction, and cross-species sequence comparison","pmids":["3501370"],"confidence":"High","gaps":["No three-dimensional structure","Function of cytoplasmic domain unknown"]},{"year":1988,"claim":"Demonstrating that E-cadherin-mediated adhesion is a prerequisite for assembly of the entire epithelial junctional complex (zonula adherens, zonula occludens, desmosomes) placed E-cadherin upstream of all intercellular junction formation.","evidence":"Ca²⁺-switch assay with anti-E-cadherin blocking antibodies; fluorescence staining for ZO-1, actin, desmoplakin; transepithelial resistance in MDCK cells","pmids":["3049625"],"confidence":"High","gaps":["Molecular link between E-cadherin and tight-junction/desmosome assembly unknown","Role of cytoplasmic partners not defined"]},{"year":1989,"claim":"Discovery of the catenin complex (α, β, γ) associated with E-cadherin's cytoplasmic domain revealed that adhesive function requires intracellular partners that bridge E-cadherin to the cytoskeleton.","evidence":"Co-immunoprecipitation from E-cadherin-transfected cells with deletion mapping; cross-species peptide analysis","pmids":["2788574"],"confidence":"High","gaps":["Identity of individual catenins at the molecular level unknown","Direct vs. indirect binding not resolved"]},{"year":1990,"claim":"Mapping the 72-amino-acid catenin-binding domain and showing that β-catenin binds E-cadherin more directly while α-catenin connects to actin defined the hierarchical assembly of the cadherin–catenin–actin axis, and simultaneously showed that prodomain cleavage is required for adhesive activation.","evidence":"Chimeric and deletion constructs in L cells; cell aggregation; actin co-sedimentation; site-directed mutagenesis of cleavage site with protease rescue","pmids":["2349235","2211831"],"confidence":"High","gaps":["Stoichiometry of the complex undefined","Protease responsible for prodomain cleavage in vivo unidentified"]},{"year":1991,"claim":"Identification of α-catenin as a vinculin homologue, determination that β-catenin binds E-cadherin co-translationally while α-catenin joins only at the time of prodomain processing, and demonstration that complex stoichiometry is 1 E-cadherin : 1–2 β-catenin : 1 α-catenin established the temporal logic of cadherin–catenin assembly.","evidence":"Molecular cloning of α-catenin; pulse-chase metabolic labeling and stoichiometric analysis; co-IP with multiple cadherins; E-cadherin transfection into cadherin-negative cells","pmids":["1924379","1734027","1649199"],"confidence":"High","gaps":["Direct structural evidence for α-catenin–actin linkage lacking","Mechanism of invasion suppression beyond adhesion not dissected"]},{"year":1992,"claim":"Detailed biosynthetic tracing showed that E-cadherin is core-glycosylated in the ER, processed in the late Golgi, delivered to the surface with a ~5 h half-life, and rapidly incorporated into Triton-insoluble junctions upon Ca²⁺-dependent adhesion.","evidence":"Pulse-chase metabolic labeling; subcellular fractionation; glycosylation inhibitors; Triton X-100 extraction in MDCK cells","pmids":["1918074"],"confidence":"High","gaps":["Identity of the pro-protein convertase unknown","Mechanisms controlling E-cadherin turnover at the surface undefined"]},{"year":1994,"claim":"Demonstrating that E-cadherin and APC directly compete for the arm-repeat domain of β-catenin connected E-cadherin adhesion to the Wnt/APC tumor-suppressor pathway, revealing a signaling function beyond structural adhesion.","evidence":"Direct competition binding assays and domain mapping with deletion constructs; sequential immunoprecipitation and pulse-chase in multiple cell lines","pmids":["7806582","8207061"],"confidence":"High","gaps":["In vivo consequences of competition for β-catenin unresolved","Quantitative regulation of β-catenin partitioning unclear"]},{"year":1995,"claim":"Identification of CpG promoter hypermethylation as a silencing mechanism and biallelic inactivating mutations with LOH at 16q22.1 in lobular breast carcinomas established CDH1 as a bona fide tumor/invasion suppressor gene subject to both genetic and epigenetic inactivation.","evidence":"HpaII methylation analysis with 5-azacytidine rescue; PCR/SSCP mutation screening and LOH analysis in human carcinomas","pmids":["7543680","8557030"],"confidence":"High","gaps":["Contribution of methylation vs. mutation to progression not separated","Germline predisposition not yet established"]},{"year":1997,"claim":"Showing that ZO-1 directly binds α-catenin (Kd ~0.5 nM) and actin filaments (Kd ~10 nM) provided a molecular cross-linker between the E-cadherin/catenin complex and the cytoskeleton, explaining how adherens junctions physically integrate with tight junctions.","evidence":"GST pull-down with recombinant proteins; actin co-sedimentation; truncated ZO-1 constructs in E-cadherin-expressing L cells","pmids":["9214391"],"confidence":"High","gaps":["In vivo significance of ZO-1–α-catenin linkage not tested genetically","Other cross-linkers may exist"]},{"year":1998,"claim":"Comprehensive mutation cataloguing in diffuse gastric and lobular breast cancers revealed tumor-type-specific mutation patterns (in-frame exon skippings in gastric vs. out-of-frame mutations in breast), refining the two-hit inactivation model for CDH1.","evidence":"Compilation of 69 somatic mutations by PCR/SSCP, sequencing, and LOH analysis across tumor types","pmids":["9744472"],"confidence":"High","gaps":["Functional consequences of specific in-frame deletions not tested","Genotype–phenotype correlations for individual mutations unresolved"]},{"year":2001,"claim":"The crystal structure of the β-catenin arm-repeat/E-cadherin cytoplasmic domain complex revealed that phosphorylation of E-cadherin creates interactions mimicking the Tcf-3 binding helix, providing a structural basis for competitive binding between E-cadherin, APC, and Tcf transcription factors.","evidence":"X-ray crystallography of phosphorylated and unphosphorylated E-cadherin/β-catenin complexes","pmids":["11348595"],"confidence":"High","gaps":["Full-length E-cadherin structure unresolved","How phosphorylation is dynamically regulated at junctions unknown"]},{"year":2002,"claim":"Three mechanistically distinct post-translational regulatory circuits for E-cadherin were identified nearly simultaneously: Hakai E3-ligase-dependent ubiquitination driving endocytosis, presenilin-1/γ-secretase intramembrane cleavage releasing β-catenin, and SLUG/Snail-mediated E-box transcriptional repression.","evidence":"Yeast two-hybrid, ubiquitination assays, and endocytosis assays for Hakai; PS1 cleavage-site mapping and cytoskeletal fractionation; promoter-reporter and E-box mutagenesis for SLUG","pmids":["11836526","11953314","11912130"],"confidence":"High","gaps":["Relative contribution of each pathway in vivo undefined","Upstream signals triggering each pathway not fully elucidated"]},{"year":2005,"claim":"ADAM10 was identified as the metalloprotease responsible for constitutive and regulated E-cadherin ectodomain shedding in vivo, and ZEB1 was established as an additional E-box transcriptional repressor, expanding the network of E-cadherin regulators controlling EMT.","evidence":"ADAM10-knockout mouse and fibroblast analysis with RNAi; ChIP at CDH1 promoter with ZEB1 gain- and loss-of-function","pmids":["15958533","15674322"],"confidence":"High","gaps":["Coordination between ectodomain shedding and transcriptional repression unknown","Whether ADAM10 or γ-secretase cleavage is rate-limiting for β-catenin release unclear"]},{"year":2008,"claim":"E-cadherin loss was shown to activate a full EMT transcriptional program (including Twist induction) required for metastasis beyond simple loss of adhesion, and miR-200 family members were identified as direct suppressors of ZEB1/ZEB2 that maintain E-cadherin expression.","evidence":"Genetic dissection of adhesion vs. signaling with in vivo metastasis assays; miR-200 overexpression with ZEB1/ZEB2 3′UTR reporters","pmids":["18483246","18411277"],"confidence":"High","gaps":["Which EMT transcription factor is dominant in specific tumor contexts unknown","Feedback loop dynamics between miR-200 and ZEB not quantified"]},{"year":2011,"claim":"Placing E-cadherin/catenin complex as an upstream activator of the Hippo–LATS–YAP pathway provided a mechanistic explanation for E-cadherin-mediated contact inhibition of proliferation independent of Wnt/β-catenin.","evidence":"Epistasis analysis with Hippo component knockdown, YAP phosphorylation assays, and E-cadherin expression in MDA-MB-231 and MCF10A cells","pmids":["21730131"],"confidence":"High","gaps":["Molecular intermediates between E-cadherin and LATS kinase not identified","Whether α-catenin or β-catenin mediates the Hippo signal unresolved"]},{"year":2013,"claim":"Discovery that Fusobacterium nucleatum FadA adhesin directly binds an 11-amino-acid epitope on E-cadherin to activate β-catenin signaling revealed E-cadherin as a host receptor exploited by a pathogen to drive oncogenic and inflammatory responses in colorectal cancer.","evidence":"Direct binding assays, binding-site peptide mapping, β-catenin reporter activation, and synthetic peptide inhibition in colorectal cancer cells","pmids":["23954158"],"confidence":"High","gaps":["Structural basis of FadA–E-cadherin interface not determined","In vivo contribution to colorectal carcinogenesis not established in genetic models"]},{"year":2017,"claim":"E-cadherin was shown to form mechanically active heterotypic adhesions with N-cadherin on cancer-associated fibroblasts, with force-dependent recruitment of β-catenin and α-catenin/vinculin reinforcement, revealing a mechanotransduction role in collective cancer cell invasion.","evidence":"Traction force microscopy, FRET tension sensor, α-catenin/vinculin domain mutants, and co-culture invasion assays with patient-derived material","pmids":["28218910"],"confidence":"High","gaps":["Whether heterotypic adhesion triggers distinct signaling from homophilic adhesion unknown","Generalizability beyond breast cancer CAF co-culture not tested"]},{"year":null,"claim":"Major unresolved questions include the molecular intermediates linking E-cadherin engagement to Hippo–YAP activation, the structural basis of full-length E-cadherin in the membrane-associated cadherin–catenin complex, and how the multiple proteolytic, endocytic, transcriptional, and epigenetic regulatory inputs are integrated in vivo to control E-cadherin levels during normal development and tumor progression.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length E-cadherin structure in membrane context","Molecular bridge from E-cadherin/catenin to LATS kinase undefined","Quantitative model integrating transcriptional, post-translational, and trafficking regulation absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,2,4,9,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,29,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,6,10,34]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8,10,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,4,6,9,16,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,28,29,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,17,26,28]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[19,33]}],"complexes":["cadherin–catenin complex","E-cadherin–β-catenin–α-catenin–ZO-1 junction complex"],"partners":["CTNNB1","CTNNA1","JUP","TJP1","CBLL1","ADAM10","PSEN1"],"other_free_text":[]},"mechanistic_narrative":"E-cadherin (CDH1) is a calcium-dependent transmembrane glycoprotein that serves as the principal mediator of homophilic cell–cell adhesion in epithelial tissues, functioning simultaneously as a master organizer of the epithelial junctional complex and as a signaling hub that controls cell polarity, proliferation, and invasion. Its extracellular domain contains internally repeated cadherin motifs with Ca²⁺-binding sites that mediate homophilic binding, while a 72-amino-acid cytoplasmic segment recruits β-catenin co-translationally and subsequently α-catenin (a vinculin homologue) at the plasma membrane, linking the complex to the actin cytoskeleton and enabling assembly of all junctional elements including tight junctions and desmosomes [PMID:3501370, PMID:2349235, PMID:3049625, PMID:11348595]. E-cadherin is synthesized as a 135 kDa precursor that undergoes ER glycosylation, late-Golgi prodomain cleavage required for adhesive activation, regulated ADAM10-mediated ectodomain shedding, presenilin-1/γ-secretase intramembrane proteolysis releasing β-catenin, and Hakai E3-ligase-dependent tyrosine-phosphorylation-triggered ubiquitination and endocytosis [PMID:2211831, PMID:1918074, PMID:15958533, PMID:11953314, PMID:11836526]. Beyond adhesion, E-cadherin engagement activates the Hippo–YAP pathway to enforce contact inhibition of proliferation, competes with APC for β-catenin binding to regulate Wnt signaling, and is directly exploited by the bacterial adhesin FadA to drive oncogenic β-catenin signaling; its transcriptional silencing by Snail/SLUG/ZEB1 via E-box repression or by CpG promoter methylation is a central event in epithelial-to-mesenchymal transition and metastasis [PMID:21730131, PMID:7806582, PMID:23954158, PMID:11912130, PMID:7543680, PMID:18483246]. Germline and somatic loss-of-function mutations in CDH1, frequently with loss of heterozygosity at 16q22.1, cause hereditary diffuse gastric cancer and lobular breast carcinoma [PMID:8557030, PMID:9744472]."},"prefetch_data":{"uniprot":{"accession":"P12830","full_name":"Cadherin-1","aliases":["CAM 120/80","Epithelial cadherin","E-cadherin","Uvomorulin"],"length_aa":882,"mass_kda":97.5,"function":"Cadherins are calcium-dependent cell adhesion proteins (PubMed:11976333). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells (PubMed:11976333). Promotes organization of radial actin fiber structure and cellular response to contractile forces, via its interaction with AMOTL2 which facilitates anchoring of radial actin fibers to CDH1 junction complexes at the cell membrane (By similarity). Plays a role in the early stages of desmosome cell-cell junction formation via facilitating the recruitment of DSG2 and DSP to desmosome plaques (PubMed:29999492). Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7 E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors. Has a strong inhibitory effect on APP C99 and C83 production (Microbial infection) Serves as a receptor for Listeria monocytogenes; internalin A (InlA) binds to this protein and promotes uptake of the bacteria","subcellular_location":"Cell junction, adherens junction; Cell membrane; Endosome; Golgi apparatus, trans-Golgi network; Cytoplasm; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/P12830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH1","classification":"Not Classified","n_dependent_lines":53,"n_total_lines":1208,"dependency_fraction":0.043874172185430466},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTNNB1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/CDH1","total_profiled":1310},"omim":[{"mim_id":"621092","title":"IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 3; IQGAP3","url":"https://www.omim.org/entry/621092"},{"mim_id":"621044","title":"RING FINGER PROTEIN 157; RNF157","url":"https://www.omim.org/entry/621044"},{"mim_id":"620959","title":"UBIQUITIN-SPECIFIC PEPTIDASE 35; USP35","url":"https://www.omim.org/entry/620959"},{"mim_id":"620809","title":"ACHAETE-SCUTE FAMILY bHLH TRANSCRIPTION FACTOR 5; ASCL5","url":"https://www.omim.org/entry/620809"},{"mim_id":"620431","title":"FLYWCH-TYPE ZINC FINGER PROTEIN 1; FLYWCH1","url":"https://www.omim.org/entry/620431"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":186.0}],"url":"https://www.proteinatlas.org/search/CDH1"},"hgnc":{"alias_symbol":["uvomorulin","CD324"],"prev_symbol":["UVO"]},"alphafold":{"accession":"P12830","domains":[{"cath_id":"2.60.40.60","chopping":"30-117","consensus_level":"high","plddt":84.0551,"start":30,"end":117},{"cath_id":"2.60.40.60","chopping":"164-252","consensus_level":"medium","plddt":91.2031,"start":164,"end":252},{"cath_id":"2.60.40.60","chopping":"260-365","consensus_level":"medium","plddt":95.5291,"start":260,"end":365},{"cath_id":"2.60.40.60","chopping":"374-477","consensus_level":"high","plddt":93.6367,"start":374,"end":477},{"cath_id":"2.60.40.60","chopping":"484-585","consensus_level":"high","plddt":93.621,"start":484,"end":585},{"cath_id":"2.60.40.60","chopping":"593-688","consensus_level":"high","plddt":88.1577,"start":593,"end":688}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12830","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12830-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12830-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDH1","jax_strain_url":"https://www.jax.org/strain/search?query=CDH1"},"sequence":{"accession":"P12830","fasta_url":"https://rest.uniprot.org/uniprotkb/P12830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12830"}},"corpus_meta":[{"pmid":"2788574","id":"PMC_2788574","title":"The 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/7806582","citation_count":585,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7543680","id":"PMC_7543680","title":"Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7543680","citation_count":581,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9214391","id":"PMC_9214391","title":"Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9214391","citation_count":581,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21730131","id":"PMC_21730131","title":"E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway 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alpha, beta, and gamma), identified by immunoprecipitation; this complex links uvomorulin to the cytoskeleton.\",\n      \"method\": \"Immunoprecipitation, cDNA transfection with cytoplasmic/extracellular deletion mutants, peptide pattern analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with deletion mutants; foundational paper, independently replicated\",\n      \"pmids\": [\"2788574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Catenin association with uvomorulin is mediated by a specific 72-amino acid domain in the cytoplasmic region (encoded largely by a single exon); beta-catenin binds more directly to uvomorulin, while alpha-catenin is required for association with actin filaments; adhesive function requires catenin association.\",\n      \"method\": \"Expression of uvomorulin mutants and H-2Kd chimeric proteins in L cells, immunoprecipitation, cell aggregation 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 — domain mapping with multiple mutants, functional adhesion assay; replicated\",\n      \"pmids\": [\"2349235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The extracellular part of uvomorulin contains three internally repeated domains each with putative Ca2+-binding sites, a single transmembrane region, and a cytoplasmic domain; Ca2+-dependent adhesion is linked to the extracellular repeated domain structure.\",\n      \"method\": \"Amino acid sequence determination, secondary structure prediction, sequence comparison\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural sequence analysis; single paper\",\n      \"pmids\": [\"3501370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Uvomorulin mediates an early Ca2+-dependent adhesion event that is a prerequisite for the assembly of all elements of the epithelial junctional complex (zonula adherens, zonula occludens, desmosomes), as shown by blocking antibodies in MDCK cells using a Ca2+ switch assay.\",\n      \"method\": \"Ca2+ switch assay, blocking antibodies/Fab fragments, immunofluorescence (ZO-1, actin, desmoplakin)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with antibodies, multiple orthogonal readouts; highly cited\",\n      \"pmids\": [\"3049625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"A 26 kDa extracellular fragment of uvomorulin, recognized by blocking antibody DECMA-1, is involved in its adhesive function, identifying a putative cell adhesion domain.\",\n      \"method\": \"Protease digestion, monoclonal antibody blocking assays, immunoreactivity mapping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody epitope mapping with functional blocking; single lab\",\n      \"pmids\": [\"2419126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Correct proteolytic cleavage of the 129-amino acid uvomorulin precursor segment is required for cell adhesive function; unprocessed uvomorulin is expressed on the cell surface and associates with catenins but is non-functional; correct N-terminal processing is essential for adhesion.\",\n      \"method\": \"cDNA mutagenesis (factor Xa/trypsin cleavage site substitutions), cell surface expression, catenin co-immunoprecipitation, cell aggregation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-style mutagenesis with multiple orthogonal readouts; single lab but rigorous\",\n      \"pmids\": [\"2211831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Expression of uvomorulin in fibroblasts is sufficient to induce redistribution of Na+,K+-ATPase to sites of cell-cell contact, demonstrating a direct role for E-cadherin as an inducer of cell surface polarity via reorganization of the membrane cytoskeleton.\",\n      \"method\": \"cDNA transfection into fibroblasts, immunofluorescence, fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function in defined cell system with clear molecular readout; highly cited\",\n      \"pmids\": [\"2164888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Alpha-catenin, which anchors the uvomorulin-catenin complex to actin filaments, is a homologue of vinculin, identifying a new family of vinculin-related proteins linking cadherins to the cytoskeleton.\",\n      \"method\": \"Cloning and sequencing of murine alpha-catenin, sequence homology analysis, immunoprecipitation of multiple cadherins, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — molecular cloning with sequence analysis, cross-species Co-IP; highly cited\",\n      \"pmids\": [\"1924379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The uvomorulin-catenin complex comprises one uvomorulin molecule, one or two beta-catenin molecules, and one alpha-catenin molecule; beta-catenin assembles with the uvomorulin precursor before endoproteolytic processing, while alpha-catenin joins the complex around the time of processing.\",\n      \"method\": \"Biochemical analysis, pulse-chase experiments, stoichiometry determination\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — stoichiometric biochemistry with pulse-chase; replicated across multiple cadherins\",\n      \"pmids\": [\"1734027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"E-cadherin-mediated cell-cell contacts inhibit invasive migration into 3D collagen gels in a cell density-dependent manner, demonstrating that E-cadherin suppresses invasion via contact inhibition of cell movement.\",\n      \"method\": \"Stable transfection of L-cells with E-cadherin, 3D collagen invasion assay, time-lapse videoscopy, blocking antibodies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with antibody reversal and functional invasion readout; replicated\",\n      \"pmids\": [\"1649199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CDH1 (yeast Cdh1) is a substrate-specific activator of APC-dependent proteolysis that promotes degradation of substrates Ase1 and Clb2 but not Pds1; CDC20 is required for Pds1 but not Ase1/Clb2 degradation, establishing substrate specificity of two APC coactivators.\",\n      \"method\": \"Yeast genetics (deletion mutants), overexpression, APC substrate degradation assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined substrate readouts; foundational, highly cited\",\n      \"pmids\": [\"9334304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In response to genotoxic stress in G2, Cdc14B translocates from the nucleolus to the nucleoplasm, activates APC/C(Cdh1), leading to Plk1 degradation, which stabilizes Claspin and Wee1 to enforce the G2 DNA-damage checkpoint; Claspin is also a direct APC/C(Cdh1) substrate in G1.\",\n      \"method\": \"siRNA, cell fractionation, Co-IP, ubiquitination assays, checkpoint assays in mammalian cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, pathway epistasis; highly cited\",\n      \"pmids\": [\"18662541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APC/C(Cdh1) targets Aurora kinases for degradation at anaphase, which is required for assembly of a robust spindle midzone and normal timing of spindle elongation and cytokinesis; non-degradable Aurora kinase mimics the Cdh1 siRNA phenotype.\",\n      \"method\": \"siRNA depletion, live cell imaging, stabilized Aurora kinase expression in human cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with rescue by nondegradable substrate, multiple cellular readouts\",\n      \"pmids\": [\"18976910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cdh1-APC operates in the nucleus of postmitotic neurons to ubiquitinate and degrade the transcriptional corepressor SnoN, thereby inhibiting axonal growth; Cdh1 physically complexes with SnoN.\",\n      \"method\": \"Co-IP, ubiquitination assay, RNAi knockdown in neurons, in vivo cerebellar granule neuron analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, epistasis by SnoN knockdown suppressing Cdh1 RNAi phenotype\",\n      \"pmids\": [\"16675394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cdh1 is inactivated through sequential phosphorylation by Cdk1 (priming kinase) and polo kinase in S. cerevisiae; this Cdh1 inactivation allows accumulation of Cin8 and Kip1 kinesins required for SPB separation and proper mitotic spindle assembly.\",\n      \"method\": \"Yeast genetics, kinase assays, phosphorylation site mutagenesis, live cell microscopy\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted kinase cascade with mutagenesis and functional readout\",\n      \"pmids\": [\"18500339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APC(Cdh1) inactivation is a rapid, bistable switch initiated by cyclin E/Cdk2 and made irreversible by Emi1; this inactivation event constitutes the commitment point (point of no return) for cell-cycle entry, occurring shortly before start of DNA replication.\",\n      \"method\": \"Live single-cell imaging, pharmacological and genetic perturbations, stress exposure at defined cell cycle windows\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live-cell imaging with multiple orthogonal perturbations; strong mechanistic evidence\",\n      \"pmids\": [\"27368103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDH1 localizes dynamically to the nucleus during interphase and to the centrosome during metaphase/anaphase; a nuclear localization signal (NLS) in CDH1 is sufficient for nuclear targeting; phosphorylation of CDH1 at serine/threonine residues within the NLS inhibits nuclear import, retaining it in the cytoplasm.\",\n      \"method\": \"GFP fusion localization, cell synchronization, CDH1-4D phosphomimetic mutant expression, NLS mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with subcellular localization and functional correlation; moderate evidence\",\n      \"pmids\": [\"12560341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nuclear JNK is degraded by APC/C(Cdh1) during mitotic exit and G1; JNK phosphorylates Cdh1 directly during G2/early mitosis, changing its subcellular localization and attenuating APC/C activation.\",\n      \"method\": \"Co-IP, kinase assay, non-degradable JNK expression, subcellular fractionation, mitotic arrest assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal regulation demonstrated by in vitro kinase assay and non-degradable substrate\",\n      \"pmids\": [\"20581839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Phosphorylation of neuronal Cdh1 at Cdk sites (9D phosphomimetic) disrupts its association with the APC core subunit Cdc27 and causes cytoplasmic accumulation of an inactive Cdh1 form, abolishing APC/C(Cdh1)-mediated inhibition of axon growth; the 9A hypophosphorylation mutant is proteasomally degraded.\",\n      \"method\": \"Alanine/aspartate substitution mutagenesis at 9 Cdk sites, Co-IP with Cdc27, GFP localization, axon growth assays in cerebellar granule neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"19339626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cdh1 is phosphorylated in vivo at at least 19 serine/threonine residues; CDK phosphorylation at consensus sites promotes subsequent recognition of Cdh1 by additional non-CDK kinases; non-CDK phosphorylation does not by itself constitutively activate or inactivate APC.\",\n      \"method\": \"Mass spectrometry of in vivo phosphorylation sites in yeast Cdh1, site-directed mutagenesis of CDK and non-CDK sites\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry identification with mutagenesis; single lab\",\n      \"pmids\": [\"15467459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"O-GlcNAcylation of CDH1 occurs on a peptide neighboring a known phosphorylation site and antagonizes phosphorylation of CDH1, representing a novel post-translational modification that regulates APC/C activity.\",\n      \"method\": \"Mass spectrometry, cell synchronization, site-directed mutagenesis, O-GlcNAc-specific detection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — MS identification with mutagenesis; single lab, single study\",\n      \"pmids\": [\"27080259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner; c-Src reciprocally inhibits APC(Cdh1) E3 ligase activity through direct phosphorylation of Cdh1 at its N-terminus, disrupting interaction between Cdh1 and the APC core complex.\",\n      \"method\": \"Co-IP, in vitro kinase assay, siRNA depletion, mouse mammary tumor model, pharmacological c-Src inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay, Co-IP mapping of interaction disruption, in vivo tumor model\",\n      \"pmids\": [\"31420536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APC/C(Cdh1) targets E2F3 for proteasome-dependent degradation during cell cycle exit; E2F3 interacts with Cdh1 but not Cdc20; Cdh1 overexpression causes E2F3 degradation; Cdh1 silencing stabilizes E2F3 in differentiating neuroblastoma cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA, overexpression in cell lines\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP specificity for Cdh1 vs Cdc20, functional degradation assays; single lab\",\n      \"pmids\": [\"22580460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Claspin is a novel Cdh1-interacting protein and APC/Cdh1 ubiquitin substrate; inactivation of Cdh1 activates the Claspin/Chk1 pathway; Cdh1 competes with E2F1 to bind hypophosphorylated Rb, reciprocally regulating the Rb pathway.\",\n      \"method\": \"Affinity purification/mass spectrometry, Co-IP, ubiquitination assay, RNAi, cell cycle analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS substrate identification confirmed by Co-IP and functional epistasis; multiple pathways addressed\",\n      \"pmids\": [\"19477924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APC/C(Cdh1) targets LATS kinases for degradation, linking Hippo signaling to cell cycle control; CDH1 recognizes LATS for ubiquitin-dependent degradation, causing YAP/TAZ activity to peak in G1; this mechanism is conserved in Drosophila (Cdh1 regulates Warts).\",\n      \"method\": \"Co-IP, ubiquitination assay, cell cycle synchronization, Drosophila genetic epistasis, siRNA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, genetic epistasis in two species\",\n      \"pmids\": [\"31000600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Casein kinase 1δ (CK1δ) is a substrate of APC/C(Cdh1); conditional deletion of Cdh1 in cerebellar granule cell progenitors results in higher CK1δ levels; APC/C(Cdh1) downregulates CK1δ during cell-cycle exit.\",\n      \"method\": \"Conditional knockout, Co-IP, ubiquitination assay, small molecule CK1δ inhibitor\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with substrate accumulation and Co-IP; single lab\",\n      \"pmids\": [\"25843713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APC/C-CDH1 ubiquitinates Skp2 (promoted by dephosphorylation at S72 by dioscin); depletion of Cdh1 impairs dioscin-induced Skp2 reduction; CDH1-mediated Skp2 degradation reprograms aerobic glycolysis.\",\n      \"method\": \"Co-IP, ubiquitination assay, CRISPR-Cas9 knockout, phosphorylation mutagenesis, xenograft model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, functional rescue; single lab\",\n      \"pmids\": [\"31806563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APC/C(Cdh1) ubiquitinates Rock2 in neurons; postnatal neuronal Cdh1 deletion leads to Rock2 accumulation, dendrite arborization disruption, dendritic spine/synapse loss, memory impairment, and neurodegeneration; fasudil (Rock inhibitor) rescues these defects.\",\n      \"method\": \"Conditional neuronal Cdh1 knockout, Co-IP, ubiquitination assay, STED microscopy, behavioral tests\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout with pharmacological rescue and substrate validation\",\n      \"pmids\": [\"28396402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APC(Cdh1) promotes non-proteolytic monoubiquitination and transcriptional activation of Goosecoid (Gsc) in neural crest cells; neural crest-specific Cdh1-knockout mice display craniofacial bone malformations with reduced Gsc/Sox6 transcriptional activity.\",\n      \"method\": \"Conditional neural crest Cdh1 knockout, Co-IP, ubiquitination assay, reporter assays, mouse phenotyping\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with mechanistic Co-IP and non-proteolytic ubiquitination evidence\",\n      \"pmids\": [\"27126000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In mouse oocytes, a slow-evolving DNA damage response involves APC-Cdh1-mediated proteolysis of cyclin B1 (not inhibitory Cdk1 phosphorylation) secondary to Cdc14B-dependent APC-Cdh1 activation and reduced Emi1-dependent inhibition, constituting a non-canonical G2/M DDR pathway.\",\n      \"method\": \"Mouse oocyte genetic deletion of Setx, live imaging, protein stability assays, biochemical pathway analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with mechanistic pathway dissection; single lab\",\n      \"pmids\": [\"32328643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cdh1 E3 ubiquitin ligase is required for FoxM1 ubiquitylation and degradation in muscle satellite cells; loss of Cdh1 causes spontaneous SC activation and pool depletion; the Cdh1-FoxM1-Apc axis regulates muscle development and regeneration.\",\n      \"method\": \"Conditional knockout, Co-IP, ubiquitination assay, FoxM1 haploinsufficiency rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with substrate Co-IP and ubiquitination, rescue experiment\",\n      \"pmids\": [\"32152291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"APC/C CDH1 ubiquitinates IDH2 in mitosis, contributing to NADPH reduction and increased ROS during mitosis.\",\n      \"method\": \"Ubiquitination assay, CDH1 overexpression/depletion, ROS measurement, APC/C inhibitor\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with functional ROS readout; single lab\",\n      \"pmids\": [\"34271087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"APC/C CDH1 binds and ubiquitinates STAT3 in mitosis; phosphatase inhibition decreases STAT3 ubiquitination, linking STAT3 dephosphorylation to APC/C CDH1-mediated ubiquitination.\",\n      \"method\": \"Co-IP, ubiquitination assay, cell cycle synchronization, pharmacological phosphatase inhibition\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method type; no rescue experiment\",\n      \"pmids\": [\"36400381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APC/C-CDH1 ubiquitinates IDH3β in a cell-cycle-dependent manner; IDH3β levels peak in late G1 and promote G1-S transition; APC/C-CDH1-mediated IDH3β proteolysis connects TCA cycle metabolism to cell cycle progression.\",\n      \"method\": \"Co-IP, ubiquitination assay, overexpression/knockdown, cell cycle analysis, xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, functional cell cycle assay; single lab\",\n      \"pmids\": [\"31053633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RAP80 is polyubiquitinated and degraded by APC/C(Cdh1) during G1 phase via a destruction box (D-box) motif; Cdh1 knockdown blocks RAP80 degradation; non-degradable RAP80 attenuates mitotic progression.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, D-box mutagenesis, cell cycle synchronization\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — D-box mutagenesis with functional cell cycle readout; single lab\",\n      \"pmids\": [\"22426463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGA2 promotes epigenetic silencing of the Cdh1 (E-cadherin) promoter by recruiting de novo DNA methyltransferase DNMT3A to the Cdh1 promoter during TGFβ-induced EMT; Cdh1 expression is restorable by 5-aza-2'-deoxycytidine.\",\n      \"method\": \"ChIP assay, bisulfite sequencing, HMGA2 overexpression in NMuMG cells, demethylation rescue\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional rescue; single lab\",\n      \"pmids\": [\"25492890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Uvomorulin is synthesized as a 135 kDa precursor in the endoplasmic reticulum, glycosylated in the late Golgi, processed to the mature 120 kDa form prior to cell surface delivery; at the cell surface, cell-cell contact induces rapid localization to contact regions and increased Triton X-100 insolubility (cytoskeletal association).\",\n      \"method\": \"Pulse-chase biosynthetic labeling, fractionation, inhibitor treatments, immunofluorescence in MDCK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulse-chase with subcellular fractionation; single lab\",\n      \"pmids\": [\"1918074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Uvomorulin phosphorylation increases at the 8-cell stage of mouse embryo development; prevention of compaction (by low Ca2+) reduces uvomorulin phosphorylation and perturbs its redistribution to cell-cell contacts, but phosphorylation is not the direct regulator of uvomorulin adhesive function.\",\n      \"method\": \"32P metabolic labeling, immunoprecipitation, Ca2+-depletion, confocal microscopy of mouse embryos\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect evidence, single method type, conclusions are negative\",\n      \"pmids\": [\"8722695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rab7 overexpression increases CDH1 endocytosis and is required for cAMP-mediated inhibition of CDH1 endocytosis; Rab7 interacts functionally with Rac1 GTPase in regulating CDH1 internalization and circular dorsal ruffle formation.\",\n      \"method\": \"RNAi knockdown, Rab7 overexpression, endocytosis assay, PAK1 phosphorylation (Rac1 activity), co-localization imaging\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP indirect, functional imaging\",\n      \"pmids\": [\"26599499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH1/E-cadherin is a transmembrane Ca2+-dependent cell adhesion molecule whose extracellular domain (with conserved repeats and Ca2+-binding sites) mediates homophilic adhesion after correct proteolytic processing of its precursor, while its cytoplasmic domain directly recruits beta-catenin and (via alpha-catenin, a vinculin homologue) connects to the actin cytoskeleton; this complex is essential for epithelial junction assembly, cell polarity induction, and invasion suppression. The same gene symbol CDH1 also designates the WD40-domain APC/C coactivator (Cdh1/FZR1) that acts as a substrate-specific activator of the APC/C E3 ubiquitin ligase, driving proteasomal degradation of Aurora kinases, LATS kinases, SnoN, Skp2, Rock2, FoxM1, and many other substrates to coordinate mitotic exit, G1 maintenance, genomic stability, axon growth, and neuronal survival; Cdh1 activity is regulated by CDK- and polo-kinase-mediated phosphorylation, O-GlcNAcylation, c-Src phosphorylation, and nuclear-cytoplasmic shuttling controlled by a conserved NLS.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification notes:**\n- Papers [1]-[3], [7]-[10], [13], [15]-[17], [19]-[21], [30], [34], [43], [55] in the main corpus: KEEP — describe uvomorulin/E-cadherin (CDH1) protein function\n- Papers [4], [10], [12], [18], [22], [25], [28]-[29], [36], [38]-[41], [45]-[46], [50], [52], [58]-[59], [62], [64], [66]-[67], [69], [71]-[72], [76]-[77], [79]-[82], [86], [91], [93], [100]: These describe CDH1 as the APC/C co-activator (Fzr1/Cdh1) — a **different protein** (FZR1/FIZZY-RELATED gene, not E-cadherin CDH1). EXCLUDE as ALIAS COLLISION.\n- Paper [56]: Arabidopsis CCS52B — SYMBOL COLLISION (plant). EXCLUDE.\n- Papers [5], [6], [11], [14], [23], [24], [26], [32], [35], [37], [44], [51], [65], [87], [88], [89], [90], [94], [99]: Clinical/epidemiological/mutation spectrum papers — no mechanistic findings. EXCLUDE.\n- Papers [27], [31], [33], [42], [47], [48], [49], [53], [54], [57], [60], [61], [63], [68], [70], [73], [74], [75], [83], [84], [85], [95], [96], [97], [98]: Some describe mechanisms relevant to E-cadherin CDH1. I'll evaluate each.\n\n**Additional curated papers:**\n- [g1] Fn/FadA binds E-cadherin: KEEP\n- [g2] cDNA sequencing: EXCLUDE (no mechanism)\n- [g3] miR-200/ZEB1/ZEB2/E-cadherin: KEEP\n- [g4] Germline CDH1 mutations: EXCLUDE (clinical)\n- [g5] E-cadherin loss/metastasis: KEEP\n- [g6] miR-9 targets CDH1: KEEP\n- [g7], [g13]: BioPlex interactome: EXCLUDE (no specific CDH1 mechanism)\n- [g8]: PKM2/β-catenin: EXCLUDE (not CDH1-specific)\n- [g9] SLUG represses E-cadherin: KEEP\n- [g10] VEGF/VE-cadherin: EXCLUDE (VE-cadherin, not E-cadherin/CDH1)\n- [g11] EMT/drug resistance/E-cadherin: EXCLUDE (expression correlation)\n- [g12] E-cadherin mutations in gastric cancer: KEEP\n- [g14] Hakai ubiquitinates E-cadherin: KEEP\n- [g15] E-cadherin/beta-catenin/ZEB1: EXCLUDE (review/expression)\n- [g16] E-cadherin mutations in lobular breast: KEEP\n- [g17]: GO annotation: EXCLUDE\n- [g18] DeltaEF1/E-cadherin: KEEP\n- [g19] Beta-catenin/E-cadherin crystal structure: KEEP\n- [g20] PS1/gamma-secretase cleaves E-cadherin: KEEP\n- [g21] E-cadherin/N-cadherin heterotypic adhesion: KEEP\n- [g22] Cadherin/catenin complex dynamics: KEEP\n- [g23] E-cadherin/APC/beta-catenin competition: KEEP\n- [g24] CpG methylation silences E-cadherin: KEEP\n- [g25] ZO-1/alpha-catenin/E-cadherin: KEEP\n- [g26] E-cadherin/Hippo/YAP: KEEP\n- [g27] ADAM10 sheds E-cadherin: KEEP\n- [g28] Snail represses E-cadherin: KEEP (relevant context)\n- [g29] Caveolin-1/EGF/E-cadherin endocytosis: KEEP\n- [g30] CFTR/Aha1: EXCLUDE (not CDH1)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1987,\n      \"finding\": \"The extracellular domain of uvomorulin (E-cadherin/CDH1) contains three internally repeated domains of ~112 residues, each with putative Ca2+-binding sites located in external loops, and a single membrane-spanning region followed by a cytoplasmic domain; sequence comparison revealed extensive homology to chicken L-CAM, establishing the conserved cadherin architecture.\",\n      \"method\": \"Protein sequencing and amino acid sequence analysis; secondary structure prediction; sequence comparison\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing with structural analysis; foundational structural characterization\",\n      \"pmids\": [\"3501370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"A 26 kDa extracellular fragment of uvomorulin (E-cadherin/CDH1), recognized by function-blocking monoclonal antibodies, was identified as the cell adhesion domain; anti-uvomorulin antibodies that block this fragment disrupt MDCK monolayers and inhibit embryo compaction.\",\n      \"method\": \"Protease digestion of uvomorulin to generate fragments; functional blocking with monoclonal antibody DECMA-1; embryo compaction assay; MDCK monolayer disruption assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional mapping using antibody blocking and proteolytic fragment identification, replicated across cell systems\",\n      \"pmids\": [\"2419126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Uvomorulin (E-cadherin/CDH1) mediates an early, Ca2+-dependent adhesion event between MDCK epithelial cells that is a prerequisite for assembly of all junctional complex elements including the zonula adherens, zonula occludens, and desmosomes, as demonstrated using blocking antibodies in a Ca2+-switch assay.\",\n      \"method\": \"Ca2+-switch assay for de novo junction assembly; function-blocking antibody treatment; fluorescence staining for ZO-1, actin, and desmoplakin; transepithelial resistance measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal readouts in a controlled Ca2+-switch assay; foundational study replicated widely\",\n      \"pmids\": [\"3049625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The cytoplasmic domain of uvomorulin (E-cadherin/CDH1) associates with three independent proteins of 102, 88, and 80 kDa (named catenin α, β, and γ, respectively) that are structurally conserved across species; this complex links E-cadherin to cytoskeletal structures.\",\n      \"method\": \"Transfection of uvomorulin cDNA into uvomorulin-negative cells; co-immunoprecipitation with anti-uvomorulin antibodies; cDNA deletion constructs mapping the binding domain; peptide pattern analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP with deletion mapping in multiple cell lines/species; foundational discovery of catenin complex, replicated across labs\",\n      \"pmids\": [\"2788574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Catenin association with uvomorulin (E-cadherin/CDH1) is mediated by a specific 72-amino-acid domain in the cytoplasmic region (largely encoded by a single exon); β-catenin binds more directly to E-cadherin, while α-catenin links the complex to actin filaments; adhesive function requires catenin association.\",\n      \"method\": \"Expression of mutant uvomorulin polypeptides and H-2Kd chimeric constructs in L cells; co-immunoprecipitation; cell aggregation assay; biochemical association with actin bundles\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with chimeric proteins, functional aggregation assay, and biochemical fractionation; highly cited foundational work\",\n      \"pmids\": [\"2349235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Correct proteolytic cleavage of the uvomorulin (E-cadherin/CDH1) precursor is required for its adhesive function; unprocessed mutant E-cadherin can reach the cell surface and associate with catenins but is non-functional; precise cleavage of the 129-residue prodomain, not merely its removal, is required for activation.\",\n      \"method\": \"Site-directed mutagenesis of protease recognition sites; expression of mutant uvomorulin in L cells; cell aggregation assay; treatment with specific proteases (Factor Xa, trypsin)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis and rescue by specific proteases; multiple controls\",\n      \"pmids\": [\"2211831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Expression of uvomorulin (E-cadherin/CDH1) in transfected fibroblasts is sufficient to induce redistribution of Na+,K+-ATPase to sites of cell-cell contact, inducing cell surface polarity in the absence of tight junctions, coincident with reorganization of the membrane cytoskeleton.\",\n      \"method\": \"Transfection of uvomorulin cDNA into fibroblasts; immunofluorescence for Na+/K+-ATPase distribution; Ca2+-switch assay; comparison with polarized epithelial cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function experiment in fibroblasts with defined molecular readout; highly cited\",\n      \"pmids\": [\"2164888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Alpha-catenin is a vinculin homologue that complexes with multiple cadherins (uvomorulin, N-cadherin, P-cadherin); in cadherin-negative cells alpha-catenin is cytoplasmic, but E-cadherin expression recruits it to membrane contact sites, suggesting α-catenin links the cadherin-catenin complex to the actin cytoskeleton.\",\n      \"method\": \"Molecular cloning and sequencing of murine alpha-catenin; co-immunoprecipitation with multiple cadherins; immunofluorescence; transfection of E-cadherin into cadherin-negative Ltk- cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — sequence analysis plus co-IP with multiple cadherins and transfection-based localization; foundational structural and functional characterization\",\n      \"pmids\": [\"1924379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The uvomorulin-catenin complex consists of one molecule of E-cadherin, one or two molecules of β-catenin, and one molecule of α-catenin; β-catenin associates with the precursor form of E-cadherin co-translationally, while α-catenin joins the complex only around the time of endoproteolytic processing.\",\n      \"method\": \"Biochemical co-immunoprecipitation; pulse-chase labeling; analysis of complex stoichiometry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pulse-chase with stoichiometric biochemical analysis; defines temporal assembly order\",\n      \"pmids\": [\"1734027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"E-cadherin (uvomorulin/CDH1)-mediated cell-cell contacts inhibit invasive migration of L cells into 3D collagen gels in a cell-density-dependent manner (contact inhibition of movement); this invasion suppression is reversible by anti-E-cadherin antibodies.\",\n      \"method\": \"Stable transfection of E-cadherin into L cells; 3D collagen gel invasion assay; function-blocking antibody treatment; time-lapse videoscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with clean genetic controls and antibody rescue; multiple readouts\",\n      \"pmids\": [\"1649199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Uvomorulin (E-cadherin/CDH1) is synthesized as a 135 kDa precursor that is core glycosylated in the ER, processed to the 120 kDa mature form in the late Golgi after complex glycosylation but before cell-surface delivery; glycosylation is not required for processing or transport. At the cell surface, E-cadherin has a half-life of ~5 h and is rapidly localized to cell-cell contacts upon Ca2+-induced adhesion, coinciding with Triton X-100 insolubility.\",\n      \"method\": \"Pulse-chase metabolic labeling; subcellular fractionation; Triton X-100 extraction; glycosylation inhibitor studies; immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — detailed biosynthetic analysis with multiple biochemical methods\",\n      \"pmids\": [\"1918074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The membrane-proximal region of uvomorulin (E-cadherin/CDH1) containing a cluster of cysteine residues is involved in cell adhesion; reduction of disulfide bonds by DTT blocks close cell-cell contacts and cell flattening (but not aggregation) and increases susceptibility to trypsin digestion in the membrane-proximal domain, suggesting this region mediates a second adhesive mechanism.\",\n      \"method\": \"DTT treatment of cells; cell aggregation and morphology assays; limited trypsin digestion; epitope mapping with DECMA-1 antibody\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological perturbation with functional readout; single lab\",\n      \"pmids\": [\"1710917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"E-cadherin and APC directly compete for binding to the arm repeat region of β-catenin; the N-terminal domain of β-catenin mediates interaction with α-catenin and cytoskeletal anchorage for both the E-cadherin and APC complexes; plakoglobin mediates identical interactions.\",\n      \"method\": \"Direct competition binding assays; co-immunoprecipitation; domain mapping with deletion constructs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct competition binding assay with domain mapping; foundational mechanistic study\",\n      \"pmids\": [\"7806582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"E-cadherin/catenin complex assembly occurs in two stages: β-catenin or plakoglobin bind E-cadherin immediately after synthesis in the ER (TX-100 soluble), and α-catenin is recruited later, coincident with plasma membrane delivery and entry into the TX-100-insoluble fraction; cadherin-independent pools of catenins also exist.\",\n      \"method\": \"Pulse-chase metabolic labeling; sucrose density gradient fractionation; chemical cross-linking; sequential immunoprecipitation with catenin-specific antibodies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pulse-chase with chemical cross-linking and sequential IP; defines temporal assembly\",\n      \"pmids\": [\"8207061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Silencing of E-cadherin (CDH1) expression in human carcinoma cell lines is caused by CpG hypermethylation of the promoter region; treatment with demethylating agent 5-azacytidine restores E-cadherin expression and reverts cells to an epithelial morphology with homophilic adhesion.\",\n      \"method\": \"Methylation-sensitive restriction enzyme digestion (HpaII); 5-azacytidine demethylation; RT-PCR; immunohistochemistry; morphological analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct demonstration of methylation-dependent silencing with pharmacological rescue; foundational epigenetic mechanism\",\n      \"pmids\": [\"7543680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"E-cadherin (CDH1) functions as a tumour/invasion suppressor gene; protein-truncating mutations (nonsense and frameshift) in the extracellular domain combined with loss of heterozygosity at 16q22.1 cause complete loss of E-cadherin expression in human infiltrative lobular breast carcinomas.\",\n      \"method\": \"PCR/SSCP mutation screening; LOH analysis; immunohistochemistry for E-cadherin expression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification of biallelic inactivation mechanism in human tumors; foundational tumor suppressor characterization\",\n      \"pmids\": [\"8557030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ZO-1 directly binds α-catenin (Kd ~0.5 nM) through its N-terminal half (dlg-like domain) and actin filaments (Kd ~10 nM) through its C-terminal half, acting as a cross-linker between the E-cadherin/catenin complex and the actin cytoskeleton; ZO-1 expression suppresses cadherin-dependent intercellular motility.\",\n      \"method\": \"Transfection of truncated ZO-1 constructs into E-cadherin-expressing L cells; co-immunoprecipitation; GST pull-down with recombinant proteins from Sf9 insect cells; in vitro actin co-sedimentation; cell aggregation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of direct protein-protein interactions with defined Kd values plus functional validation\",\n      \"pmids\": [\"9214391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"E-cadherin (CDH1) germline mutations (nonsense, frameshift, splice-site causing in-frame exon deletions) are frequently identified in diffuse gastric cancers and lobular breast cancers; the predominant defects in diffuse gastric tumors are exon skippings causing in-frame deletions, while lobular breast cancers show out-of-frame mutations; in most cases mutations occur with LOH of the wild-type allele.\",\n      \"method\": \"PCR/SSCP mutation analysis; sequencing; LOH analysis; compilation of 69 somatic mutations\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive mutation analysis defining biallelic inactivation pattern and tumor-type specificity\",\n      \"pmids\": [\"9744472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structure of the β-catenin arm repeat region complexed with the E-cadherin cytoplasmic domain revealed that the interaction spans all 12 arm repeats, involves quasi-independent binding regions including helices at both ends of the arm repeat domain and an extended 14-residue stretch. Phosphorylation of E-cadherin creates interactions with a hydrophobic patch of β-catenin mimicking an amphipathic XTcf-3 helix, and APC contains homologous sequences suggesting similar binding mode.\",\n      \"method\": \"X-ray crystallography of unphosphorylated and phosphorylated E-cadherin cytoplasmic domain/β-catenin arm repeat complex\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional implications for phosphorylation-dependent binding\",\n      \"pmids\": [\"11348595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Hakai, a c-Cbl-like E3 ubiquitin ligase, binds E-cadherin in a tyrosine phosphorylation-dependent manner via its SH2 domain, induces ubiquitination of the E-cadherin complex, and promotes endocytosis of E-cadherin; Hakai expression in epithelial cells disrupts cell-cell contacts and enhances cell motility.\",\n      \"method\": \"Modified yeast two-hybrid screen; co-immunoprecipitation; ubiquitination assay; endocytosis assay; domain analysis (SH2, RING); transfection and cell morphology/motility assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identified E3 ligase with mechanistic ubiquitination assay and functional cellular readouts\",\n      \"pmids\": [\"11836526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Presenilin-1 (PS1)/γ-secretase cleaves E-cadherin between residues Leu731 and Arg732 (membrane-cytoplasm interface), stimulated by apoptosis or calcium influx; this cleavage dissociates E-cadherin, β-catenin and α-catenin from the cytoskeleton, promoting adherens junction disassembly and releasing cytoplasmic β-catenin.\",\n      \"method\": \"Mapping of PS1/γ-secretase cleavage site by sequencing; pharmacological inhibition; apoptosis induction; calcium influx experiments; cytoskeletal fractionation; co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — precise cleavage site mapping with mechanistic dissection of complex disassembly consequences\",\n      \"pmids\": [\"11953314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SLUG (SNAI2) zinc-finger transcription factor directly binds E-box elements in the E-cadherin (CDH1) proximal promoter and represses E-cadherin transcription; SLUG expression strongly correlates with loss of E-cadherin in breast cancer cell lines.\",\n      \"method\": \"Reporter gene assays with E-box mutant promoter constructs; endogenous E-cadherin expression analysis; RT-PCR; co-transfection of SLUG/SNAIL expression constructs\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter reporter assays with E-box mutagenesis plus endogenous gene regulation; foundational EMT transcriptional repressor study\",\n      \"pmids\": [\"11912130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Snail directly represses transcription of claudin and occludin genes by binding E-boxes in their promoters during EMT; Snail-induced EMT involves simultaneous transcriptional repression of E-cadherin and tight junction proteins, establishing a coordinated program of epithelial junction loss.\",\n      \"method\": \"Snail overexpression in epithelial cells; promoter reporter assays; electrophoretic mobility shift assay; RT-PCR and immunoblot for junction proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding demonstrated by EMSA with functional reporter assays\",\n      \"pmids\": [\"12668723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM10 metalloprotease is responsible for both constitutive and regulated ectodomain shedding of E-cadherin; ADAM10 deficiency abolishes C-terminal fragment generation in vivo; ADAM10-mediated E-cadherin shedding affects cell-cell adhesion, migration, and β-catenin subcellular localization/downstream signaling including cyclin D1 induction.\",\n      \"method\": \"ADAM10-deficient fibroblast analysis; metalloprotease inhibitors; RNA interference; ADAM10-deficient mouse embryo analysis; β-catenin transcriptional reporter; cell adhesion and migration 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 — genetic KO mouse, RNAi, and inhibitor studies with multiple orthogonal readouts; in vivo validation\",\n      \"pmids\": [\"15958533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DeltaEF1 (ZEB1) directly binds the E-cadherin promoter via E-box elements and functions as a transcriptional repressor; ectopic DeltaEF1 is sufficient to downregulate E-cadherin and induce EMT; RNAi-mediated DeltaEF1 knockdown in cancer cells derepresses E-cadherin and restores cell-cell adhesion.\",\n      \"method\": \"Chromatin immunoprecipitation; promoter reporter assays; DeltaEF1 overexpression and RNAi; E-cadherin expression analysis; cell morphology\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus gain- and loss-of-function with defined molecular and cellular readouts\",\n      \"pmids\": [\"15674322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"VEGF promotes vascular permeability by inducing beta-arrestin2-dependent endocytosis of VE-cadherin (not E-cadherin/CDH1); this is mediated through Src-dependent Vav2 activation, Rac/PAK, and serine phosphorylation of VE-cadherin's intracellular tail, recruiting beta-arrestin2.\",\n      \"method\": \"Phosphorylation mapping; beta-arrestin2 co-IP; endocytosis assays; clathrin coated vesicle analysis; RNAi\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistically detailed but concerns VE-cadherin not E-cadherin; EXCLUDE from E-cadherin findings\",\n      \"pmids\": [\"17060906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of E-cadherin (CDH1) protein promotes metastasis not simply by disrupting cell-cell contacts but by inducing an EMT program including invasiveness and anoikis resistance; β-catenin is necessary but not sufficient for these phenotypes; E-cadherin loss induces multiple transcription factors including Twist, which is required for E-cadherin loss-induced metastasis.\",\n      \"method\": \"Two methods to inhibit E-cadherin function distinguishing adhesion vs. signaling; gene expression profiling; Twist knockdown; in vivo metastasis assays; anoikis resistance assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of adhesion vs. signaling using multiple genetic and functional approaches with in vivo validation\",\n      \"pmids\": [\"18483246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"miR-200 family members (two genomic clusters) directly target ZEB1 and ZEB2 mRNAs, repressing their translation; loss of miR-200 during TGF-β-induced EMT leads to ZEB1/ZEB2-mediated E-cadherin repression; ectopic miR-200 restores E-cadherin expression and inhibits cell motility in mesenchymal carcinoma cells.\",\n      \"method\": \"TGF-β EMT assay; miRNA overexpression; luciferase reporter with ZEB1/ZEB2 3'UTR; E-cadherin western blot; cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation with 3'UTR reporter plus functional cell migration readout\",\n      \"pmids\": [\"18411277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-9, activated by MYC/MYCN, directly targets the CDH1 (E-cadherin) mRNA 3'UTR, reducing E-cadherin protein levels; this leads to β-catenin nuclear signaling, increased VEGF expression, and enhanced tumour angiogenesis; miR-9 overexpression enables pulmonary micrometastasis formation in mice.\",\n      \"method\": \"miR-9 overexpression and 'sponge' inhibition; luciferase reporter with CDH1 3'UTR; β-catenin signaling assays; VEGF measurement; in vivo mouse metastasis model; MYC/MYCN promoter binding at mir-9-3 locus\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR reporter validation plus in vivo metastasis assay with mechanistic downstream pathway\",\n      \"pmids\": [\"20173740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E-cadherin (CDH1) homophilic binding at the cell surface mediates contact inhibition of proliferation through the Hippo signaling pathway; E-cadherin/catenin complex functions as an upstream regulator of LATS/YAP in mammalian cells; β-catenin depletion (depleting E-cadherin-bound β-catenin) reduces YAP phosphorylation and increases nuclear YAP.\",\n      \"method\": \"Hippo component knockdown; YAP overexpression; E-cadherin expression in MDA-MB-231 cells; β-catenin RNAi in confluent MCF10A cells; YAP phosphorylation and nuclear localization assays; cell proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis analysis with multiple genetic perturbations and defined pathway placement\",\n      \"pmids\": [\"21730131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fusobacterium nucleatum FadA adhesin binds directly to E-cadherin (CDH1); the FadA binding site on E-cadherin was mapped to an 11-amino-acid region; FadA-E-cadherin binding activates β-catenin signaling and induces oncogenic and inflammatory responses in colorectal cancer cells; a synthetic peptide from the FadA-binding region of E-cadherin abolishes these effects.\",\n      \"method\": \"Direct binding/invasion assays; E-cadherin binding site mapping with peptides; β-catenin reporter; gene expression analysis; synthetic peptide inhibition\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding site mapping with peptide inhibition and defined downstream signaling; highly cited\",\n      \"pmids\": [\"23954158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGA2 epigenetically silences the Cdh1 (E-cadherin) promoter during EMT by recruiting the de novo DNA methyltransferase DNMT3A to the Cdh1 promoter, causing hypermethylation; E-cadherin expression can be restored by the demethylating agent 5-aza-2'-deoxycytidine; this mechanism acts downstream of HMGA2-mediated induction of EMT transcription factors.\",\n      \"method\": \"Constitutive HMGA2 expression in NMuMG mammary epithelial cells; bisulfite sequencing; ChIP for DNMT3A binding to Cdh1 promoter; 5-aza-2'-deoxycytidine treatment; cell motility and invasion assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct DNMT3A recruitment with pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"25492890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ABCG2 localizes to the nucleus in lung cancer cells where it binds to the E-box of the CDH1 (E-cadherin) promoter and upregulates CDH1 transcription; increased ABCG2 increases E-cadherin and attenuates cell migration, while ABCG2 knockdown downregulates E-cadherin and enhances cell motility.\",\n      \"method\": \"Nuclear fractionation; chromatin immunoprecipitation at CDH1 E-box; ABCG2 overexpression and RNAi knockdown; cell migration assays; mouse xenograft metastasis model\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP with functional gain/loss-of-function; single lab\",\n      \"pmids\": [\"25810011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rab7 regulates E-cadherin (CDH1) endocytosis in thyroid FRT cells; Rab7 overexpression strongly reduces CDH1 endocytosis and promotes circular dorsal ruffle (CDR) formation co-localizing with cortactin and F-actin; cAMP stimulation induces Rab7 expression and blocks CDH1 endocytosis.\",\n      \"method\": \"Rab7 overexpression and RNAi in FRT cells; CDH1 endocytosis assay; co-localization by immunofluorescence; PAK1 phosphorylation as Rac1 activity readout; cAMP stimulation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression and RNAi with functional endocytosis assay; single lab, one cell type\",\n      \"pmids\": [\"26599499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cancer-associated fibroblasts (CAFs) exert physical force on cancer cells through a mechanically active heterotypic E-cadherin (cancer cell)/N-cadherin (CAF) adhesion; this adhesion triggers β-catenin recruitment and reinforcement dependent on α-catenin/vinculin interaction under force; E-cadherin/N-cadherin adhesion is required for CAF-guided collective invasion.\",\n      \"method\": \"Traction force microscopy; FRET-based tension sensor; blocking antibodies; α-catenin/vinculin domain mutants; co-culture invasion assay; patient-derived material analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical force measurement combined with molecular perturbation and patient validation; highly cited\",\n      \"pmids\": [\"28218910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Prevention of compaction in mouse embryos by low Ca2+ reduces overall uvomorulin (E-cadherin) phosphorylation and perturbs its localization to cell-cell contact regions in 8-cell embryos; phosphorylation of E-cadherin correlates with its redistribution during compaction but does not directly regulate adhesive function.\",\n      \"method\": \"Ca2+ depletion to prevent compaction; radioactive phosphorylation analysis; immunocytochemistry for uvomorulin localization\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative phosphorylation analysis; cannot establish direct causation\",\n      \"pmids\": [\"8722695\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"E-cadherin (CDH1) is a transmembrane Ca2+-dependent cell adhesion molecule whose extracellular domain mediates homophilic binding and whose cytoplasmic domain recruits β-catenin directly and then α-catenin (a vinculin homologue) to form the cadherin–catenin complex that links E-cadherin to the actin cytoskeleton; this complex is essential for E-cadherin's adhesive function, formation of the epithelial junctional complex, and induction of cell surface polarity. E-cadherin undergoes sequential biosynthetic processing (ER glycosylation → late Golgi cleavage of a 129-residue prodomain → cell surface delivery), regulated ectodomain shedding by ADAM10, γ-secretase/PS1 intramembrane cleavage releasing β-catenin, tyrosine-phosphorylation-dependent ubiquitination by the E3 ligase Hakai leading to endocytosis, and promoter silencing by CpG methylation or transcriptional repressors (Snail/SLUG/ZEB1/DeltaEF1) that bind E-box elements. As a signaling hub, E-cadherin competes with APC for β-catenin binding, activates the Hippo–YAP pathway to mediate contact inhibition of proliferation, and is directly targeted by bacterial FadA adhesin to drive β-catenin oncogenic signaling; its loss promotes EMT, metastasis, and β-catenin nuclear signaling via multiple transcriptional programs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDH1 encodes two functionally distinct gene products studied under the same symbol: E-cadherin, a transmembrane Ca²⁺-dependent homophilic adhesion molecule essential for epithelial junction assembly, cell polarity, and invasion suppression; and Cdh1/FZR1, a WD40-repeat coactivator of the APC/C E3 ubiquitin ligase that drives substrate-specific ubiquitination to coordinate mitotic exit, G1 maintenance, DNA-damage checkpoints, and neuronal morphogenesis. E-cadherin's extracellular domain contains repeated Ca²⁺-binding motifs that mediate adhesion after proteolytic processing of its precursor, while its cytoplasmic domain directly binds β-catenin, which in turn recruits α-catenin (a vinculin homologue) to link the complex to the actin cytoskeleton; this catenin association is required for adhesive function and for organizing epithelial junctional complexes and membrane polarity [PMID:2788574, PMID:2349235, PMID:3049625, PMID:2164888]. APC/C coactivator Cdh1 confers substrate specificity for degradation of Aurora kinases, Plk1, Claspin, SnoN, Skp2, Rock2, LATS kinases, FoxM1, and cell-cycle regulators such as cyclins, with its activity controlled by CDK/polo-kinase phosphorylation, O-GlcNAcylation, and c-Src-mediated phosphorylation that regulate nuclear–cytoplasmic shuttling and APC/C core binding; bistable APC/C(Cdh1) inactivation by cyclin E/Cdk2 and Emi1 constitutes the commitment point for cell-cycle entry [PMID:9334304, PMID:27368103, PMID:18662541, PMID:19339626, PMID:31420536]. In postmitotic neurons, APC/C(Cdh1) ubiquitinates SnoN to restrain axon growth and Rock2 to maintain dendritic arborization and synaptic integrity; its loss causes neurodegeneration rescuable by Rock inhibition [PMID:16675394, PMID:28396402].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Identifying a functional adhesion domain on E-cadherin established that a discrete extracellular fragment mediates Ca²⁺-dependent cell–cell adhesion.\",\n      \"evidence\": \"Protease digestion and monoclonal antibody blocking in mouse cells\",\n      \"pmids\": [\"2419126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise boundaries and atomic structure of the adhesion domain unknown\", \"Ca²⁺-binding stoichiometry not determined\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Sequencing of E-cadherin revealed internally repeated extracellular domains with Ca²⁺-binding motifs, providing the first structural framework for the cadherin superfamily.\",\n      \"evidence\": \"Amino acid sequence analysis and secondary structure prediction\",\n      \"pmids\": [\"3501370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Number of functional repeats differs from later crystal structures\", \"No experimental confirmation of Ca²⁺ binding per repeat\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstrating that E-cadherin-mediated adhesion is a prerequisite for assembly of all junctional elements (tight junctions, adherens junctions, desmosomes) established E-cadherin as the master organizer of epithelial polarity.\",\n      \"evidence\": \"Antibody blocking in MDCK Ca²⁺-switch assay with immunofluorescence for ZO-1, desmoplakin, actin\",\n      \"pmids\": [\"3049625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling cascades linking E-cadherin to tight junction assembly unresolved\", \"Whether E-cadherin acts instructively or permissively not fully distinguished\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of α-, β-, and γ-catenins as cytoplasmic partners of E-cadherin revealed the cadherin–catenin complex as the molecular unit linking adhesion to the cytoskeleton.\",\n      \"evidence\": \"Immunoprecipitation with deletion mutants and peptide pattern analysis\",\n      \"pmids\": [\"2788574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect catenin binding hierarchy not resolved\", \"γ-catenin functional role relative to β-catenin unclear\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Mapping the 72-amino-acid catenin-binding domain and showing that β-catenin binds directly while α-catenin links to actin, and that proteolytic processing of the E-cadherin precursor is required for adhesive function, defined the minimal molecular requirements for functional adhesion.\",\n      \"evidence\": \"Chimeric protein expression, cell aggregation assays, mutagenesis of precursor cleavage sites in L cells\",\n      \"pmids\": [\"2349235\", \"2211831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for precursor cleavage not identified\", \"Whether unprocessed E-cadherin has any signaling role unknown\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Showing that E-cadherin expression suffices to redistribute Na⁺/K⁺-ATPase to cell contacts demonstrated a direct role in inducing membrane polarity independent of epithelial differentiation programs.\",\n      \"evidence\": \"cDNA transfection into fibroblasts with immunofluorescence\",\n      \"pmids\": [\"2164888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ATPase recruitment (direct interaction vs. cytoskeletal remodeling) not established\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Cloning α-catenin as a vinculin homologue and demonstrating E-cadherin suppresses invasive migration established dual roles: cytoskeletal linkage through a vinculin-related protein and functional invasion suppression.\",\n      \"evidence\": \"Molecular cloning/sequence homology; E-cadherin-transfected L-cell 3D collagen invasion assays with antibody reversal\",\n      \"pmids\": [\"1924379\", \"1649199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether α-catenin binds actin directly or through intermediaries debated\", \"In vivo metastasis suppression not tested\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Determining the stoichiometry (1 E-cadherin : 1–2 β-catenin : 1 α-catenin) and showing β-catenin assembles with the precursor while α-catenin joins after processing revealed the ordered assembly of the adhesion complex.\",\n      \"evidence\": \"Pulse-chase biochemistry and stoichiometry analysis\",\n      \"pmids\": [\"1734027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 1:2 stoichiometry is physiological or artefactual not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery that yeast Cdh1 activates APC for degradation of specific substrates (Ase1, Clb2) distinct from Cdc20 substrates established Cdh1 as a substrate-specificity factor for the APC/C ubiquitin ligase.\",\n      \"evidence\": \"Yeast deletion genetics and substrate degradation assays\",\n      \"pmids\": [\"9334304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for substrate discrimination between Cdh1 and Cdc20 not known\", \"Mammalian conservation not yet shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that Cdh1 contains a functional NLS, localizes to the nucleus in interphase and centrosomes in mitosis, and that CDK phosphorylation within the NLS blocks nuclear import established phosphorylation-dependent nucleo-cytoplasmic shuttling as a key regulatory mechanism.\",\n      \"evidence\": \"GFP fusions, phosphomimetic mutants, cell synchronization in mammalian cells\",\n      \"pmids\": [\"12560341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Export mechanism not identified\", \"Whether centrosomal localization has functional consequence unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of SnoN as an APC/C(Cdh1) substrate in postmitotic neurons revealed a non-mitotic function: Cdh1-dependent SnoN degradation restricts axonal growth, extending APC/C(Cdh1) biology beyond cell-cycle control.\",\n      \"evidence\": \"Co-IP, ubiquitination, RNAi in cerebellar granule neurons with in vivo analysis\",\n      \"pmids\": [\"16675394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APC/C(Cdh1) regulates axon guidance in addition to growth unknown\", \"Full neuronal substrate repertoire not catalogued\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Multiple studies showed APC/C(Cdh1) degrades Plk1 downstream of Cdc14B during the G2 DNA-damage checkpoint and Aurora kinases at anaphase for proper spindle midzone assembly, establishing Cdh1 as a checkpoint effector and mitotic-exit coordinator.\",\n      \"evidence\": \"siRNA, non-degradable substrate expression, live imaging, checkpoint assays in human cells; yeast kinase cascade reconstitution\",\n      \"pmids\": [\"18662541\", \"18976910\", \"18500339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cdc14B–Cdh1 axis operates identically in human somatic cells unclear\", \"Relative contributions of individual Aurora isoforms not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Phosphomimetic mutagenesis of 9 CDK sites on neuronal Cdh1 showed phosphorylation disrupts Cdc27 binding and causes cytoplasmic retention, while Claspin and Rb were identified as additional APC/C(Cdh1) substrates, broadening the substrate repertoire and linking Cdh1 inactivation to checkpoint and Rb pathways.\",\n      \"evidence\": \"Alanine/aspartate substitution, Co-IP with Cdc27, axon growth assays; AP-MS for Claspin identification\",\n      \"pmids\": [\"19339626\", \"19477924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of phosphatases that reactivate Cdh1 in neurons not established\", \"Relative importance of individual CDK sites unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of E2F3 and RAP80 as APC/C(Cdh1) substrates expanded the known roles of Cdh1 in controlling G1 transcription programs and DNA damage signaling.\",\n      \"evidence\": \"Co-IP, D-box mutagenesis, ubiquitination assays, cell cycle analysis\",\n      \"pmids\": [\"22580460\", \"22426463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RAP80 degradation on HR repair not fully tested\", \"E2F3 finding from single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"HMGA2-mediated recruitment of DNMT3A to the E-cadherin promoter during TGFβ-induced EMT established an epigenetic silencing mechanism for CDH1 transcription.\",\n      \"evidence\": \"ChIP, bisulfite sequencing, demethylation rescue in NMuMG cells\",\n      \"pmids\": [\"25492890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this mechanism operates in human tumors in vivo not confirmed\", \"Other epigenetic regulators of CDH1 promoter not integrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Live single-cell imaging revealed that APC/C(Cdh1) inactivation by cyclin E/Cdk2 and Emi1 constitutes a bistable, irreversible commitment point for cell-cycle entry, answering the long-standing question of what defines the mammalian restriction point at the molecular level.\",\n      \"evidence\": \"Live imaging with pharmacological and genetic perturbations in human cells\",\n      \"pmids\": [\"27368103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative parameters of the bistable switch in different cell types not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of O-GlcNAcylation on Cdh1 that antagonizes phosphorylation revealed a metabolic input into APC/C regulation; separately, APC/C(Cdh1) was shown to promote non-proteolytic monoubiquitination of Goosecoid for transcriptional activation in neural crest cells.\",\n      \"evidence\": \"Mass spectrometry and mutagenesis for O-GlcNAc; conditional neural crest Cdh1 KO with reporter assays for Gsc\",\n      \"pmids\": [\"27080259\", \"27126000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAcylation sites not fully mapped\", \"Monoubiquitination mechanism and whether other APC/C substrates are similarly modified unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"APC/C(Cdh1) was shown to ubiquitinate LATS kinases (connecting Hippo signaling to cell cycle) and Rock2 in neurons (whose accumulation upon Cdh1 loss causes neurodegeneration rescuable by fasudil), revealing critical Cdh1 substrates in signaling and neuronal homeostasis.\",\n      \"evidence\": \"Co-IP, ubiquitination, Drosophila epistasis for LATS; conditional neuronal KO with behavioral rescue for Rock2\",\n      \"pmids\": [\"31000600\", \"28396402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LATS degradation timing affects Hippo-dependent organ size control in vivo not tested\", \"Whether Rock2 accumulation explains all neurodegenerative phenotypes of Cdh1 loss unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"c-Src was identified as both a regulator and an APC-independent binding partner of Cdh1: c-Src phosphorylates Cdh1 to disrupt APC core binding, while Cdh1 reciprocally suppresses c-Src kinase activity, establishing a mutual antagonism relevant to tumorigenesis.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, siRNA, mouse mammary tumor model\",\n      \"pmids\": [\"31420536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for APC-independent Cdh1–c-Src interaction not determined\", \"Generality across tumor types unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of metabolic enzymes IDH3β and Skp2 as APC/C(Cdh1) substrates linked Cdh1 activity to TCA-cycle regulation and aerobic glycolysis reprogramming.\",\n      \"evidence\": \"Co-IP, ubiquitination, cell cycle analysis, xenograft models\",\n      \"pmids\": [\"31053633\", \"31806563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct metabolic flux measurements upon Cdh1 manipulation lacking\", \"Single-lab findings for each substrate\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"APC/C(Cdh1)-mediated cyclin B1 degradation was shown to execute a non-canonical G2/M DNA damage response in oocytes, and FoxM1 was identified as a Cdh1 substrate controlling muscle satellite cell quiescence.\",\n      \"evidence\": \"Mouse oocyte Setx deletion with live imaging; conditional Cdh1 KO in satellite cells with FoxM1 haploinsufficiency rescue\",\n      \"pmids\": [\"32328643\", \"32152291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of oocyte DDR mechanism to somatic cells not tested\", \"Whether FoxM1 is the sole Cdh1 substrate maintaining SC quiescence unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the complete substrate repertoire of APC/C(Cdh1) across tissues, structural determinants distinguishing proteolytic from non-proteolytic ubiquitination by APC/C(Cdh1), and the integration of metabolic signals (O-GlcNAcylation, TCA intermediates) into Cdh1 regulation in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No systematic in vivo substrate screen across tissues\", \"Structural basis for Cdh1 substrate recognition beyond D-box/KEN-box not resolved\", \"Cross-talk between E-cadherin adhesion signaling and APC/C(Cdh1) cell-cycle control unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 4, 5, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 12, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 13, 24, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5, 6, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 12, 14, 15]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 6, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 13, 24, 27, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 29]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 18, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"complexes\": [\n      \"APC/C (Cdh1 coactivator form)\",\n      \"Cadherin–catenin complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"CTNNA1\",\n      \"CDC27\",\n      \"AURKA\",\n      \"PLK1\",\n      \"SKIL\",\n      \"ROCK2\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"E-cadherin (CDH1) is a calcium-dependent transmembrane glycoprotein that serves as the principal mediator of homophilic cell–cell adhesion in epithelial tissues, functioning simultaneously as a master organizer of the epithelial junctional complex and as a signaling hub that controls cell polarity, proliferation, and invasion. Its extracellular domain contains internally repeated cadherin motifs with Ca²⁺-binding sites that mediate homophilic binding, while a 72-amino-acid cytoplasmic segment recruits β-catenin co-translationally and subsequently α-catenin (a vinculin homologue) at the plasma membrane, linking the complex to the actin cytoskeleton and enabling assembly of all junctional elements including tight junctions and desmosomes [PMID:3501370, PMID:2349235, PMID:3049625, PMID:11348595]. E-cadherin is synthesized as a 135 kDa precursor that undergoes ER glycosylation, late-Golgi prodomain cleavage required for adhesive activation, regulated ADAM10-mediated ectodomain shedding, presenilin-1/γ-secretase intramembrane proteolysis releasing β-catenin, and Hakai E3-ligase-dependent tyrosine-phosphorylation-triggered ubiquitination and endocytosis [PMID:2211831, PMID:1918074, PMID:15958533, PMID:11953314, PMID:11836526]. Beyond adhesion, E-cadherin engagement activates the Hippo–YAP pathway to enforce contact inhibition of proliferation, competes with APC for β-catenin binding to regulate Wnt signaling, and is directly exploited by the bacterial adhesin FadA to drive oncogenic β-catenin signaling; its transcriptional silencing by Snail/SLUG/ZEB1 via E-box repression or by CpG promoter methylation is a central event in epithelial-to-mesenchymal transition and metastasis [PMID:21730131, PMID:7806582, PMID:23954158, PMID:11912130, PMID:7543680, PMID:18483246]. Germline and somatic loss-of-function mutations in CDH1, frequently with loss of heterozygosity at 16q22.1, cause hereditary diffuse gastric cancer and lobular breast carcinoma [PMID:8557030, PMID:9744472].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Identifying the adhesion-mediating extracellular domain of E-cadherin established that a discrete proteolytic fragment is both necessary and sufficient for Ca²⁺-dependent cell–cell binding and embryo compaction.\",\n      \"evidence\": \"Protease digestion of uvomorulin and functional blocking with DECMA-1 antibody in MDCK cells and mouse embryos\",\n      \"pmids\": [\"2419126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the adhesion domain unresolved\", \"No information on cytoplasmic partners\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Sequencing revealed the conserved cadherin architecture — three ~112-residue extracellular repeats with Ca²⁺-binding sites, a single transmembrane pass, and a cytoplasmic domain — establishing the molecular template for the cadherin superfamily.\",\n      \"evidence\": \"Protein sequencing, secondary structure prediction, and cross-species sequence comparison\",\n      \"pmids\": [\"3501370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No three-dimensional structure\", \"Function of cytoplasmic domain unknown\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstrating that E-cadherin-mediated adhesion is a prerequisite for assembly of the entire epithelial junctional complex (zonula adherens, zonula occludens, desmosomes) placed E-cadherin upstream of all intercellular junction formation.\",\n      \"evidence\": \"Ca²⁺-switch assay with anti-E-cadherin blocking antibodies; fluorescence staining for ZO-1, actin, desmoplakin; transepithelial resistance in MDCK cells\",\n      \"pmids\": [\"3049625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between E-cadherin and tight-junction/desmosome assembly unknown\", \"Role of cytoplasmic partners not defined\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Discovery of the catenin complex (α, β, γ) associated with E-cadherin's cytoplasmic domain revealed that adhesive function requires intracellular partners that bridge E-cadherin to the cytoskeleton.\",\n      \"evidence\": \"Co-immunoprecipitation from E-cadherin-transfected cells with deletion mapping; cross-species peptide analysis\",\n      \"pmids\": [\"2788574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of individual catenins at the molecular level unknown\", \"Direct vs. indirect binding not resolved\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Mapping the 72-amino-acid catenin-binding domain and showing that β-catenin binds E-cadherin more directly while α-catenin connects to actin defined the hierarchical assembly of the cadherin–catenin–actin axis, and simultaneously showed that prodomain cleavage is required for adhesive activation.\",\n      \"evidence\": \"Chimeric and deletion constructs in L cells; cell aggregation; actin co-sedimentation; site-directed mutagenesis of cleavage site with protease rescue\",\n      \"pmids\": [\"2349235\", \"2211831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex undefined\", \"Protease responsible for prodomain cleavage in vivo unidentified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of α-catenin as a vinculin homologue, determination that β-catenin binds E-cadherin co-translationally while α-catenin joins only at the time of prodomain processing, and demonstration that complex stoichiometry is 1 E-cadherin : 1–2 β-catenin : 1 α-catenin established the temporal logic of cadherin–catenin assembly.\",\n      \"evidence\": \"Molecular cloning of α-catenin; pulse-chase metabolic labeling and stoichiometric analysis; co-IP with multiple cadherins; E-cadherin transfection into cadherin-negative cells\",\n      \"pmids\": [\"1924379\", \"1734027\", \"1649199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural evidence for α-catenin–actin linkage lacking\", \"Mechanism of invasion suppression beyond adhesion not dissected\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Detailed biosynthetic tracing showed that E-cadherin is core-glycosylated in the ER, processed in the late Golgi, delivered to the surface with a ~5 h half-life, and rapidly incorporated into Triton-insoluble junctions upon Ca²⁺-dependent adhesion.\",\n      \"evidence\": \"Pulse-chase metabolic labeling; subcellular fractionation; glycosylation inhibitors; Triton X-100 extraction in MDCK cells\",\n      \"pmids\": [\"1918074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the pro-protein convertase unknown\", \"Mechanisms controlling E-cadherin turnover at the surface undefined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that E-cadherin and APC directly compete for the arm-repeat domain of β-catenin connected E-cadherin adhesion to the Wnt/APC tumor-suppressor pathway, revealing a signaling function beyond structural adhesion.\",\n      \"evidence\": \"Direct competition binding assays and domain mapping with deletion constructs; sequential immunoprecipitation and pulse-chase in multiple cell lines\",\n      \"pmids\": [\"7806582\", \"8207061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of competition for β-catenin unresolved\", \"Quantitative regulation of β-catenin partitioning unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of CpG promoter hypermethylation as a silencing mechanism and biallelic inactivating mutations with LOH at 16q22.1 in lobular breast carcinomas established CDH1 as a bona fide tumor/invasion suppressor gene subject to both genetic and epigenetic inactivation.\",\n      \"evidence\": \"HpaII methylation analysis with 5-azacytidine rescue; PCR/SSCP mutation screening and LOH analysis in human carcinomas\",\n      \"pmids\": [\"7543680\", \"8557030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of methylation vs. mutation to progression not separated\", \"Germline predisposition not yet established\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that ZO-1 directly binds α-catenin (Kd ~0.5 nM) and actin filaments (Kd ~10 nM) provided a molecular cross-linker between the E-cadherin/catenin complex and the cytoskeleton, explaining how adherens junctions physically integrate with tight junctions.\",\n      \"evidence\": \"GST pull-down with recombinant proteins; actin co-sedimentation; truncated ZO-1 constructs in E-cadherin-expressing L cells\",\n      \"pmids\": [\"9214391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of ZO-1–α-catenin linkage not tested genetically\", \"Other cross-linkers may exist\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Comprehensive mutation cataloguing in diffuse gastric and lobular breast cancers revealed tumor-type-specific mutation patterns (in-frame exon skippings in gastric vs. out-of-frame mutations in breast), refining the two-hit inactivation model for CDH1.\",\n      \"evidence\": \"Compilation of 69 somatic mutations by PCR/SSCP, sequencing, and LOH analysis across tumor types\",\n      \"pmids\": [\"9744472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of specific in-frame deletions not tested\", \"Genotype–phenotype correlations for individual mutations unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The crystal structure of the β-catenin arm-repeat/E-cadherin cytoplasmic domain complex revealed that phosphorylation of E-cadherin creates interactions mimicking the Tcf-3 binding helix, providing a structural basis for competitive binding between E-cadherin, APC, and Tcf transcription factors.\",\n      \"evidence\": \"X-ray crystallography of phosphorylated and unphosphorylated E-cadherin/β-catenin complexes\",\n      \"pmids\": [\"11348595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length E-cadherin structure unresolved\", \"How phosphorylation is dynamically regulated at junctions unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Three mechanistically distinct post-translational regulatory circuits for E-cadherin were identified nearly simultaneously: Hakai E3-ligase-dependent ubiquitination driving endocytosis, presenilin-1/γ-secretase intramembrane cleavage releasing β-catenin, and SLUG/Snail-mediated E-box transcriptional repression.\",\n      \"evidence\": \"Yeast two-hybrid, ubiquitination assays, and endocytosis assays for Hakai; PS1 cleavage-site mapping and cytoskeletal fractionation; promoter-reporter and E-box mutagenesis for SLUG\",\n      \"pmids\": [\"11836526\", \"11953314\", \"11912130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each pathway in vivo undefined\", \"Upstream signals triggering each pathway not fully elucidated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"ADAM10 was identified as the metalloprotease responsible for constitutive and regulated E-cadherin ectodomain shedding in vivo, and ZEB1 was established as an additional E-box transcriptional repressor, expanding the network of E-cadherin regulators controlling EMT.\",\n      \"evidence\": \"ADAM10-knockout mouse and fibroblast analysis with RNAi; ChIP at CDH1 promoter with ZEB1 gain- and loss-of-function\",\n      \"pmids\": [\"15958533\", \"15674322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between ectodomain shedding and transcriptional repression unknown\", \"Whether ADAM10 or γ-secretase cleavage is rate-limiting for β-catenin release unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"E-cadherin loss was shown to activate a full EMT transcriptional program (including Twist induction) required for metastasis beyond simple loss of adhesion, and miR-200 family members were identified as direct suppressors of ZEB1/ZEB2 that maintain E-cadherin expression.\",\n      \"evidence\": \"Genetic dissection of adhesion vs. signaling with in vivo metastasis assays; miR-200 overexpression with ZEB1/ZEB2 3′UTR reporters\",\n      \"pmids\": [\"18483246\", \"18411277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which EMT transcription factor is dominant in specific tumor contexts unknown\", \"Feedback loop dynamics between miR-200 and ZEB not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placing E-cadherin/catenin complex as an upstream activator of the Hippo–LATS–YAP pathway provided a mechanistic explanation for E-cadherin-mediated contact inhibition of proliferation independent of Wnt/β-catenin.\",\n      \"evidence\": \"Epistasis analysis with Hippo component knockdown, YAP phosphorylation assays, and E-cadherin expression in MDA-MB-231 and MCF10A cells\",\n      \"pmids\": [\"21730131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular intermediates between E-cadherin and LATS kinase not identified\", \"Whether α-catenin or β-catenin mediates the Hippo signal unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that Fusobacterium nucleatum FadA adhesin directly binds an 11-amino-acid epitope on E-cadherin to activate β-catenin signaling revealed E-cadherin as a host receptor exploited by a pathogen to drive oncogenic and inflammatory responses in colorectal cancer.\",\n      \"evidence\": \"Direct binding assays, binding-site peptide mapping, β-catenin reporter activation, and synthetic peptide inhibition in colorectal cancer cells\",\n      \"pmids\": [\"23954158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FadA–E-cadherin interface not determined\", \"In vivo contribution to colorectal carcinogenesis not established in genetic models\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"E-cadherin was shown to form mechanically active heterotypic adhesions with N-cadherin on cancer-associated fibroblasts, with force-dependent recruitment of β-catenin and α-catenin/vinculin reinforcement, revealing a mechanotransduction role in collective cancer cell invasion.\",\n      \"evidence\": \"Traction force microscopy, FRET tension sensor, α-catenin/vinculin domain mutants, and co-culture invasion assays with patient-derived material\",\n      \"pmids\": [\"28218910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether heterotypic adhesion triggers distinct signaling from homophilic adhesion unknown\", \"Generalizability beyond breast cancer CAF co-culture not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the molecular intermediates linking E-cadherin engagement to Hippo–YAP activation, the structural basis of full-length E-cadherin in the membrane-associated cadherin–catenin complex, and how the multiple proteolytic, endocytic, transcriptional, and epigenetic regulatory inputs are integrated in vivo to control E-cadherin levels during normal development and tumor progression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length E-cadherin structure in membrane context\", \"Molecular bridge from E-cadherin/catenin to LATS kinase undefined\", \"Quantitative model integrating transcriptional, post-translational, and trafficking regulation absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2, 4, 9, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 29, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 6, 10, 34]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8, 10, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 4, 6, 9, 16, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 28, 29, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 17, 26, 28]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [19, 33]}\n    ],\n    \"complexes\": [\n      \"cadherin–catenin complex\",\n      \"E-cadherin–β-catenin–α-catenin–ZO-1 junction complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"CTNNA1\",\n      \"JUP\",\n      \"TJP1\",\n      \"CBLL1\",\n      \"ADAM10\",\n      \"PSEN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}