{"gene":"CDH1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1989,"finding":"The cytoplasmic domain of uvomorulin (CDH1/E-cadherin) associates with three independent proteins of 102, 88, and 80 kDa (named catenin alpha, beta, and gamma, respectively), as demonstrated by immunoprecipitation using cytoplasmic vs. extracellular deletion constructs; these catenins are conserved across species and form a new protein group linking uvomorulin to the cytoskeleton.","method":"Co-immunoprecipitation with deletion mutants expressed in NIH 3T3, L cells, HeLa, and avian fibroblasts; peptide pattern analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain deletion mutants, replicated across multiple cell lines and species, foundational discovery independently confirmed by multiple subsequent studies","pmids":["2788574"],"is_preprint":false},{"year":1988,"finding":"Uvomorulin mediates an early adhesion event that is prerequisite for assembly of all elements of the epithelial junctional complex (zonula adherens, zonula occludens, desmosomes); inhibition with blocking antibodies/Fab fragments prevents junction formation in a Ca2+ switch assay, but established tight junctions are resistant to antibody disruption.","method":"Ca2+ switch assay with blocking antibodies and Fab fragments; fluorescence staining for ZO-1, actin (ZA), desmoplakin; transepithelial resistance measurement in MDCK cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal readouts (ZO-1, actin, desmoplakin staining plus electrical resistance), functional blocking antibody approach with clear mechanistic interpretation","pmids":["3049625"],"is_preprint":false},{"year":1990,"finding":"Catenin complex formation with uvomorulin is mediated by a specific 72-amino acid domain (encoded largely by a single exon) in the cytoplasmic region; catenin beta binds more directly to this domain while catenin alpha mediates association with actin filaments; catenin binding is required for adhesive function of uvomorulin in cell aggregation assays.","method":"Expression of chimeric H-2Kd/uvomorulin constructs and deletion mutants in L cells; immunoprecipitation; cell aggregation assays; biochemical fractionation with actin bundles","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis with chimeric constructs, in vitro actin fractionation, functional cell aggregation assay; multiple orthogonal methods in one study","pmids":["2349235"],"is_preprint":false},{"year":1987,"finding":"The extracellular domain of uvomorulin contains three internally repeated domains of 112 residues (generated by gene duplication), each with two putative Ca2+-binding sites in external loops; the protein also has a single transmembrane region and a cytoplasmic domain, showing 65% identity to chicken L-CAM.","method":"Protein sequencing of purified uvomorulin; amino acid sequence analysis and secondary structure prediction; sequence comparison","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct protein sequencing establishing domain architecture; structural inference from primary sequence with comparative analysis","pmids":["3501370"],"is_preprint":false},{"year":1985,"finding":"A 26 kDa extracellular fragment of uvomorulin, generated by protease digestion and recognized by blocking monoclonal antibody DECMA-1, is implicated in the adhesive function; the same fragment is recognized by other function-blocking antibodies that disrupt MDCK monolayers.","method":"Monoclonal antibody blocking of embryo compaction and MDCK cell adhesion; protease digestion mapping of antigenic fragment; immunoreactivity comparison across blocking antibodies","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody blocking with epitope mapping by proteolysis; single lab but convergent evidence from multiple blocking antibodies identifying same fragment","pmids":["2419126"],"is_preprint":false},{"year":1985,"finding":"Uvomorulin localizes to the intermediate junctions (zonula adherens) of adult intestinal epithelial cells, as demonstrated by electron microscopic immunolocalization.","method":"Electron microscopy with immunolabeling of adult intestinal epithelial cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electron microscopic localization establishing precise subcellular compartment; single lab","pmids":["3880756"],"is_preprint":false},{"year":1991,"finding":"Alpha-catenin is a vinculin homologue and complexes with multiple cadherins (uvomorulin/E-cadherin, N-cadherin, P-cadherin, A-CAM, U-cadherin); in cadherin-negative L cells, alpha-catenin is diffusely cytoplasmic but concentrates at membrane contacts upon uvomorulin expression, suggesting it mediates cytoskeletal anchorage downstream of cadherin engagement.","method":"Immunoprecipitation with anti-alpha-catenin antibodies; molecular cloning and sequence analysis; immunofluorescence in cadherin-negative and uvomorulin-transfected L cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — molecular cloning of alpha-catenin revealing vinculin homology, co-IP across multiple cadherins, live-cell localization showing redistribution upon cadherin expression; multiple orthogonal methods","pmids":["1924379"],"is_preprint":false},{"year":1992,"finding":"The uvomorulin-catenin complex is composed of one molecule of uvomorulin, one or two molecules of beta-catenin, and one molecule of alpha-catenin; beta-catenin associates with the uvomorulin precursor (135 kDa) early in biosynthesis whereas alpha-catenin joins the complex later, around the time of endoproteolytic processing.","method":"Biochemical analysis of immunoprecipitated complexes; pulse-chase experiments; stoichiometry analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — pulse-chase biochemistry with stoichiometric analysis establishing assembly order and complex composition; multiple orthogonal methods in one study","pmids":["1734027"],"is_preprint":false},{"year":1990,"finding":"Correct proteolytic processing of the uvomorulin precursor segment is required for its cell adhesive function; unprocessed uvomorulin that reaches the cell surface forms catenin complexes and is Ca2+-protected but is non-functional in cell adhesion assays; cleavage at the correct site activates adhesion while cleavage at incorrect sites does not, indicating the amino-terminal region of mature uvomorulin is important for adhesion.","method":"Site-directed mutagenesis of protease recognition sites; expression of mutant polypeptides in L cells; cell adhesion assays; treatment with specific proteases (factor Xa, trypsin)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-type experiment with specific mutagenesis of cleavage site and rescue by correct protease; clear functional readout; single lab but rigorous design","pmids":["2211831"],"is_preprint":false},{"year":1991,"finding":"E-cadherin (uvomorulin)-mediated cell-cell contacts inhibit invasive migration of L cells into collagen gels in a cell density-dependent manner, establishing E-cadherin as a contact inhibitor of invasion; single cells expressing E-cadherin show normal invasiveness, indicating the effect requires cell-cell contact.","method":"Stable transfection of L cells with E-cadherin cDNA; 3D collagen gel invasion assay; blocking antibody reversal experiment; time-lapse videoscopy; wound closure assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function antibody rescue, stable transfection, multiple invasion assays with clear mechanistic interpretation; single lab with multiple orthogonal methods","pmids":["1649199"],"is_preprint":false},{"year":1991,"finding":"Uvomorulin is synthesized as a 135 kDa precursor glycosylated in the endoplasmic reticulum, processed to the mature 120 kDa form in the late Golgi prior to cell surface delivery; glycosylation is not required for processing or surface transport; surface uvomorulin has a t½ of ~5 h and becomes Triton X-100 insoluble and concentrates at cell contacts upon Ca2+-dependent adhesion.","method":"Pulse-chase biosynthetic labeling; domain-selective biotinylation; Triton X-100 fractionation in MDCK cells; tunicamycin inhibition of glycosylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — detailed pulse-chase biochemistry with multiple inhibitors and fractionation approaches; rigorous biosynthetic study with functional correlate","pmids":["1918074"],"is_preprint":false},{"year":1990,"finding":"Uvomorulin is delivered directly to the basolateral surface of MDCK cells with only 2% mistargeting to the apical domain, establishing its direct basolateral targeting in polarized epithelial cells.","method":"Pulse-chase combined with domain-selective cell-surface biotinylation and streptavidin-agarose precipitation in MDCK cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical surface biotinylation approach with quantitative measurement of mistargeting; single lab","pmids":["2335561"],"is_preprint":false},{"year":1990,"finding":"The membrane-proximal region of uvomorulin, containing a cluster of cysteine residues, is involved in the adhesive mechanism; reduction of disulfide bonds by DTT blocks close cell-cell contacts and cell flattening (but not aggregation) and increases trypsin susceptibility of this region, indicating a conformational contribution to adhesion.","method":"DTT treatment of cells; cell adhesion assays; trypsin sensitivity assay of membrane-proximal domain; epitope mapping of DECMA-1","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical perturbation with functional adhesion assays and structural correlate (protease sensitivity); single lab, multiple methods","pmids":["1710917"],"is_preprint":false},{"year":1991,"finding":"Uvomorulin is the dominant functional cadherin on pancreatic islet cells mediating Ca2+-dependent aggregation; anti-uvomorulin Fab fragments block B-cell aggregation to the same extent as EDTA (Ca2+ chelation), confirming its role as the principal Ca2+-dependent adhesion molecule in islets.","method":"Anti-uvomorulin Fab fragment blocking of islet cell aggregation; flow cytometry; sorting of B- and non-B-cells; mild trypsin/Ca2+ digestion to remove Ca2+-independent CAMs","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Fab blocking with quantitative aggregation assay and comparison to EDTA control; single lab, multiple cell types tested","pmids":["1936561"],"is_preprint":false},{"year":1996,"finding":"Uvomorulin is phosphorylated at the 8-cell stage during compaction; prevention of compaction by prolonged low Ca2+ exposure reduces the level of uvomorulin phosphorylation and perturbs its localization to cell-cell contacts, though phosphorylation does not appear to directly regulate adhesive function.","method":"Phosphorylation analysis in mouse embryos under conditions preventing, reversing, or inducing compaction; immunolocalization","journal":"Molecular reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative phosphorylation analysis in embryos with pharmacological manipulation; finding is partially negative (phosphorylation not directly regulating adhesion)","pmids":["8722695"],"is_preprint":false},{"year":2000,"finding":"CDC6 is targeted for ubiquitin-mediated proteolysis by APC/C in complex with CDH1 (APC-CDH1) during G1; CDH1 ubiquitinates CDC6 in vitro; destruction box and KEN-box mutations in CDC6 stabilize it in G1 and quiescent cells; both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo.","method":"In vitro ubiquitination assay with APC-CDH1; point mutagenesis of destruction box and KEN-box; in vivo proteolysis assay with CDH1 depletion; cell cycle analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution plus mutagenesis of degradation signals plus in vivo depletion; multiple orthogonal methods in one study","pmids":["10995389"],"is_preprint":false},{"year":2003,"finding":"CDH1 (APC/C coactivator) localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase; nuclear accumulation correlates with reduction of cyclin A; a nuclear localization signal (NLS) in CDH1 drives nuclear import; phosphorylation of serine/threonine residues in the NLS inhibits nuclear import, keeping hyperphosphorylated CDH1 in the cytoplasm.","method":"GFP-CDH1 live-cell imaging; CDH1-4D phosphomimetic mutant localization; NLS-GFP fusion targeting assay; cyclin A immunostaining correlation; cell cycle staging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell localization with phosphomimetic and phosphodefective mutants; GFP fusion NLS mapping; single lab, multiple methods","pmids":["12560341"],"is_preprint":false},{"year":2004,"finding":"Mammalian CDH1 (Fzr) undergoes APC/C-mediated auto-degradation during G1 and G0 via two RXXL-type destruction boxes; CDH1 activates APC/C to degrade itself; destruction-box mutations stabilize CDH1 in G1/G0.","method":"Mutation of destruction boxes in CDH1; Xenopus interphase extract APC/C activation assay; cell cycle analysis of CDH1 levels; APC/C co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — destruction box mutagenesis combined with in vitro Xenopus extract reconstitution and in vivo co-IP; multiple orthogonal methods","pmids":["15029244"],"is_preprint":false},{"year":2005,"finding":"Cdh1-APC (APC/C-Cdh1) is active in postmitotic neurons and required for their survival; Cdh1 depletion by shRNA causes cyclin B1 accumulation, aberrant S-phase entry, and apoptotic death in terminally differentiated neurons, demonstrating that Cdh1 prevents aberrant cell cycle re-entry by keeping cyclin B1 low.","method":"shRNA knockdown of Cdh1 in postmitotic neurons; cyclin B1 immunoblot; BrdU incorporation for S-phase entry; apoptosis assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean shRNA knockdown with defined molecular (cyclin B1) and cellular (S-phase entry, apoptosis) phenotypic readouts; single lab, multiple assays","pmids":["16148219"],"is_preprint":false},{"year":2008,"finding":"In the G2 DNA damage response, Cdc14B phosphatase translocates from the nucleolus to the nucleoplasm and activates APC/C(Cdh1), which then degrades Plk1; this stabilizes Claspin and Wee1 to enforce G2 checkpoint arrest; Claspin is also an APC/C(Cdh1) substrate in G1 and is protected from degradation by deubiquitylase Usp28 in response to G2 damage.","method":"Cdc14B translocation imaging; Plk1 degradation assay after DNA damage; Claspin and Wee1 stability assays; Cdh1 siRNA depletion; G2 checkpoint analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple substrate identification and pathway placement with siRNA, imaging, and checkpoint assays; Cell journal, rigorous multi-component epistasis","pmids":["18662541"],"is_preprint":false},{"year":2009,"finding":"Claspin is a novel Cdh1 substrate; Cdh1 inactivation leads to Claspin accumulation and activation of the Claspin/Chk1 pathway; Cdh1 also competes with E2F1 to bind hypophosphorylated Rb, reciprocally regulating the Rb pathway; acute Cdh1 depletion in primary fibroblasts (with intact p53/Rb) induces premature senescence, while depletion in HeLa cells causes premature S-phase entry.","method":"Affinity purification-mass spectrometry; co-immunoprecipitation of Claspin-Cdh1; siRNA knockdown; Chk1 activation assay; senescence assay; S-phase entry analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS substrate identification plus co-IP, with functional siRNA depletion; single lab, multiple methods","pmids":["19477924"],"is_preprint":false},{"year":2009,"finding":"Cdh1 controls TACC3 protein stability through APC/C; Cdh1 physically interacts with TACC3; Cdh1 depletion prolongs TACC3 levels during mitotic exit; overexpression or knockdown of Cdh1 increases or decreases ubiquitinated TACC3, respectively; multiple domains of TACC3 are involved in Cdh1-regulated degradation.","method":"Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown; ubiquitination assay; domain mapping","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid + co-IP + ubiquitination assay; single lab, multiple orthogonal methods","pmids":["19823035"],"is_preprint":false},{"year":2010,"finding":"Nuclear-localized JNK is degraded by APC/C(Cdh1) during mitotic exit and G1; conversely, JNK phosphorylates Cdh1 during G2 and early mitosis, changing Cdh1 subcellular localization and reducing its ability to activate APC/C during G2/M; expression of non-degradable JNK induces prometaphase-like arrest.","method":"Co-immunoprecipitation; in vitro kinase assay (JNK phosphorylation of Cdh1); non-degradable JNK expression; subcellular localization imaging; APC/C activity assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus co-IP plus functional non-degradable mutant with mitotic arrest phenotype; Nature Cell Biology, multiple orthogonal methods","pmids":["20581839"],"is_preprint":false},{"year":2013,"finding":"APC/C-Cdh1 ubiquitin ligase activity is required for terminal differentiation of cortical neurons and neurogenesis in vivo; Cdh1 knockout in mouse embryos delays cell cycle exit of neural progenitors, causing replicative stress and p53-mediated apoptosis, resulting in reduced cortical neuron number and cortex size.","method":"Embryo-restricted Cdh1 knockout mouse; cortical neuron differentiation assay in vitro; in vivo cortex size measurement; p53 pathway analysis; cell cycle exit assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout mouse with defined molecular mechanism (replicative stress, p53 apoptosis) and quantitative in vivo neurogenesis readout; single lab but rigorous in vivo genetics","pmids":["24301314"],"is_preprint":false},{"year":2014,"finding":"APC/C(Cdh1) controls CtIP stability during the cell cycle and after DNA damage; CtIP interacts with Cdh1 through a conserved KEN box; KEN-box mutation impedes CtIP ubiquitylation and stabilizes CtIP in G1 and after DNA damage in G2; disruption of the CtIP-Cdh1 interaction delays CtIP clearance from damage foci, increases DNA-end resection, and reduces homologous recombination efficiency.","method":"Integrated proteomics; co-immunoprecipitation; KEN-box mutagenesis; ubiquitylation assay; DNA damage foci analysis; HR efficiency assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proteomics identification + co-IP + KEN-box mutagenesis + functional HR assay; EMBO Journal, multiple orthogonal methods in one study","pmids":["25349192"],"is_preprint":false},{"year":2014,"finding":"HMGA2 epigenetically silences the Cdh1 (E-cadherin) gene during EMT by remodeling chromatin to recruit de novo DNA methyltransferase DNMT3A to the Cdh1 promoter, leading to promoter hypermethylation; CDH1 expression can be restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine.","method":"Ectopic HMGA2 expression in NMuMG cells; bisulfite sequencing of Cdh1 promoter; ChIP for DNMT3A binding; 5-aza-2'-deoxycytidine rescue experiment; invasion assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating DNMT3A recruitment, bisulfite sequencing, and pharmacological rescue; single lab, multiple orthogonal methods","pmids":["25492890"],"is_preprint":false},{"year":2016,"finding":"APC/C(Cdh1) inactivation is the commitment (point of no return) for cell-cycle entry; APC/C(Cdh1) inactivation occurs as a rapid, bistable switch shortly before DNA replication, initiated by cyclin E/Cdk2 and made irreversible by Emi1; cells exposed to stress after APC/C(Cdh1) inactivation cannot return to quiescence, while stress before inactivation can revert them.","method":"Single-cell live imaging with APC/C(Cdh1) reporter; cyclin E/Cdk2 perturbation; Emi1 depletion; stress exposure at defined cell cycle stages; flow cytometry","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-cell live imaging reporter with genetic perturbations (Cdk2, Emi1) establishing bistable switch; Cell journal, multiple orthogonal methods","pmids":["27368103"],"is_preprint":false},{"year":2016,"finding":"Cdh1 promotes APC-dependent non-proteolytic monoubiquitination and transcriptional activation of the homeobox transcription factor Goosecoid (Gsc) to regulate craniofacial development; neural crest-specific Cdh1-knockout mice display domed skull, short snout, and twisted nasal bone, with reduced Gsc/Sox6 transcriptional activity.","method":"Neural crest-specific Cdh1 conditional knockout mice; ubiquitination assay of Gsc; gene expression analysis of Gsc targets; phenotypic analysis of craniofacial bones; comparison with Wwp2-deficient mice","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined substrate (Gsc non-proteolytic ubiquitination) and in vivo phenotype; single lab, multiple methods","pmids":["27126000"],"is_preprint":false},{"year":2017,"finding":"APC/C(Cdh1) degrades LATS kinases to regulate Hippo signaling during the cell cycle; CDH1 recognizes LATS kinases and promotes their degradation, causing YAP/TAZ activity to peak in G1; in Drosophila, Cdh1 regulates the LATS homolog Warts through a conserved mechanism, and Cdh1 reduction increases Warts levels and decreases eye/wing size in a Yorkie-dependent manner.","method":"Co-immunoprecipitation of Cdh1-LATS interaction; LATS protein stability assay after CDH1 knockdown/overexpression; YAP/TAZ reporter assay; Drosophila genetic epistasis (Cdh1/Warts/Yorkie); cell cycle synchronization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, stability assays, reporter assays, and Drosophila in vivo epistasis confirming conservation; replicated across species with multiple orthogonal methods","pmids":["31000600"],"is_preprint":false},{"year":2017,"finding":"APC/C(Cdh1)-mediated degradation of Rock2 (Rho kinase 2) maintains dendritic network integrity and memory formation in neurons; postnatal Cdh1 conditional knockout causes Rock2 accumulation, dendritic spine/synapse loss, memory impairment, and neurodegeneration; pharmacological inhibition of Rock activity with fasudil prevents these defects.","method":"Cdh1 conditional knockout mouse (postnatal); Rock2 ubiquitination and stability assay; dendritic morphology analysis; memory tests; fasudil pharmacological rescue; Rock2 accumulation in AD patient brain","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with in vivo substrate validation, pharmacological rescue, and human AD tissue correlation; multiple orthogonal methods","pmids":["28396402"],"is_preprint":false},{"year":2019,"finding":"Cdh1 suppresses c-Src kinase activity in an APC-independent manner; hyperactive c-Src reciprocally inhibits APC(Cdh1) E3 ligase activity by directly phosphorylating Cdh1 at its N-terminus, disrupting interaction between Cdh1 and the APC core complex; pharmacological c-Src inhibition restores APC(Cdh1) tumor suppressor function.","method":"Cdh1 depletion in breast cancer cells; co-immunoprecipitation of Cdh1-APC; in vitro kinase assay (c-Src phosphorylation of Cdh1); APC ubiquitination assay; mouse mammary tumor model with PTEN loss","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay + co-IP + in vivo mouse model; multiple orthogonal methods in one study identifying a reciprocal feedback mechanism","pmids":["31420536"],"is_preprint":false},{"year":2019,"finding":"APC/C-Cdh1 promotes Skp2 ubiquitination and degradation by recognizing Skp2 after dephosphorylation at S72; dioscin attenuates Skp2 S72 phosphorylation, promoting Skp2-Cdh1 interaction and K48-linked polyubiquitination, leading to Skp2 degradation and suppression of glycolysis in colorectal cancer cells.","method":"Co-immunoprecipitation of Skp2-Cdh1; ubiquitination assay (K48 linkage); CRISPR-Cas9 Cdh1 knockout rescue experiment; Skp2 half-life assay; xenograft model","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, CRISPR rescue, in vivo xenograft; single lab, multiple methods","pmids":["31806563"],"is_preprint":false},{"year":2019,"finding":"APC/C-CDH1 targets IDH3β (isocitrate dehydrogenase 3β) for proteasomal degradation during G1; IDH3β overexpression accelerates G1-S transition and promotes cell proliferation in vitro and in vivo partly through α-ketoglutarate production and PFKFB3 upregulation.","method":"Co-immunoprecipitation of CDH1-IDH3β; IDH3β protein stability assay; cell cycle synchronization; proliferation assay; xenograft; α-KG and PFKFB3 metabolic analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + stability assay + functional proliferation/xenograft; single lab, multiple methods","pmids":["31053633"],"is_preprint":false},{"year":2020,"finding":"Cdh1-APC regulates protein synthesis in neurons through an FMRP-dependent mechanism; Cdh1-APC interacts with stress granule proteins including FMRP; inhibition of Cdh1-APC activity increases stress granule formation in a FMRP-dependent manner, proposing that Cdh1-APC targets stress granule proteins to inhibit their formation and promote protein synthesis.","method":"Proteomic profiling of Cdh1-APC interactome; stress granule assay upon Cdh1-APC inhibition; FMRP dependency test using knockdown; co-immunoprecipitation","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP/proteomics with stress granule assay; mechanistic model is proposed but FMRP as direct APC/C-Cdh1 substrate not rigorously demonstrated; single lab, limited functional validation","pmids":["32434143"],"is_preprint":false},{"year":2020,"finding":"In mouse oocytes, a slow-evolving DNA damage response involves APC-Cdh1-mediated proteolysis of cyclin B1 (Cdk1 activator) rather than inhibitory Cdk1 phosphorylation; this pathway requires Cdc14B-dependent APC-Cdh1 activation and is counteracted by Emi1; loss of Senataxin (Setx) causes DNA damage accumulation and APC-Cdh1-dependent G2 arrest in oocytes.","method":"Setx-deleted mouse oocytes; DNA damage induction; cyclin B1 protein level assay; Cdk1 phosphorylation assay; Cdc14B and Emi1 manipulation; G2 arrest assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus pharmacological manipulation with clear mechanistic distinction from canonical DDR; single lab, multiple orthogonal methods","pmids":["32328643"],"is_preprint":false},{"year":2020,"finding":"The Cdh1-FoxM1-Apc axis regulates muscle development and regeneration; Cdh1 (Fzr1) is required for FoxM1 ubiquitylation and degradation in muscle satellite cells; loss of Cdh1 promotes satellite cell cycle entry and pool depletion after serial injuries; haploinsufficiency of FoxM1 ameliorates regeneration defects in Cdh1 knockout mice.","method":"Cdh1 conditional knockout in muscle satellite cells; FoxM1 ubiquitination assay; serial muscle injury model; FoxM1 haploinsufficiency rescue; gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with genetic rescue (FoxM1 haploinsufficiency), ubiquitination assay; single lab, multiple methods","pmids":["32152291"],"is_preprint":false},{"year":2022,"finding":"APC/C CDH1 binds and ubiquitinates STAT3 preferentially during mitosis; inhibition of phosphatases decreases STAT3 ubiquitination, suggesting that dephosphorylated STAT3 is the preferred substrate.","method":"Co-immunoprecipitation of APC/C CDH1-STAT3; ubiquitination assay across cell cycle phases; phosphatase inhibitor experiments in HEK293T cells","journal":"The international journal of biochemistry & cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and ubiquitination assay; single lab, single publication, limited mechanistic follow-up","pmids":["36400381"],"is_preprint":false},{"year":2022,"finding":"Amyloid-β (Aβ25-35) triggers Cdk5-mediated phosphorylation of Cdh1 in neurons, causing Cdh1 disassembly from the APC/C complex, inactivating APC/C-Cdh1, which leads to Rock2 protein stabilization and activation; a phosphodefective Cdh1 mutant prevents Aβ-induced neuronal apoptosis, while a phosphomimetic Cdh1 does not.","method":"Phosphodefective and phosphomimetic Cdh1 mutant expression; co-immunoprecipitation of Cdh1-APC/C; Rock2 stability assay; Cdk5 kinase assay; neuronal apoptosis assay in vitro and in vivo","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomimetic/phosphodefective mutant rescue plus co-IP and in vivo mouse hippocampus; single lab, multiple orthogonal methods","pmids":["35496276"],"is_preprint":false},{"year":2015,"finding":"Casein kinase 1δ (CK1δ) is an APC/C(Cdh1) substrate; conditional deletion of Cdh1 in cerebellar granule cell progenitors results in higher CK1δ levels; APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit, controlling granule cell progenitor expansion vs. differentiation.","method":"Conditional Cdh1 deletion in cerebellar GCPs; CK1δ protein level assay; CK1δ degradation assay by APC/C(Cdh1); GCP proliferation and cell-cycle exit assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with substrate identification; single lab, in vitro and in vivo approaches","pmids":["25843713"],"is_preprint":false}],"current_model":"CDH1/E-cadherin (uvomorulin) is a Ca2+-dependent transmembrane cell adhesion molecule whose extracellular domain mediates homophilic adhesion (requiring correct proteolytic processing of the pro-peptide and intact disulfide bonds in the membrane-proximal region), while its cytoplasmic domain directly recruits beta-catenin and, through it, alpha-catenin (a vinculin homologue) to form the uvomorulin-catenin complex that links E-cadherin to the actin cytoskeleton; this complex is essential for adhesive function, localizes to adherens junctions, and is delivered directly to the basolateral membrane in polarized epithelial cells. Separately, a distinct mammalian protein called CDH1 (also Fzr1/Cdh1) acts as a co-activator of the APC/C E3 ubiquitin ligase, targeting diverse substrates (cyclins, Plk1, CDC6, Claspin, CtIP, Skp2, LATS kinases, Rock2, FoxM1, CK1δ, TACC3, IDH3β, STAT3, JNK, and others) for proteasomal degradation to control mitotic exit, G1 maintenance, the G2 DNA-damage checkpoint, neuronal survival, dendritic integrity, and organ development; Cdh1 itself is regulated by phosphorylation (inhibiting its nuclear import and APC/C binding), auto-degradation via its own destruction boxes, and phosphorylation by JNK and c-Src (which disrupts Cdh1-APC core interaction), while Cdk5-mediated phosphorylation of Cdh1 in neurons disassembles it from APC/C leading to substrate stabilization in the context of amyloid-β toxicity."},"narrative":{"mechanistic_narrative":"The CDH1 timeline describes two distinct, internally coherent proteins that share the symbol: the cell-adhesion molecule E-cadherin/uvomorulin and the APC/C co-activator Cdh1/Fzr1. As an adhesion molecule, uvomorulin/E-cadherin is a Ca2+-dependent transmembrane glycoprotein whose extracellular region is built from internally repeated domains carrying putative Ca2+-binding sites and whose membrane-proximal cysteine cluster contributes a conformational requirement for adhesion [PMID:3501370, PMID:1710917]; it mediates the early adhesion event prerequisite for assembly of the entire epithelial junctional complex and concentrates at the zonula adherens [PMID:3049625, PMID:3880756]. Its cytoplasmic tail recruits the catenins through a discrete ~72-residue domain, with beta-catenin binding directly and alpha-catenin (a vinculin homologue) linking the complex to actin filaments; this catenin association is required for adhesive function [PMID:2788574, PMID:2349235, PMID:1924379]. The protein is synthesized as a 135 kDa precursor processed to the mature 120 kDa form in the late Golgi, and correct pro-peptide cleavage is essential to activate adhesion, while the complex is delivered directly to the basolateral surface of polarized epithelia [PMID:2211831, PMID:1918074, PMID:2335561]. Functionally, E-cadherin-mediated contact inhibits invasive migration, and its gene is epigenetically silenced during EMT via HMGA2-directed DNMT3A recruitment and promoter hypermethylation [PMID:1649199, PMID:25492890]. The unrelated APC/C co-activator Cdh1/Fzr1 confers substrate specificity on the anaphase-promoting complex to drive ubiquitin-mediated proteolysis controlling cell-cycle exit and G1 maintenance, targeting CDC6, cyclin B1, Skp2, and IDH3β, and recognizing substrates through destruction-box and KEN-box motifs [PMID:10995389, PMID:16148219, PMID:31806563, PMID:31053633, PMID:25349192]. Its inactivation—a bistable switch initiated by cyclin E/Cdk2 and locked in by Emi1—marks the irreversible commitment to cell-cycle entry [PMID:27368103]. APC/C(Cdh1) enforces the G2 DNA-damage checkpoint through Cdc14B-dependent degradation of Plk1 and controls DNA-end resection and homologous recombination via CtIP turnover [PMID:18662541, PMID:25349192]. Beyond the cycle it degrades LATS kinases to gate Hippo/YAP signaling, sustains neuronal survival and dendritic integrity by clearing cyclin B1 and Rock2, and governs neurogenesis, cerebellar progenitor expansion, craniofacial development, and muscle satellite-cell maintenance through substrates including CK1δ, FoxM1, and non-proteolytic ubiquitination of Goosecoid [PMID:31000600, PMID:16148219, PMID:28396402, PMID:24301314, PMID:25843713, PMID:32152291, PMID:27126000]. Cdh1 is itself controlled by phosphorylation that blocks its nuclear import and APC core binding, by APC/C-mediated auto-degradation, and by inhibitory phosphorylation from JNK, c-Src, and Cdk5, the last linking its inactivation to Rock2 stabilization in amyloid-β neurotoxicity [PMID:12560341, PMID:15029244, PMID:20581839, PMID:31420536, PMID:35496276].","teleology":[{"year":1987,"claim":"Establishing the domain architecture of uvomorulin was needed to understand how a single transmembrane protein could mediate Ca2+-dependent adhesion; protein sequencing revealed the modular extracellular repeats with Ca2+-binding loops.","evidence":"Protein sequencing and secondary-structure prediction of purified uvomorulin with comparison to L-CAM","pmids":["3501370"],"confidence":"High","gaps":["Ca2+-binding sites inferred from sequence, not structurally resolved","homophilic binding interface not defined"]},{"year":1985,"claim":"Pinpointing which region mediates adhesion was needed; function-blocking antibodies and protease mapping localized adhesive activity to a 26 kDa extracellular fragment and to the zonula adherens.","evidence":"Monoclonal antibody (DECMA-1) blocking of compaction/MDCK adhesion plus proteolytic epitope mapping; immuno-EM localization","pmids":["2419126","3880756"],"confidence":"Medium","gaps":["fragment identity at residue level not defined","single-lab localization"]},{"year":1988,"claim":"Whether adhesion drives broader junction assembly was unresolved; Ca2+-switch blocking showed uvomorulin engagement is prerequisite for assembling all junctional elements.","evidence":"Ca2+ switch assay with blocking antibodies, junction-marker staining, and transepithelial resistance in MDCK cells","pmids":["3049625"],"confidence":"High","gaps":["molecular link between adhesion and tight-junction nucleation not defined"]},{"year":1989,"claim":"How the cytoplasmic tail connects to the cytoskeleton was unknown; co-IP with deletion mutants identified the three catenins as conserved tail-associated partners.","evidence":"Co-immunoprecipitation with cytoplasmic vs extracellular deletion constructs across multiple cell lines","pmids":["2788574"],"confidence":"High","gaps":["direct vs indirect binding of each catenin not yet resolved here"]},{"year":1990,"claim":"Mapping the catenin-binding determinant and testing its functional necessity defined a 72-residue cytoplasmic domain required for adhesion, with beta-catenin binding directly and alpha-catenin linking to actin.","evidence":"Chimeric/deletion constructs in L cells, immunoprecipitation, actin-bundle fractionation, and cell aggregation assays","pmids":["2349235"],"confidence":"High","gaps":["atomic details of catenin-tail contacts not defined"]},{"year":1990,"claim":"Whether the mature protein required correct biosynthetic processing and where it is delivered was unclear; pro-peptide cleavage was shown essential for adhesion and the protein targeted directly to the basolateral surface.","evidence":"Cleavage-site mutagenesis with protease rescue and adhesion assays; domain-selective surface biotinylation in MDCK cells","pmids":["2211831","2335561"],"confidence":"High","gaps":["basolateral targeting signal not mapped","physiological protease identity not defined"]},{"year":1991,"claim":"Defining alpha-catenin's identity and complex assembly clarified the cytoskeletal link and showed catenins associate with multiple cadherins; biosynthesis tracking established complex stoichiometry and assembly order.","evidence":"Cloning of alpha-catenin (vinculin homology), co-IP across cadherins, localization in transfected L cells; pulse-chase stoichiometry; biosynthetic maturation analysis","pmids":["1924379","1734027","1918074"],"confidence":"High","gaps":["regulation of complex assembly timing not fully resolved","glycosylation dispensable but role unclear"]},{"year":1991,"claim":"Whether E-cadherin function extends beyond static adhesion was tested; ectopic expression showed contact-dependent inhibition of invasion, and it was confirmed the principal Ca2+-dependent adhesion molecule of islet cells.","evidence":"Stable transfection of L cells, 3D collagen invasion and wound assays with antibody reversal; Fab-blocking aggregation in islet cells","pmids":["1649199","1936561"],"confidence":"High","gaps":["signaling pathway mediating contact inhibition not defined"]},{"year":1996,"claim":"Whether phosphorylation regulates adhesion during compaction was probed; phosphorylation tracked with compaction but did not directly control adhesive function.","evidence":"Correlative phosphorylation analysis in mouse embryos under compaction-perturbing conditions","pmids":["8722695"],"confidence":"Low","gaps":["correlative only, no causal manipulation","phosphosite and kinase not identified"]},{"year":2000,"claim":"The basis of G1 substrate proteolysis by the APC/C co-activator was unknown; CDH1 was shown to ubiquitinate CDC6 via destruction-box/KEN-box recognition.","evidence":"In vitro ubiquitination, degradation-signal mutagenesis, and in vivo CDH1 depletion","pmids":["10995389"],"confidence":"High","gaps":["full G1 substrate repertoire not yet defined"]},{"year":2003,"claim":"How Cdh1 activity is spatially and temporally restricted was addressed; an NLS drives nuclear import that is blocked by phosphorylation of NLS serines/threonines.","evidence":"GFP-Cdh1 live imaging, phosphomimetic mutants, NLS-fusion targeting, cyclin A correlation","pmids":["12560341"],"confidence":"Medium","gaps":["responsible kinase(s) not identified","single-lab localization"]},{"year":2004,"claim":"How Cdh1 levels themselves are controlled was unresolved; Cdh1 was shown to drive its own APC/C-mediated auto-degradation via RXXL destruction boxes.","evidence":"Destruction-box mutagenesis, Xenopus extract APC/C activation, and cell-cycle level analysis","pmids":["15029244"],"confidence":"High","gaps":["physiological trigger of auto-degradation timing not defined"]},{"year":2005,"claim":"Whether APC/C-Cdh1 has a postmitotic role was unknown; in neurons it keeps cyclin B1 low to prevent aberrant cell-cycle re-entry and apoptosis.","evidence":"shRNA knockdown in postmitotic neurons with cyclin B1, BrdU, and apoptosis readouts","pmids":["16148219"],"confidence":"High","gaps":["additional neuronal substrates not identified here"]},{"year":2008,"claim":"How APC/C-Cdh1 enforces the G2 DNA-damage checkpoint was defined; Cdc14B activates APC/C(Cdh1) to degrade Plk1, stabilizing Claspin and Wee1.","evidence":"Cdc14B translocation imaging, Plk1/Claspin/Wee1 stability assays, Cdh1 siRNA, checkpoint analysis","pmids":["18662541"],"confidence":"High","gaps":["upstream activation of Cdc14B relay not fully resolved"]},{"year":2009,"claim":"Substrate discovery extended the Cdh1 network; Claspin and TACC3 were identified as Cdh1 substrates, and Cdh1 was linked to Rb/E2F regulation and senescence control.","evidence":"AP-MS and yeast two-hybrid substrate identification with co-IP, ubiquitination, siRNA, and senescence/S-phase assays","pmids":["19477924","19823035"],"confidence":"Medium","gaps":["context-dependence of senescence vs S-phase outcomes not reconciled"]},{"year":2010,"claim":"Reciprocal regulation of Cdh1 by mitotic kinases was uncovered; JNK is both an APC/C(Cdh1) substrate and a kinase that phosphorylates Cdh1 to restrain its activity in G2/M.","evidence":"Co-IP, in vitro kinase assay, non-degradable JNK expression with mitotic arrest phenotype","pmids":["20581839"],"confidence":"High","gaps":["phosphosites on Cdh1 not fully mapped"]},{"year":2013,"claim":"The in vivo developmental requirement for Cdh1 was tested; embryonic Cdh1 knockout delays neural progenitor cell-cycle exit, causing replicative stress and p53-driven apoptosis and reduced cortex size.","evidence":"Embryo-restricted Cdh1 knockout mouse with differentiation, cortex-size, and p53-pathway analysis","pmids":["24301314"],"confidence":"High","gaps":["specific substrate driving the neurogenesis defect not isolated"]},{"year":2014,"claim":"Cdh1's role in DNA repair regulation was defined; APC/C(Cdh1) controls CtIP stability through a KEN box, tuning end-resection and homologous recombination.","evidence":"Proteomics, co-IP, KEN-box mutagenesis, damage-foci and HR-efficiency assays","pmids":["25349192"],"confidence":"High","gaps":["balance with other resection regulators not quantified"]},{"year":2015,"claim":"Cdh1 control of cerebellar progenitors was probed; CK1δ was identified as a substrate whose downregulation governs granule progenitor cell-cycle exit.","evidence":"Conditional Cdh1 deletion in cerebellar GCPs with CK1δ level and proliferation assays","pmids":["25843713"],"confidence":"Medium","gaps":["direct ubiquitination kinetics of CK1δ not fully characterized"]},{"year":2016,"claim":"The decision-making logic of cell-cycle entry was clarified; APC/C(Cdh1) inactivation is a bistable, irreversible commitment switch initiated by cyclin E/Cdk2 and locked by Emi1.","evidence":"Single-cell live imaging reporter with Cdk2 and Emi1 perturbations and stress challenges","pmids":["27368103"],"confidence":"High","gaps":["molecular feedback architecture of bistability not fully reconstituted"]},{"year":2016,"claim":"A non-degradative Cdh1 output in development was found; Cdh1 directs APC-dependent monoubiquitination and transcriptional activation of Goosecoid to control craniofacial bone formation.","evidence":"Neural-crest-specific Cdh1 knockout, Gsc ubiquitination and target-gene analysis, craniofacial phenotyping","pmids":["27126000"],"confidence":"Medium","gaps":["how monoubiquitination activates Gsc transcription mechanistically unclear"]},{"year":2017,"claim":"Cdh1 was linked to growth-control signaling and neuronal maintenance; it degrades LATS kinases to time YAP/TAZ activity and degrades Rock2 to preserve dendrites and memory.","evidence":"Co-IP, stability and reporter assays, Drosophila epistasis; conditional Cdh1 KO with Rock2 readouts and fasudil rescue","pmids":["31000600","28396402"],"confidence":"High","gaps":["crosstalk between Hippo and cell-cycle Cdh1 functions not integrated"]},{"year":2019,"claim":"Additional metabolic and oncogenic substrates and an APC-independent function emerged; Cdh1 degrades Skp2 and IDH3β and suppresses c-Src, while c-Src reciprocally phosphorylates Cdh1 to inhibit APC core binding.","evidence":"Co-IP, ubiquitination, CRISPR rescue, half-life, in vitro kinase assay, and xenograft/mouse tumor models","pmids":["31806563","31053633","31420536"],"confidence":"High","gaps":["mechanism of APC-independent c-Src suppression not defined"]},{"year":2020,"claim":"Tissue- and stress-specific Cdh1 functions were extended; Cdh1-FoxM1 controls muscle satellite-cell maintenance, an APC-Cdh1-cyclin B1 route drives a slow oocyte DDR, and Cdh1-APC influences neuronal protein synthesis via stress-granule/FMRP interactions.","evidence":"Conditional KO with FoxM1 rescue; Setx-null oocyte DDR analysis; interactome/stress-granule assays with FMRP knockdown","pmids":["32152291","32328643","32434143"],"confidence":"Medium","gaps":["FMRP as direct Cdh1-APC substrate not rigorously demonstrated","generality of slow oocyte DDR pathway unclear"]},{"year":2022,"claim":"Disease-relevant and mitosis-specific substrate recognition was probed; Cdk5 phosphorylation disassembles Cdh1 from APC/C in amyloid-β toxicity stabilizing Rock2, and dephosphorylated STAT3 is a preferred mitotic substrate.","evidence":"Phosphomutant rescue, co-IP, Rock2 stability and apoptosis assays; cell-cycle-resolved co-IP and ubiquitination with phosphatase inhibition","pmids":["35496276","36400381"],"confidence":"Medium","gaps":["STAT3 finding based on single-lab co-IP/ubiquitination with limited functional follow-up","in vivo relevance of STAT3 turnover not established"]},{"year":null,"claim":"It remains unresolved how the two distinct proteins sharing the CDH1 symbol—E-cadherin adhesion molecule and APC/C co-activator Fzr1/Cdh1—are functionally delineated, and a structural basis for E-cadherin homophilic binding and for Cdh1 substrate-motif selectivity is not established in this corpus.","evidence":"No timeline discovery resolves these questions","pmids":[],"confidence":"Low","gaps":["no structural model of E-cadherin trans-dimer","no unified rule for Cdh1 KEN/D-box substrate selection","symbol collision risk between the two proteins"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,9,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,24,31,19]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[15,24,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,17,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,10,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15,18,26,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[19,24]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,17,24,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[23,27,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[28]}],"complexes":["uvomorulin-catenin complex / adherens junction","APC/C"],"partners":["CTNNB1","CTNNA1","CDC6","PLK1","CTIP","SKP2","LATS","ROCK2"],"other_free_text":[]}},"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 cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species.","date":"1989","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2788574","citation_count":1299,"is_preprint":false},{"pmid":"3049625","id":"PMC_3049625","title":"The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex.","date":"1988","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/3049625","citation_count":748,"is_preprint":false},{"pmid":"2349235","id":"PMC_2349235","title":"Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2349235","citation_count":747,"is_preprint":false},{"pmid":"26182300","id":"PMC_26182300","title":"Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.","date":"2015","source":"JAMA oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26182300","citation_count":523,"is_preprint":false},{"pmid":"9744472","id":"PMC_9744472","title":"Mutations of the human E-cadherin (CDH1) gene.","date":"1998","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/9744472","citation_count":475,"is_preprint":false},{"pmid":"3880756","id":"PMC_3880756","title":"Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells.","date":"1985","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/3880756","citation_count":407,"is_preprint":false},{"pmid":"1924379","id":"PMC_1924379","title":"The uvomorulin-anchorage protein alpha catenin is a vinculin 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cancer.","date":"2007","source":"JAMA","url":"https://pubmed.ncbi.nlm.nih.gov/17545690","citation_count":327,"is_preprint":false},{"pmid":"3501370","id":"PMC_3501370","title":"The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+-dependent cell adhesion.","date":"1987","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3501370","citation_count":291,"is_preprint":false},{"pmid":"10072428","id":"PMC_10072428","title":"Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10072428","citation_count":279,"is_preprint":false},{"pmid":"2419126","id":"PMC_2419126","title":"Identification of a putative cell adhesion domain of uvomorulin.","date":"1985","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2419126","citation_count":247,"is_preprint":false},{"pmid":"3315781","id":"PMC_3315781","title":"Expression and distribution of cell adhesion molecule uvomorulin in mouse preimplantation embryos.","date":"1987","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/3315781","citation_count":239,"is_preprint":false},{"pmid":"10995389","id":"PMC_10995389","title":"Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1.","date":"2000","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10995389","citation_count":231,"is_preprint":false},{"pmid":"1649199","id":"PMC_1649199","title":"Cell-cell contacts mediated by E-cadherin (uvomorulin) restrict invasive behavior of L-cells.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1649199","citation_count":219,"is_preprint":false},{"pmid":"2211831","id":"PMC_2211831","title":"Correct proteolytic cleavage is required for the cell adhesive function of uvomorulin.","date":"1990","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2211831","citation_count":195,"is_preprint":false},{"pmid":"27368103","id":"PMC_27368103","title":"Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27368103","citation_count":194,"is_preprint":false},{"pmid":"1793731","id":"PMC_1793731","title":"Cell adhesion molecule uvomorulin expression in human breast cancer cell lines: relationship to morphology and invasive capacities.","date":"1991","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/1793731","citation_count":193,"is_preprint":false},{"pmid":"1918074","id":"PMC_1918074","title":"Biosynthesis of the cell adhesion molecule uvomorulin (E-cadherin) in Madin-Darby canine kidney epithelial cells.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1918074","citation_count":192,"is_preprint":false},{"pmid":"3902535","id":"PMC_3902535","title":"Cell-adhesion molecule uvomorulin during kidney development.","date":"1985","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/3902535","citation_count":190,"is_preprint":false},{"pmid":"1999432","id":"PMC_1999432","title":"Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (uvomorulin). 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protein group linking uvomorulin to the cytoskeleton.\",\n      \"method\": \"Co-immunoprecipitation with deletion mutants expressed in NIH 3T3, L cells, HeLa, and avian fibroblasts; peptide pattern analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain deletion mutants, replicated across multiple cell lines and species, foundational discovery independently confirmed by multiple subsequent studies\",\n      \"pmids\": [\"2788574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Uvomorulin mediates an early adhesion event that is prerequisite for assembly of all elements of the epithelial junctional complex (zonula adherens, zonula occludens, desmosomes); inhibition with blocking antibodies/Fab fragments prevents junction formation in a Ca2+ switch assay, but established tight junctions are resistant to antibody disruption.\",\n      \"method\": \"Ca2+ switch assay with blocking antibodies and Fab fragments; fluorescence staining for ZO-1, actin (ZA), desmoplakin; transepithelial resistance measurement in MDCK cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal readouts (ZO-1, actin, desmoplakin staining plus electrical resistance), functional blocking antibody approach with clear mechanistic interpretation\",\n      \"pmids\": [\"3049625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Catenin complex formation with uvomorulin is mediated by a specific 72-amino acid domain (encoded largely by a single exon) in the cytoplasmic region; catenin beta binds more directly to this domain while catenin alpha mediates association with actin filaments; catenin binding is required for adhesive function of uvomorulin in cell aggregation assays.\",\n      \"method\": \"Expression of chimeric H-2Kd/uvomorulin constructs and deletion mutants in L cells; immunoprecipitation; cell aggregation assays; biochemical fractionation 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 / Strong — mutagenesis with chimeric constructs, in vitro actin fractionation, functional cell aggregation assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"2349235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The extracellular domain of uvomorulin contains three internally repeated domains of 112 residues (generated by gene duplication), each with two putative Ca2+-binding sites in external loops; the protein also has a single transmembrane region and a cytoplasmic domain, showing 65% identity to chicken L-CAM.\",\n      \"method\": \"Protein sequencing of purified uvomorulin; amino acid sequence analysis and secondary structure prediction; sequence comparison\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct protein sequencing establishing domain architecture; structural inference from primary sequence with comparative analysis\",\n      \"pmids\": [\"3501370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"A 26 kDa extracellular fragment of uvomorulin, generated by protease digestion and recognized by blocking monoclonal antibody DECMA-1, is implicated in the adhesive function; the same fragment is recognized by other function-blocking antibodies that disrupt MDCK monolayers.\",\n      \"method\": \"Monoclonal antibody blocking of embryo compaction and MDCK cell adhesion; protease digestion mapping of antigenic fragment; immunoreactivity comparison across blocking antibodies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody blocking with epitope mapping by proteolysis; single lab but convergent evidence from multiple blocking antibodies identifying same fragment\",\n      \"pmids\": [\"2419126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Uvomorulin localizes to the intermediate junctions (zonula adherens) of adult intestinal epithelial cells, as demonstrated by electron microscopic immunolocalization.\",\n      \"method\": \"Electron microscopy with immunolabeling of adult intestinal epithelial cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electron microscopic localization establishing precise subcellular compartment; single lab\",\n      \"pmids\": [\"3880756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Alpha-catenin is a vinculin homologue and complexes with multiple cadherins (uvomorulin/E-cadherin, N-cadherin, P-cadherin, A-CAM, U-cadherin); in cadherin-negative L cells, alpha-catenin is diffusely cytoplasmic but concentrates at membrane contacts upon uvomorulin expression, suggesting it mediates cytoskeletal anchorage downstream of cadherin engagement.\",\n      \"method\": \"Immunoprecipitation with anti-alpha-catenin antibodies; molecular cloning and sequence analysis; immunofluorescence in cadherin-negative and uvomorulin-transfected L cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — molecular cloning of alpha-catenin revealing vinculin homology, co-IP across multiple cadherins, live-cell localization showing redistribution upon cadherin expression; multiple orthogonal methods\",\n      \"pmids\": [\"1924379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The uvomorulin-catenin complex is composed of one molecule of uvomorulin, one or two molecules of beta-catenin, and one molecule of alpha-catenin; beta-catenin associates with the uvomorulin precursor (135 kDa) early in biosynthesis whereas alpha-catenin joins the complex later, around the time of endoproteolytic processing.\",\n      \"method\": \"Biochemical analysis of immunoprecipitated complexes; pulse-chase experiments; stoichiometry analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — pulse-chase biochemistry with stoichiometric analysis establishing assembly order and complex composition; multiple orthogonal methods in one study\",\n      \"pmids\": [\"1734027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Correct proteolytic processing of the uvomorulin precursor segment is required for its cell adhesive function; unprocessed uvomorulin that reaches the cell surface forms catenin complexes and is Ca2+-protected but is non-functional in cell adhesion assays; cleavage at the correct site activates adhesion while cleavage at incorrect sites does not, indicating the amino-terminal region of mature uvomorulin is important for adhesion.\",\n      \"method\": \"Site-directed mutagenesis of protease recognition sites; expression of mutant polypeptides in L cells; cell adhesion assays; treatment with specific proteases (factor Xa, trypsin)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-type experiment with specific mutagenesis of cleavage site and rescue by correct protease; clear functional readout; single lab but rigorous design\",\n      \"pmids\": [\"2211831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"E-cadherin (uvomorulin)-mediated cell-cell contacts inhibit invasive migration of L cells into collagen gels in a cell density-dependent manner, establishing E-cadherin as a contact inhibitor of invasion; single cells expressing E-cadherin show normal invasiveness, indicating the effect requires cell-cell contact.\",\n      \"method\": \"Stable transfection of L cells with E-cadherin cDNA; 3D collagen gel invasion assay; blocking antibody reversal experiment; time-lapse videoscopy; wound closure assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function antibody rescue, stable transfection, multiple invasion assays with clear mechanistic interpretation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"1649199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Uvomorulin is synthesized as a 135 kDa precursor glycosylated in the endoplasmic reticulum, processed to the mature 120 kDa form in the late Golgi prior to cell surface delivery; glycosylation is not required for processing or surface transport; surface uvomorulin has a t½ of ~5 h and becomes Triton X-100 insoluble and concentrates at cell contacts upon Ca2+-dependent adhesion.\",\n      \"method\": \"Pulse-chase biosynthetic labeling; domain-selective biotinylation; Triton X-100 fractionation in MDCK cells; tunicamycin inhibition of glycosylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — detailed pulse-chase biochemistry with multiple inhibitors and fractionation approaches; rigorous biosynthetic study with functional correlate\",\n      \"pmids\": [\"1918074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Uvomorulin is delivered directly to the basolateral surface of MDCK cells with only 2% mistargeting to the apical domain, establishing its direct basolateral targeting in polarized epithelial cells.\",\n      \"method\": \"Pulse-chase combined with domain-selective cell-surface biotinylation and streptavidin-agarose precipitation in MDCK cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical surface biotinylation approach with quantitative measurement of mistargeting; single lab\",\n      \"pmids\": [\"2335561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The membrane-proximal region of uvomorulin, containing a cluster of cysteine residues, is involved in the adhesive mechanism; reduction of disulfide bonds by DTT blocks close cell-cell contacts and cell flattening (but not aggregation) and increases trypsin susceptibility of this region, indicating a conformational contribution to adhesion.\",\n      \"method\": \"DTT treatment of cells; cell adhesion assays; trypsin sensitivity assay of membrane-proximal domain; epitope mapping of DECMA-1\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical perturbation with functional adhesion assays and structural correlate (protease sensitivity); single lab, multiple methods\",\n      \"pmids\": [\"1710917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Uvomorulin is the dominant functional cadherin on pancreatic islet cells mediating Ca2+-dependent aggregation; anti-uvomorulin Fab fragments block B-cell aggregation to the same extent as EDTA (Ca2+ chelation), confirming its role as the principal Ca2+-dependent adhesion molecule in islets.\",\n      \"method\": \"Anti-uvomorulin Fab fragment blocking of islet cell aggregation; flow cytometry; sorting of B- and non-B-cells; mild trypsin/Ca2+ digestion to remove Ca2+-independent CAMs\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Fab blocking with quantitative aggregation assay and comparison to EDTA control; single lab, multiple cell types tested\",\n      \"pmids\": [\"1936561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Uvomorulin is phosphorylated at the 8-cell stage during compaction; prevention of compaction by prolonged low Ca2+ exposure reduces the level of uvomorulin phosphorylation and perturbs its localization to cell-cell contacts, though phosphorylation does not appear to directly regulate adhesive function.\",\n      \"method\": \"Phosphorylation analysis in mouse embryos under conditions preventing, reversing, or inducing compaction; immunolocalization\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative phosphorylation analysis in embryos with pharmacological manipulation; finding is partially negative (phosphorylation not directly regulating adhesion)\",\n      \"pmids\": [\"8722695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CDC6 is targeted for ubiquitin-mediated proteolysis by APC/C in complex with CDH1 (APC-CDH1) during G1; CDH1 ubiquitinates CDC6 in vitro; destruction box and KEN-box mutations in CDC6 stabilize it in G1 and quiescent cells; both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo.\",\n      \"method\": \"In vitro ubiquitination assay with APC-CDH1; point mutagenesis of destruction box and KEN-box; in vivo proteolysis assay with CDH1 depletion; cell cycle analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution plus mutagenesis of degradation signals plus in vivo depletion; multiple orthogonal methods in one study\",\n      \"pmids\": [\"10995389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDH1 (APC/C coactivator) localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase; nuclear accumulation correlates with reduction of cyclin A; a nuclear localization signal (NLS) in CDH1 drives nuclear import; phosphorylation of serine/threonine residues in the NLS inhibits nuclear import, keeping hyperphosphorylated CDH1 in the cytoplasm.\",\n      \"method\": \"GFP-CDH1 live-cell imaging; CDH1-4D phosphomimetic mutant localization; NLS-GFP fusion targeting assay; cyclin A immunostaining correlation; cell cycle staging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell localization with phosphomimetic and phosphodefective mutants; GFP fusion NLS mapping; single lab, multiple methods\",\n      \"pmids\": [\"12560341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian CDH1 (Fzr) undergoes APC/C-mediated auto-degradation during G1 and G0 via two RXXL-type destruction boxes; CDH1 activates APC/C to degrade itself; destruction-box mutations stabilize CDH1 in G1/G0.\",\n      \"method\": \"Mutation of destruction boxes in CDH1; Xenopus interphase extract APC/C activation assay; cell cycle analysis of CDH1 levels; APC/C co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — destruction box mutagenesis combined with in vitro Xenopus extract reconstitution and in vivo co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"15029244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdh1-APC (APC/C-Cdh1) is active in postmitotic neurons and required for their survival; Cdh1 depletion by shRNA causes cyclin B1 accumulation, aberrant S-phase entry, and apoptotic death in terminally differentiated neurons, demonstrating that Cdh1 prevents aberrant cell cycle re-entry by keeping cyclin B1 low.\",\n      \"method\": \"shRNA knockdown of Cdh1 in postmitotic neurons; cyclin B1 immunoblot; BrdU incorporation for S-phase entry; apoptosis assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean shRNA knockdown with defined molecular (cyclin B1) and cellular (S-phase entry, apoptosis) phenotypic readouts; single lab, multiple assays\",\n      \"pmids\": [\"16148219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In the G2 DNA damage response, Cdc14B phosphatase translocates from the nucleolus to the nucleoplasm and activates APC/C(Cdh1), which then degrades Plk1; this stabilizes Claspin and Wee1 to enforce G2 checkpoint arrest; Claspin is also an APC/C(Cdh1) substrate in G1 and is protected from degradation by deubiquitylase Usp28 in response to G2 damage.\",\n      \"method\": \"Cdc14B translocation imaging; Plk1 degradation assay after DNA damage; Claspin and Wee1 stability assays; Cdh1 siRNA depletion; G2 checkpoint analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple substrate identification and pathway placement with siRNA, imaging, and checkpoint assays; Cell journal, rigorous multi-component epistasis\",\n      \"pmids\": [\"18662541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Claspin is a novel Cdh1 substrate; Cdh1 inactivation leads to Claspin accumulation and activation of the Claspin/Chk1 pathway; Cdh1 also competes with E2F1 to bind hypophosphorylated Rb, reciprocally regulating the Rb pathway; acute Cdh1 depletion in primary fibroblasts (with intact p53/Rb) induces premature senescence, while depletion in HeLa cells causes premature S-phase entry.\",\n      \"method\": \"Affinity purification-mass spectrometry; co-immunoprecipitation of Claspin-Cdh1; siRNA knockdown; Chk1 activation assay; senescence assay; S-phase entry analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS substrate identification plus co-IP, with functional siRNA depletion; single lab, multiple methods\",\n      \"pmids\": [\"19477924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdh1 controls TACC3 protein stability through APC/C; Cdh1 physically interacts with TACC3; Cdh1 depletion prolongs TACC3 levels during mitotic exit; overexpression or knockdown of Cdh1 increases or decreases ubiquitinated TACC3, respectively; multiple domains of TACC3 are involved in Cdh1-regulated degradation.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown; ubiquitination assay; domain mapping\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid + co-IP + ubiquitination assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19823035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nuclear-localized JNK is degraded by APC/C(Cdh1) during mitotic exit and G1; conversely, JNK phosphorylates Cdh1 during G2 and early mitosis, changing Cdh1 subcellular localization and reducing its ability to activate APC/C during G2/M; expression of non-degradable JNK induces prometaphase-like arrest.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay (JNK phosphorylation of Cdh1); non-degradable JNK expression; subcellular localization imaging; APC/C activity assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus co-IP plus functional non-degradable mutant with mitotic arrest phenotype; Nature Cell Biology, multiple orthogonal methods\",\n      \"pmids\": [\"20581839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APC/C-Cdh1 ubiquitin ligase activity is required for terminal differentiation of cortical neurons and neurogenesis in vivo; Cdh1 knockout in mouse embryos delays cell cycle exit of neural progenitors, causing replicative stress and p53-mediated apoptosis, resulting in reduced cortical neuron number and cortex size.\",\n      \"method\": \"Embryo-restricted Cdh1 knockout mouse; cortical neuron differentiation assay in vitro; in vivo cortex size measurement; p53 pathway analysis; cell cycle exit assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mouse with defined molecular mechanism (replicative stress, p53 apoptosis) and quantitative in vivo neurogenesis readout; single lab but rigorous in vivo genetics\",\n      \"pmids\": [\"24301314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APC/C(Cdh1) controls CtIP stability during the cell cycle and after DNA damage; CtIP interacts with Cdh1 through a conserved KEN box; KEN-box mutation impedes CtIP ubiquitylation and stabilizes CtIP in G1 and after DNA damage in G2; disruption of the CtIP-Cdh1 interaction delays CtIP clearance from damage foci, increases DNA-end resection, and reduces homologous recombination efficiency.\",\n      \"method\": \"Integrated proteomics; co-immunoprecipitation; KEN-box mutagenesis; ubiquitylation assay; DNA damage foci analysis; HR efficiency assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proteomics identification + co-IP + KEN-box mutagenesis + functional HR assay; EMBO Journal, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25349192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGA2 epigenetically silences the Cdh1 (E-cadherin) gene during EMT by remodeling chromatin to recruit de novo DNA methyltransferase DNMT3A to the Cdh1 promoter, leading to promoter hypermethylation; CDH1 expression can be restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine.\",\n      \"method\": \"Ectopic HMGA2 expression in NMuMG cells; bisulfite sequencing of Cdh1 promoter; ChIP for DNMT3A binding; 5-aza-2'-deoxycytidine rescue experiment; invasion assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating DNMT3A recruitment, bisulfite sequencing, and pharmacological rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25492890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APC/C(Cdh1) inactivation is the commitment (point of no return) for cell-cycle entry; APC/C(Cdh1) inactivation occurs as a rapid, bistable switch shortly before DNA replication, initiated by cyclin E/Cdk2 and made irreversible by Emi1; cells exposed to stress after APC/C(Cdh1) inactivation cannot return to quiescence, while stress before inactivation can revert them.\",\n      \"method\": \"Single-cell live imaging with APC/C(Cdh1) reporter; cyclin E/Cdk2 perturbation; Emi1 depletion; stress exposure at defined cell cycle stages; flow cytometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell live imaging reporter with genetic perturbations (Cdk2, Emi1) establishing bistable switch; Cell journal, multiple orthogonal methods\",\n      \"pmids\": [\"27368103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdh1 promotes APC-dependent non-proteolytic monoubiquitination and transcriptional activation of the homeobox transcription factor Goosecoid (Gsc) to regulate craniofacial development; neural crest-specific Cdh1-knockout mice display domed skull, short snout, and twisted nasal bone, with reduced Gsc/Sox6 transcriptional activity.\",\n      \"method\": \"Neural crest-specific Cdh1 conditional knockout mice; ubiquitination assay of Gsc; gene expression analysis of Gsc targets; phenotypic analysis of craniofacial bones; comparison with Wwp2-deficient mice\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined substrate (Gsc non-proteolytic ubiquitination) and in vivo phenotype; single lab, multiple methods\",\n      \"pmids\": [\"27126000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APC/C(Cdh1) degrades LATS kinases to regulate Hippo signaling during the cell cycle; CDH1 recognizes LATS kinases and promotes their degradation, causing YAP/TAZ activity to peak in G1; in Drosophila, Cdh1 regulates the LATS homolog Warts through a conserved mechanism, and Cdh1 reduction increases Warts levels and decreases eye/wing size in a Yorkie-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation of Cdh1-LATS interaction; LATS protein stability assay after CDH1 knockdown/overexpression; YAP/TAZ reporter assay; Drosophila genetic epistasis (Cdh1/Warts/Yorkie); cell cycle synchronization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, stability assays, reporter assays, and Drosophila in vivo epistasis confirming conservation; replicated across species with multiple orthogonal methods\",\n      \"pmids\": [\"31000600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APC/C(Cdh1)-mediated degradation of Rock2 (Rho kinase 2) maintains dendritic network integrity and memory formation in neurons; postnatal Cdh1 conditional knockout causes Rock2 accumulation, dendritic spine/synapse loss, memory impairment, and neurodegeneration; pharmacological inhibition of Rock activity with fasudil prevents these defects.\",\n      \"method\": \"Cdh1 conditional knockout mouse (postnatal); Rock2 ubiquitination and stability assay; dendritic morphology analysis; memory tests; fasudil pharmacological rescue; Rock2 accumulation in AD patient brain\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with in vivo substrate validation, pharmacological rescue, and human AD tissue correlation; multiple orthogonal methods\",\n      \"pmids\": [\"28396402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cdh1 suppresses c-Src kinase activity in an APC-independent manner; hyperactive c-Src reciprocally inhibits APC(Cdh1) E3 ligase activity by directly phosphorylating Cdh1 at its N-terminus, disrupting interaction between Cdh1 and the APC core complex; pharmacological c-Src inhibition restores APC(Cdh1) tumor suppressor function.\",\n      \"method\": \"Cdh1 depletion in breast cancer cells; co-immunoprecipitation of Cdh1-APC; in vitro kinase assay (c-Src phosphorylation of Cdh1); APC ubiquitination assay; mouse mammary tumor model with PTEN loss\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay + co-IP + in vivo mouse model; multiple orthogonal methods in one study identifying a reciprocal feedback mechanism\",\n      \"pmids\": [\"31420536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APC/C-Cdh1 promotes Skp2 ubiquitination and degradation by recognizing Skp2 after dephosphorylation at S72; dioscin attenuates Skp2 S72 phosphorylation, promoting Skp2-Cdh1 interaction and K48-linked polyubiquitination, leading to Skp2 degradation and suppression of glycolysis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of Skp2-Cdh1; ubiquitination assay (K48 linkage); CRISPR-Cas9 Cdh1 knockout rescue experiment; Skp2 half-life assay; xenograft model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, CRISPR rescue, in vivo xenograft; single lab, multiple methods\",\n      \"pmids\": [\"31806563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APC/C-CDH1 targets IDH3β (isocitrate dehydrogenase 3β) for proteasomal degradation during G1; IDH3β overexpression accelerates G1-S transition and promotes cell proliferation in vitro and in vivo partly through α-ketoglutarate production and PFKFB3 upregulation.\",\n      \"method\": \"Co-immunoprecipitation of CDH1-IDH3β; IDH3β protein stability assay; cell cycle synchronization; proliferation assay; xenograft; α-KG and PFKFB3 metabolic analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + stability assay + functional proliferation/xenograft; single lab, multiple methods\",\n      \"pmids\": [\"31053633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cdh1-APC regulates protein synthesis in neurons through an FMRP-dependent mechanism; Cdh1-APC interacts with stress granule proteins including FMRP; inhibition of Cdh1-APC activity increases stress granule formation in a FMRP-dependent manner, proposing that Cdh1-APC targets stress granule proteins to inhibit their formation and promote protein synthesis.\",\n      \"method\": \"Proteomic profiling of Cdh1-APC interactome; stress granule assay upon Cdh1-APC inhibition; FMRP dependency test using knockdown; co-immunoprecipitation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP/proteomics with stress granule assay; mechanistic model is proposed but FMRP as direct APC/C-Cdh1 substrate not rigorously demonstrated; single lab, limited functional validation\",\n      \"pmids\": [\"32434143\"],\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 (Cdk1 activator) rather than inhibitory Cdk1 phosphorylation; this pathway requires Cdc14B-dependent APC-Cdh1 activation and is counteracted by Emi1; loss of Senataxin (Setx) causes DNA damage accumulation and APC-Cdh1-dependent G2 arrest in oocytes.\",\n      \"method\": \"Setx-deleted mouse oocytes; DNA damage induction; cyclin B1 protein level assay; Cdk1 phosphorylation assay; Cdc14B and Emi1 manipulation; G2 arrest assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus pharmacological manipulation with clear mechanistic distinction from canonical DDR; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32328643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Cdh1-FoxM1-Apc axis regulates muscle development and regeneration; Cdh1 (Fzr1) is required for FoxM1 ubiquitylation and degradation in muscle satellite cells; loss of Cdh1 promotes satellite cell cycle entry and pool depletion after serial injuries; haploinsufficiency of FoxM1 ameliorates regeneration defects in Cdh1 knockout mice.\",\n      \"method\": \"Cdh1 conditional knockout in muscle satellite cells; FoxM1 ubiquitination assay; serial muscle injury model; FoxM1 haploinsufficiency rescue; gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with genetic rescue (FoxM1 haploinsufficiency), ubiquitination assay; single lab, multiple methods\",\n      \"pmids\": [\"32152291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"APC/C CDH1 binds and ubiquitinates STAT3 preferentially during mitosis; inhibition of phosphatases decreases STAT3 ubiquitination, suggesting that dephosphorylated STAT3 is the preferred substrate.\",\n      \"method\": \"Co-immunoprecipitation of APC/C CDH1-STAT3; ubiquitination assay across cell cycle phases; phosphatase inhibitor experiments in HEK293T cells\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and ubiquitination assay; single lab, single publication, limited mechanistic follow-up\",\n      \"pmids\": [\"36400381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Amyloid-β (Aβ25-35) triggers Cdk5-mediated phosphorylation of Cdh1 in neurons, causing Cdh1 disassembly from the APC/C complex, inactivating APC/C-Cdh1, which leads to Rock2 protein stabilization and activation; a phosphodefective Cdh1 mutant prevents Aβ-induced neuronal apoptosis, while a phosphomimetic Cdh1 does not.\",\n      \"method\": \"Phosphodefective and phosphomimetic Cdh1 mutant expression; co-immunoprecipitation of Cdh1-APC/C; Rock2 stability assay; Cdk5 kinase assay; neuronal apoptosis assay in vitro and in vivo\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomimetic/phosphodefective mutant rescue plus co-IP and in vivo mouse hippocampus; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35496276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Casein kinase 1δ (CK1δ) is an APC/C(Cdh1) substrate; conditional deletion of Cdh1 in cerebellar granule cell progenitors results in higher CK1δ levels; APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit, controlling granule cell progenitor expansion vs. differentiation.\",\n      \"method\": \"Conditional Cdh1 deletion in cerebellar GCPs; CK1δ protein level assay; CK1δ degradation assay by APC/C(Cdh1); GCP proliferation and cell-cycle exit assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with substrate identification; single lab, in vitro and in vivo approaches\",\n      \"pmids\": [\"25843713\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH1/E-cadherin (uvomorulin) is a Ca2+-dependent transmembrane cell adhesion molecule whose extracellular domain mediates homophilic adhesion (requiring correct proteolytic processing of the pro-peptide and intact disulfide bonds in the membrane-proximal region), while its cytoplasmic domain directly recruits beta-catenin and, through it, alpha-catenin (a vinculin homologue) to form the uvomorulin-catenin complex that links E-cadherin to the actin cytoskeleton; this complex is essential for adhesive function, localizes to adherens junctions, and is delivered directly to the basolateral membrane in polarized epithelial cells. Separately, a distinct mammalian protein called CDH1 (also Fzr1/Cdh1) acts as a co-activator of the APC/C E3 ubiquitin ligase, targeting diverse substrates (cyclins, Plk1, CDC6, Claspin, CtIP, Skp2, LATS kinases, Rock2, FoxM1, CK1δ, TACC3, IDH3β, STAT3, JNK, and others) for proteasomal degradation to control mitotic exit, G1 maintenance, the G2 DNA-damage checkpoint, neuronal survival, dendritic integrity, and organ development; Cdh1 itself is regulated by phosphorylation (inhibiting its nuclear import and APC/C binding), auto-degradation via its own destruction boxes, and phosphorylation by JNK and c-Src (which disrupts Cdh1-APC core interaction), while Cdk5-mediated phosphorylation of Cdh1 in neurons disassembles it from APC/C leading to substrate stabilization in the context of amyloid-β toxicity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The CDH1 timeline describes two distinct, internally coherent proteins that share the symbol: the cell-adhesion molecule E-cadherin/uvomorulin and the APC/C co-activator Cdh1/Fzr1. As an adhesion molecule, uvomorulin/E-cadherin is a Ca2+-dependent transmembrane glycoprotein whose extracellular region is built from internally repeated domains carrying putative Ca2+-binding sites and whose membrane-proximal cysteine cluster contributes a conformational requirement for adhesion [#3, #12]; it mediates the early adhesion event prerequisite for assembly of the entire epithelial junctional complex and concentrates at the zonula adherens [#1, #5]. Its cytoplasmic tail recruits the catenins through a discrete ~72-residue domain, with beta-catenin binding directly and alpha-catenin (a vinculin homologue) linking the complex to actin filaments; this catenin association is required for adhesive function [#0, #2, #6]. The protein is synthesized as a 135 kDa precursor processed to the mature 120 kDa form in the late Golgi, and correct pro-peptide cleavage is essential to activate adhesion, while the complex is delivered directly to the basolateral surface of polarized epithelia [#8, #10, #11]. Functionally, E-cadherin-mediated contact inhibits invasive migration, and its gene is epigenetically silenced during EMT via HMGA2-directed DNMT3A recruitment and promoter hypermethylation [#9, #25]. The unrelated APC/C co-activator Cdh1/Fzr1 confers substrate specificity on the anaphase-promoting complex to drive ubiquitin-mediated proteolysis controlling cell-cycle exit and G1 maintenance, targeting CDC6, cyclin B1, Skp2, and IDH3\\u03b2, and recognizing substrates through destruction-box and KEN-box motifs [#15, #18, #31, #32, #24]. Its inactivation\\u2014a bistable switch initiated by cyclin E/Cdk2 and locked in by Emi1\\u2014marks the irreversible commitment to cell-cycle entry [#26]. APC/C(Cdh1) enforces the G2 DNA-damage checkpoint through Cdc14B-dependent degradation of Plk1 and controls DNA-end resection and homologous recombination via CtIP turnover [#19, #24]. Beyond the cycle it degrades LATS kinases to gate Hippo/YAP signaling, sustains neuronal survival and dendritic integrity by clearing cyclin B1 and Rock2, and governs neurogenesis, cerebellar progenitor expansion, craniofacial development, and muscle satellite-cell maintenance through substrates including CK1\\u03b4, FoxM1, and non-proteolytic ubiquitination of Goosecoid [#28, #18, #29, #23, #38, #35, #27]. Cdh1 is itself controlled by phosphorylation that blocks its nuclear import and APC core binding, by APC/C-mediated auto-degradation, and by inhibitory phosphorylation from JNK, c-Src, and Cdk5, the last linking its inactivation to Rock2 stabilization in amyloid-\\u03b2 neurotoxicity [#16, #17, #22, #30, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing the domain architecture of uvomorulin was needed to understand how a single transmembrane protein could mediate Ca2+-dependent adhesion; protein sequencing revealed the modular extracellular repeats with Ca2+-binding loops.\",\n      \"evidence\": \"Protein sequencing and secondary-structure prediction of purified uvomorulin with comparison to L-CAM\",\n      \"pmids\": [\"3501370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ca2+-binding sites inferred from sequence, not structurally resolved\", \"homophilic binding interface not defined\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Pinpointing which region mediates adhesion was needed; function-blocking antibodies and protease mapping localized adhesive activity to a 26 kDa extracellular fragment and to the zonula adherens.\",\n      \"evidence\": \"Monoclonal antibody (DECMA-1) blocking of compaction/MDCK adhesion plus proteolytic epitope mapping; immuno-EM localization\",\n      \"pmids\": [\"2419126\", \"3880756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"fragment identity at residue level not defined\", \"single-lab localization\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Whether adhesion drives broader junction assembly was unresolved; Ca2+-switch blocking showed uvomorulin engagement is prerequisite for assembling all junctional elements.\",\n      \"evidence\": \"Ca2+ switch assay with blocking antibodies, junction-marker staining, and transepithelial resistance in MDCK cells\",\n      \"pmids\": [\"3049625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular link between adhesion and tight-junction nucleation not defined\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"How the cytoplasmic tail connects to the cytoskeleton was unknown; co-IP with deletion mutants identified the three catenins as conserved tail-associated partners.\",\n      \"evidence\": \"Co-immunoprecipitation with cytoplasmic vs extracellular deletion constructs across multiple cell lines\",\n      \"pmids\": [\"2788574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct vs indirect binding of each catenin not yet resolved here\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Mapping the catenin-binding determinant and testing its functional necessity defined a 72-residue cytoplasmic domain required for adhesion, with beta-catenin binding directly and alpha-catenin linking to actin.\",\n      \"evidence\": \"Chimeric/deletion constructs in L cells, immunoprecipitation, actin-bundle fractionation, and cell aggregation assays\",\n      \"pmids\": [\"2349235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"atomic details of catenin-tail contacts not defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Whether the mature protein required correct biosynthetic processing and where it is delivered was unclear; pro-peptide cleavage was shown essential for adhesion and the protein targeted directly to the basolateral surface.\",\n      \"evidence\": \"Cleavage-site mutagenesis with protease rescue and adhesion assays; domain-selective surface biotinylation in MDCK cells\",\n      \"pmids\": [\"2211831\", \"2335561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"basolateral targeting signal not mapped\", \"physiological protease identity not defined\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defining alpha-catenin's identity and complex assembly clarified the cytoskeletal link and showed catenins associate with multiple cadherins; biosynthesis tracking established complex stoichiometry and assembly order.\",\n      \"evidence\": \"Cloning of alpha-catenin (vinculin homology), co-IP across cadherins, localization in transfected L cells; pulse-chase stoichiometry; biosynthetic maturation analysis\",\n      \"pmids\": [\"1924379\", \"1734027\", \"1918074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"regulation of complex assembly timing not fully resolved\", \"glycosylation dispensable but role unclear\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Whether E-cadherin function extends beyond static adhesion was tested; ectopic expression showed contact-dependent inhibition of invasion, and it was confirmed the principal Ca2+-dependent adhesion molecule of islet cells.\",\n      \"evidence\": \"Stable transfection of L cells, 3D collagen invasion and wound assays with antibody reversal; Fab-blocking aggregation in islet cells\",\n      \"pmids\": [\"1649199\", \"1936561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signaling pathway mediating contact inhibition not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Whether phosphorylation regulates adhesion during compaction was probed; phosphorylation tracked with compaction but did not directly control adhesive function.\",\n      \"evidence\": \"Correlative phosphorylation analysis in mouse embryos under compaction-perturbing conditions\",\n      \"pmids\": [\"8722695\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"correlative only, no causal manipulation\", \"phosphosite and kinase not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The basis of G1 substrate proteolysis by the APC/C co-activator was unknown; CDH1 was shown to ubiquitinate CDC6 via destruction-box/KEN-box recognition.\",\n      \"evidence\": \"In vitro ubiquitination, degradation-signal mutagenesis, and in vivo CDH1 depletion\",\n      \"pmids\": [\"10995389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full G1 substrate repertoire not yet defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"How Cdh1 activity is spatially and temporally restricted was addressed; an NLS drives nuclear import that is blocked by phosphorylation of NLS serines/threonines.\",\n      \"evidence\": \"GFP-Cdh1 live imaging, phosphomimetic mutants, NLS-fusion targeting, cyclin A correlation\",\n      \"pmids\": [\"12560341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"responsible kinase(s) not identified\", \"single-lab localization\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"How Cdh1 levels themselves are controlled was unresolved; Cdh1 was shown to drive its own APC/C-mediated auto-degradation via RXXL destruction boxes.\",\n      \"evidence\": \"Destruction-box mutagenesis, Xenopus extract APC/C activation, and cell-cycle level analysis\",\n      \"pmids\": [\"15029244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological trigger of auto-degradation timing not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Whether APC/C-Cdh1 has a postmitotic role was unknown; in neurons it keeps cyclin B1 low to prevent aberrant cell-cycle re-entry and apoptosis.\",\n      \"evidence\": \"shRNA knockdown in postmitotic neurons with cyclin B1, BrdU, and apoptosis readouts\",\n      \"pmids\": [\"16148219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"additional neuronal substrates not identified here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How APC/C-Cdh1 enforces the G2 DNA-damage checkpoint was defined; Cdc14B activates APC/C(Cdh1) to degrade Plk1, stabilizing Claspin and Wee1.\",\n      \"evidence\": \"Cdc14B translocation imaging, Plk1/Claspin/Wee1 stability assays, Cdh1 siRNA, checkpoint analysis\",\n      \"pmids\": [\"18662541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"upstream activation of Cdc14B relay not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Substrate discovery extended the Cdh1 network; Claspin and TACC3 were identified as Cdh1 substrates, and Cdh1 was linked to Rb/E2F regulation and senescence control.\",\n      \"evidence\": \"AP-MS and yeast two-hybrid substrate identification with co-IP, ubiquitination, siRNA, and senescence/S-phase assays\",\n      \"pmids\": [\"19477924\", \"19823035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"context-dependence of senescence vs S-phase outcomes not reconciled\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reciprocal regulation of Cdh1 by mitotic kinases was uncovered; JNK is both an APC/C(Cdh1) substrate and a kinase that phosphorylates Cdh1 to restrain its activity in G2/M.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, non-degradable JNK expression with mitotic arrest phenotype\",\n      \"pmids\": [\"20581839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"phosphosites on Cdh1 not fully mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The in vivo developmental requirement for Cdh1 was tested; embryonic Cdh1 knockout delays neural progenitor cell-cycle exit, causing replicative stress and p53-driven apoptosis and reduced cortex size.\",\n      \"evidence\": \"Embryo-restricted Cdh1 knockout mouse with differentiation, cortex-size, and p53-pathway analysis\",\n      \"pmids\": [\"24301314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"specific substrate driving the neurogenesis defect not isolated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cdh1's role in DNA repair regulation was defined; APC/C(Cdh1) controls CtIP stability through a KEN box, tuning end-resection and homologous recombination.\",\n      \"evidence\": \"Proteomics, co-IP, KEN-box mutagenesis, damage-foci and HR-efficiency assays\",\n      \"pmids\": [\"25349192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"balance with other resection regulators not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Cdh1 control of cerebellar progenitors was probed; CK1\\u03b4 was identified as a substrate whose downregulation governs granule progenitor cell-cycle exit.\",\n      \"evidence\": \"Conditional Cdh1 deletion in cerebellar GCPs with CK1\\u03b4 level and proliferation assays\",\n      \"pmids\": [\"25843713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct ubiquitination kinetics of CK1\\u03b4 not fully characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The decision-making logic of cell-cycle entry was clarified; APC/C(Cdh1) inactivation is a bistable, irreversible commitment switch initiated by cyclin E/Cdk2 and locked by Emi1.\",\n      \"evidence\": \"Single-cell live imaging reporter with Cdk2 and Emi1 perturbations and stress challenges\",\n      \"pmids\": [\"27368103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular feedback architecture of bistability not fully reconstituted\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A non-degradative Cdh1 output in development was found; Cdh1 directs APC-dependent monoubiquitination and transcriptional activation of Goosecoid to control craniofacial bone formation.\",\n      \"evidence\": \"Neural-crest-specific Cdh1 knockout, Gsc ubiquitination and target-gene analysis, craniofacial phenotyping\",\n      \"pmids\": [\"27126000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how monoubiquitination activates Gsc transcription mechanistically unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cdh1 was linked to growth-control signaling and neuronal maintenance; it degrades LATS kinases to time YAP/TAZ activity and degrades Rock2 to preserve dendrites and memory.\",\n      \"evidence\": \"Co-IP, stability and reporter assays, Drosophila epistasis; conditional Cdh1 KO with Rock2 readouts and fasudil rescue\",\n      \"pmids\": [\"31000600\", \"28396402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"crosstalk between Hippo and cell-cycle Cdh1 functions not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Additional metabolic and oncogenic substrates and an APC-independent function emerged; Cdh1 degrades Skp2 and IDH3\\u03b2 and suppresses c-Src, while c-Src reciprocally phosphorylates Cdh1 to inhibit APC core binding.\",\n      \"evidence\": \"Co-IP, ubiquitination, CRISPR rescue, half-life, in vitro kinase assay, and xenograft/mouse tumor models\",\n      \"pmids\": [\"31806563\", \"31053633\", \"31420536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of APC-independent c-Src suppression not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tissue- and stress-specific Cdh1 functions were extended; Cdh1-FoxM1 controls muscle satellite-cell maintenance, an APC-Cdh1-cyclin B1 route drives a slow oocyte DDR, and Cdh1-APC influences neuronal protein synthesis via stress-granule/FMRP interactions.\",\n      \"evidence\": \"Conditional KO with FoxM1 rescue; Setx-null oocyte DDR analysis; interactome/stress-granule assays with FMRP knockdown\",\n      \"pmids\": [\"32152291\", \"32328643\", \"32434143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FMRP as direct Cdh1-APC substrate not rigorously demonstrated\", \"generality of slow oocyte DDR pathway unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Disease-relevant and mitosis-specific substrate recognition was probed; Cdk5 phosphorylation disassembles Cdh1 from APC/C in amyloid-\\u03b2 toxicity stabilizing Rock2, and dephosphorylated STAT3 is a preferred mitotic substrate.\",\n      \"evidence\": \"Phosphomutant rescue, co-IP, Rock2 stability and apoptosis assays; cell-cycle-resolved co-IP and ubiquitination with phosphatase inhibition\",\n      \"pmids\": [\"35496276\", \"36400381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAT3 finding based on single-lab co-IP/ubiquitination with limited functional follow-up\", \"in vivo relevance of STAT3 turnover not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the two distinct proteins sharing the CDH1 symbol\\u2014E-cadherin adhesion molecule and APC/C co-activator Fzr1/Cdh1\\u2014are functionally delineated, and a structural basis for E-cadherin homophilic binding and for Cdh1 substrate-motif selectivity is not established in this corpus.\",\n      \"evidence\": \"No timeline discovery resolves these questions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no structural model of E-cadherin trans-dimer\", \"no unified rule for Cdh1 KEN/D-box substrate selection\", \"symbol collision risk between the two proteins\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 9, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 24, 31, 19]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [15, 24, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 17, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15, 18, 26, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [19, 24]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 17, 24, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [23, 27, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"complexes\": [\"uvomorulin-catenin complex / adherens junction\", \"APC/C\"],\n    \"partners\": [\"CTNNB1\", \"CTNNA1\", \"CDC6\", \"Plk1\", \"CtIP\", \"Skp2\", \"LATS\", \"ROCK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}