{"gene":"CDH13","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2000,"finding":"CDH13/T-cadherin, when transfected into T-cadherin-negative neuroblastoma cells (TGW and NH-12), abolished the mitogenic proliferative response to epidermal growth factor, identifying it as a negative regulator of EGF-driven neural cell growth.","method":"Transfection of CDH13 cDNA expression vector into neuroblastoma cells, proliferation assay with EGF stimulation","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean gain-of-function with defined cellular phenotype, single lab","pmids":["10737605"],"is_preprint":false},{"year":2001,"finding":"CDH13/T-cadherin is anchored to the cell surface membrane exclusively through a glycosyl phosphatidylinositol (GPI) moiety, lacking a cytoplasmic domain and transmembrane region, distinguishing it structurally from classical cadherins.","method":"Structural/biochemical characterization reviewed; GPI-anchor confirmed by domain analysis","journal":"Histology and histopathology","confidence":"High","confidence_rationale":"Tier 1 — structural feature established by biochemical characterization, replicated across multiple labs","pmids":["11642747"],"is_preprint":false},{"year":2001,"finding":"Forced expression of T-cadherin (CDH13) in A549 human lung cancer cells (alveolar type-II characteristics) suppressed surfactant protein D (SP-D) mRNA and protein expression, demonstrating CDH13-mediated transcriptional downregulation of SP-D in bronchioloalveolar cells.","method":"Transfection of T-cadherin expression vector into A549 cells; RT-PCR and Western immunoblotting for SP-D","journal":"Virchows Archiv","confidence":"Medium","confidence_rationale":"Tier 2 — defined molecular phenotype with two orthogonal detection methods, single lab","pmids":["11355171"],"is_preprint":false},{"year":2001,"finding":"Aberrant promoter methylation of the CDH13 gene causes transcriptional silencing; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores CDH13 expression in methylated breast and lung cancer cell lines, confirming promoter methylation as the epigenetic mechanism of silencing.","method":"Methylation-specific PCR, RT-PCR, 5-aza-2'-deoxycytidine demethylation rescue","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — demethylation rescue with expression restoration, replicated across multiple cancer types and labs","pmids":["11389090","12067979","9737784"],"is_preprint":false},{"year":2002,"finding":"CDH13 promoter activity was confirmed by luciferase reporter assay, establishing that the 5' region of CDH13 functions as an active promoter susceptible to epigenetic silencing.","method":"Luciferase reporter assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1 — direct reporter assay, single lab","pmids":["12067979"],"is_preprint":false},{"year":2013,"finding":"CDH13 expression is a direct transcriptional target of the repressor BRN2 in melanoma cells; BRN2 binds the CDH13 promoter at a defined element (-219 bp upstream of start codon, sequence 5'-CATGCAAAA-3') and suppresses CDH13 transcription, contributing to loss of T-cadherin and increased melanoma invasion.","method":"Reporter gene assay, electrophoretic mobility shift assay (EMSA), BRN2 overexpression and siRNA knockdown with CDH13 mRNA/protein measurement","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1-2 — EMSA identifies binding element, reporter assay and reciprocal OE/KD experiments with multiple readouts, single lab","pmids":["23069940"],"is_preprint":false},{"year":2013,"finding":"Loss of T-cadherin (CDH13) in melanoma promotes tumor growth by desensitizing cells to apoptosis; restoration of T-cadherin expression causes AKT and FoxO3a hypophosphorylation, downregulation of anti-apoptotic molecules BCL-2, BCL-x and Clusterin, and sensitization to CD95/Fas-induced apoptosis, while NFκB, TCF/LEF and mTOR signaling are not part of this pathway.","method":"T-cadherin expression in melanoma cells; in vivo xenograft tumor growth; Western blot for AKT, FoxO3a, BCL-2, BCL-x, Clusterin; transcriptional activity assays for CREB, AP-1, NFκB, TCF/LEF, mTOR; CD95/Fas apoptosis assay","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, in vivo and in vitro, with pathway exclusions tested","pmids":["23625515"],"is_preprint":false},{"year":2011,"finding":"T-cadherin (Cdh13) localizes to insulin secretory granules in mouse and human pancreatic β-cells, and Cdh13-knockout mice exhibit impaired glucose-induced second-phase insulin secretion in vivo and in vitro without altered islet architecture, first-phase release, or insulin content, demonstrating a role for CDH13 in insulin granule function independent of adiponectin interaction.","method":"Immunohistochemistry, electron microscopy, RFP/GFP co-targeting in isolated β-cells, glucose-stimulated insulin secretion from primary islets, hyperglycemic clamp in Tcad-KO mice, glucose tolerance testing","journal":"Islets","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution-level localization with electron microscopy, KO with multiple in vivo and in vitro functional readouts","pmids":["21975561"],"is_preprint":false},{"year":2012,"finding":"T-cadherin (Cdh13) deficiency in mice leads to markedly elevated serum adiponectin, because adiponectin normally sequestered by endothelial T-cadherin remains free in circulation; combined adiponectin/T-cad bideficiency reverses the phenotype, demonstrating that T-cadherin acts as a vascular sequestration receptor for high-molecular-weight adiponectin rather than mediating its downstream signaling.","method":"T-cad-/-, adiponectin/T-cad bideficient mice; OVA-challenge allergic airways model; serum adiponectin ELISA; BAL cell counts; histology","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with bideficient rescue, functional phenotype, replicated in pulmonary ozone model","pmids":["22815927","23755285"],"is_preprint":false},{"year":2012,"finding":"CDH13 knockdown in bladder TCC 5637 cells increases cell migration, invasion, adhesion, and MMP2 expression, demonstrating that CDH13 suppresses invasiveness partly by limiting matrix metalloproteinase-2 upregulation.","method":"RNA interference knockdown of CDH13; Boyden chamber migration/invasion assay; adhesion assay; MMP2 expression by Western blot/RT-PCR","journal":"Urologia internationalis","confidence":"Medium","confidence_rationale":"Tier 2 — defined loss-of-function phenotype with molecular readout, single lab","pmids":["23235385"],"is_preprint":false},{"year":2013,"finding":"T-cadherin (CDH13) wild-type and missense variant proteins are processed via the canonical GPI-anchor processing pathway; protein expression and cell-surface localization are similar for wild-type and ADHD-associated missense variants, as shown in CHO and HEK293 cells.","method":"Expression of GFP-tagged wild-type and mutant CDH13 in CHO and HEK293 cells; protein expression levels and subcellular distribution imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implication for variant biology, single lab","pmids":["23936508"],"is_preprint":false},{"year":2015,"finding":"CDH13 promoter methylation is regulated by a UHRF1/PRMT5 epigenetic complex; co-immunoprecipitation demonstrated PRMT5 binding to UHRF1, and combined treatment with 5-Aza-CdR and TSA completely reversed CDH13 promoter methylation and restored expression, indicating that both DNA methylation and histone modification cooperate in CDH13 silencing in endometrial carcinoma.","method":"Co-immunoprecipitation of UHRF1 and PRMT5; methylation-specific PCR; qRT-PCR; 5-Aza-CdR and TSA treatment","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP identifies complex, functional rescue with two agents, single lab","pmids":["26597461"],"is_preprint":false},{"year":2018,"finding":"CDH13 promoter methylation in cisplatin-resistant lung cancer cells (A549/DDP) suppresses CDH13 expression; demethylation with 5-Aza-CdR restores CDH13 expression, increases apoptosis, and reverses cisplatin resistance by 3.35-fold, demonstrating a causal link between CDH13 methylation and drug resistance.","method":"RT-PCR, methylation-specific PCR, MTT assay, flow cytometry apoptosis assay, 5-Aza-CdR treatment in A549 vs A549/DDP cells","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts with mechanistic molecular explanation, single lab","pmids":["30344726"],"is_preprint":false},{"year":2018,"finding":"MicroRNA-377 directly targets CDH13 mRNA 3'-UTR to regulate its expression; in an Alzheimer's disease cell model, CDH13 is upregulated and miR-377 is downregulated; CDH13 knockdown rescues the cell viability reduction and apoptosis increase caused by miR-377 knockdown, placing CDH13 downstream of miR-377.","method":"Dual-luciferase reporter gene assay, qRT-PCR, Western blot, CCK-8 viability assay, flow cytometry apoptosis in SH-SY5Y AD model","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase confirms direct miRNA-UTR interaction, epistasis by CDH13 KD rescue, single lab","pmids":["29771432"],"is_preprint":false},{"year":2018,"finding":"CDH13 knockdown during adipogenesis in 3T3-L1 cells reduces fatty acid uptake, lipid content, and induction of the adipogenic transcription factors PPARγ and C/EBPα, demonstrating that CDH13 is required for normal adipocyte differentiation at the lipid metabolism and transcription factor level.","method":"CDH13 siRNA knockdown in 3T3-L1 adipocytes; fatty acid uptake assay; lipid staining; PPARγ and C/EBPα mRNA/protein quantification","journal":"International journal of obesity","confidence":"Medium","confidence_rationale":"Tier 2 — defined loss-of-function in differentiation model with molecular readouts, single lab","pmids":["29467502"],"is_preprint":false},{"year":2020,"finding":"DNA polymerase β (Pol β) suppresses cancer cell migration and invasion by promoting CDH13 expression through active DNA demethylation of the CDH13 promoter via base excision repair; CDH13 knockdown restores migratory, invasive capabilities and angiogenesis that were impaired by Pol β overexpression, placing CDH13 downstream of Pol β in the BER-demethylation pathway.","method":"Pol β overexpression and knockdown in breast/lung cancer cells and xenografts; CDH13 KD rescue; CDH13 promoter methylation assay; migration/invasion assays; tube formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via CDH13 KD rescue, in vivo and in vitro with multiple readouts, single lab","pmids":["32641859"],"is_preprint":false},{"year":2022,"finding":"hsa_circ_0000119 acts as a sponge for miR-142-5p to increase DNMT1 expression, which then promotes CDH13 promoter methylation and silences CDH13; CDH13 re-expression or miR-142-5p overexpression reversed the pro-tumorigenic effects of hsa_circ_0000119 in ovarian cancer cells.","method":"circRNA overexpression/silencing, luciferase reporter assay for miR-142-5p binding, DNMT1 expression, CDH13 promoter methylation assay, CDH13 rescue experiments, proliferation/migration/invasion assays","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase confirms miRNA-circ interaction, methylation measured, rescue experiments performed, single lab","pmids":["36482494"],"is_preprint":false},{"year":2024,"finding":"The lncRNA CDH13-AS2 physically binds CDH13 mRNA in human endothelial cells (confirmed by dCas13-mediated RNA immunoprecipitation); CDH13-AS2 knockout is atherogenic and CDH13-AS2 CRISPRa activation is atheroprotective, effects mediated by CDH13 mRNA stability. Four miRNAs (miR-19b-3p, miR-125b-2-3p, miR-433-3p, miR-7b-5p) bind CDH13 3'UTR and accelerate mRNA degradation; CDH13-AS2 CRISPRa neutralizes this miRNA-mediated degradation.","method":"dCas13-RNA immunoprecipitation, CRISPR/Cas9 KO and CRISPRa of CDH13-AS2, in vitro miRNA binding assay, CDH13 mRNA stability measurements, atherosclerosis plaque assay in Cdh13/Apoe double-KO mice","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct RNA-RNA binding confirmed by RIP, CRISPR functional validation in cells and mice; preprint, not yet peer-reviewed","pmids":["40894025"],"is_preprint":true},{"year":2024,"finding":"Potassium dehydroandrographolide succinate (PDA) upregulates MyD88 in smooth muscle cells, which physically interacts with T-cadherin (CDH13) as demonstrated by molecular docking and co-immunoprecipitation; this MyD88/CDH13 interaction augments SMC proliferation, migration, and extracellular matrix deposition, exacerbating pathological vascular remodeling.","method":"Molecular docking simulation, co-immunoprecipitation, SMC proliferation (BrdU), Boyden chamber migration, spheroid sprouting, tube formation assays, carotid ligation mouse model","journal":"Chinese journal of natural medicines","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with molecular docking, mechanistic interpretation limited, single lab","pmids":["38278560"],"is_preprint":false},{"year":2024,"finding":"CDH13 loss-of-function increases atherosclerotic plaque size in Cdh13/Apoe double-knockout mice on a Western diet compared to Apoe single-knockout mice, demonstrating an atheroprotective role for CDH13 in vascular biology.","method":"Cdh13/Apoe double-KO mouse model on Western diet; atherosclerotic plaque quantification","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined in vivo phenotype; preprint status limits confidence","pmids":["40894025"],"is_preprint":true},{"year":2024,"finding":"saRNA-mediated activation of CDH13 expression in BCR-ABL1-independent imatinib-resistant CML cells inhibits the NF-κB signaling pathway and induces apoptosis, overcoming drug resistance both in vitro and in a xenograft model.","method":"saRNA targeting CDH13 promoter; qPCR and Western blot for CDH13; NF-κB pathway analysis; apoptosis assay; clone formation assay; LNP-saRNA xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with molecular pathway readout, in vivo validation, single lab","pmids":["39179585"],"is_preprint":false},{"year":2018,"finding":"CDH13 expression is restricted to the presynaptic compartment of inhibitory GABAergic synapses in the adult hippocampus; Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, causing a shift in excitatory/inhibitory balance, and CDH13 moderates the migration of serotonergic neurons in the dorsal raphe nucleus during brain development.","method":"Cdh13 KO mouse behavioral battery, transcriptome analysis of hippocampus, electrophysiology implied by description of inhibitory drive; expression localization in brain","journal":"Progress in neuro-psychopharmacology & biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with electrophysiology-based circuit phenotype and localization data, referenced from prior work; single lab","pmids":["30165120"],"is_preprint":false},{"year":2017,"finding":"Cdh13 knockout rats show increased cue-induced reinstatement of cocaine seeking (instrumental conditioning) compared to wild-type, while Cdh13 deficiency does not alter conditioned place preference or locomotor response to cocaine, establishing Cdh13 as a modulator of drug-cue associative learning.","method":"Cdh13 KO rat intravenous cocaine self-administration, cue-induced reinstatement, conditioned place preference, locomotor assay","journal":"Genes, brain, and behavior","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO model with specific behavioral paradigms discriminating different conditioning types, single lab","pmids":["28387990"],"is_preprint":false},{"year":2005,"finding":"CDH13/T-cadherin is expressed on the apical membrane of differentiating podocytes in fetal human glomeruli and becomes restricted to foot processes at the advanced capillary loop stage, implicating CDH13 in podocyte differentiation and formation of the glomerular filtration barrier.","method":"Immunohistochemistry with anti-T-/H-cadherin antiserum on human fetal kidney tissue sections; developmental staging","journal":"Virchows Archiv","confidence":"Low","confidence_rationale":"Tier 3 — direct localization by IHC with developmental context, no functional loss-of-function","pmids":["16133358"],"is_preprint":false}],"current_model":"CDH13/T-cadherin is a GPI-anchored cell-adhesion glycoprotein that functions as a receptor/sequestration site for high-molecular-weight adiponectin on vascular endothelium and as a component of insulin secretory granules in β-cells; it acts as a tumor suppressor by promoting apoptosis and suppressing AKT/CREB/AP-1 signaling, and its expression is silenced in many cancers through promoter hypermethylation (regulated by UHRF1/PRMT5 and counteracted by Pol β-mediated BER-dependent demethylation), transcriptional repression by BRN2, and post-transcriptional regulation by miRNAs (including miR-377 and miR-19b/125b/433/7b) whose activity is buffered by the lncRNA CDH13-AS2; in the nervous system CDH13 localizes to presynaptic GABAergic terminals in hippocampus, and its loss shifts the excitatory/inhibitory balance and impairs inhibitory neurotransmission."},"narrative":{"teleology":[{"year":2000,"claim":"Whether CDH13 influences cell proliferation was unknown; forced expression in neuroblastoma cells abolished the mitogenic response to EGF, establishing CDH13 as a growth-suppressive molecule.","evidence":"CDH13 cDNA transfection into T-cadherin-negative neuroblastoma lines with EGF proliferation assay","pmids":["10737605"],"confidence":"Medium","gaps":["Mechanism linking GPI-anchored CDH13 to intracellular EGF signaling not defined","No loss-of-function complement"]},{"year":2001,"claim":"The structural basis of CDH13's unusual biology was clarified: unlike classical cadherins, CDH13 is anchored exclusively by a GPI moiety and lacks a cytoplasmic domain, explaining its inability to directly engage catenin signaling.","evidence":"Biochemical/structural characterization of GPI anchor, replicated across multiple labs","pmids":["11642747"],"confidence":"High","gaps":["How GPI-anchored CDH13 transduces signals intracellularly remains unresolved","No crystal structure of the full extracellular domain"]},{"year":2001,"claim":"Epigenetic silencing of CDH13 was established as a general cancer mechanism when promoter hypermethylation was shown to cause transcriptional shutdown in breast and lung cancers, reversible by 5-aza-2′-deoxycytidine.","evidence":"Methylation-specific PCR, RT-PCR, and demethylation rescue across multiple cancer cell lines","pmids":["11389090","12067979","9737784"],"confidence":"High","gaps":["Identity of the methyltransferases responsible was unknown at this stage","Whether methylation is a driver or passenger in tumorigenesis was unresolved"]},{"year":2011,"claim":"CDH13's metabolic role was expanded beyond vasculature: CDH13 localizes to insulin secretory granules in β-cells and is required for second-phase glucose-stimulated insulin secretion, independent of adiponectin.","evidence":"Immunohistochemistry, electron microscopy, hyperglycemic clamp, and glucose-stimulated insulin secretion in Cdh13-KO mice and isolated islets","pmids":["21975561"],"confidence":"High","gaps":["Molecular mechanism by which CDH13 facilitates granule exocytosis is unknown","Whether GPI-anchor cleavage releases CDH13 into the granule lumen was not tested"]},{"year":2012,"claim":"The long-debated question of whether CDH13 is a signaling receptor or a sequestration site for adiponectin was resolved: genetic epistasis in bideficient mice showed CDH13 sequesters high-molecular-weight adiponectin on vascular endothelium rather than transducing its signal.","evidence":"T-cad−/−, adiponectin/T-cad double-KO mice; serum adiponectin ELISA; OVA-challenge and ozone pulmonary models","pmids":["22815927","23755285"],"confidence":"High","gaps":["Fate of sequestered adiponectin (internalization vs surface retention) not determined","Tissue-specific contribution of endothelial vs other cell CDH13 pools not dissected"]},{"year":2013,"claim":"CDH13's tumor-suppressive signaling was mechanistically delineated: re-expression in melanoma causes AKT/FoxO3a hypophosphorylation, loss of BCL-2/BCL-x/Clusterin, and apoptosis sensitization, while NF-κB, TCF/LEF, and mTOR pathways are excluded.","evidence":"CDH13 expression in melanoma cells; xenograft growth; Western blot for AKT, FoxO3a, BCL-2 family; transcriptional reporter assays; CD95/Fas apoptosis assay","pmids":["23625515"],"confidence":"High","gaps":["Proximal signal transduction from GPI-anchored CDH13 to AKT inhibition unknown","No identification of a co-receptor or lipid-raft partner mediating signal relay"]},{"year":2013,"claim":"Transcriptional repression of CDH13 was linked to a specific transcription factor: BRN2 directly binds the CDH13 promoter at −219 bp and suppresses transcription, promoting melanoma invasion.","evidence":"EMSA for BRN2 binding element, reporter assay, reciprocal BRN2 overexpression/siRNA with CDH13 measurement","pmids":["23069940"],"confidence":"High","gaps":["Whether BRN2-mediated repression cooperates with DNA methylation was not tested","Relevance beyond melanoma undetermined"]},{"year":2015,"claim":"The epigenetic machinery responsible for CDH13 methylation was identified: UHRF1 and PRMT5 form a complex that maintains CDH13 promoter methylation, and combined DNA methylation plus histone modification inhibition fully restores expression.","evidence":"Co-immunoprecipitation of UHRF1/PRMT5; methylation-specific PCR; 5-Aza-CdR + TSA dual treatment in endometrial carcinoma cells","pmids":["26597461"],"confidence":"Medium","gaps":["No reciprocal IP or endogenous complex validation","Whether PRMT5 acts via histone arginine methylation at CDH13 locus specifically was not shown"]},{"year":2017,"claim":"CDH13's role in addiction-relevant behavior was established: Cdh13-KO rats show enhanced cue-induced reinstatement of cocaine seeking without altered conditioned place preference, dissociating CDH13 from drug reward per se and linking it to drug-cue associative learning.","evidence":"Cdh13-KO rat; intravenous cocaine self-administration, cue-induced reinstatement, conditioned place preference, locomotor assays","pmids":["28387990"],"confidence":"Medium","gaps":["Circuit-level mechanism (which brain region and synapse type) not identified","Whether the phenotype maps to GABAergic synapse dysfunction was not tested"]},{"year":2018,"claim":"CDH13's neural circuit function was defined: in adult hippocampus CDH13 is restricted to presynaptic GABAergic terminals, and its loss increases inhibitory drive onto CA1 pyramidal neurons, shifting excitatory/inhibitory balance.","evidence":"Cdh13-KO mouse; hippocampal expression localization; electrophysiology-derived inhibitory drive measurement; serotonergic neuron migration analysis","pmids":["30165120"],"confidence":"Medium","gaps":["Whether CDH13 acts as a synapse-organizing molecule or modulates GABA release probability is unknown","Causal link between hippocampal E/I shift and behavioral phenotypes not established"]},{"year":2020,"claim":"An active demethylation pathway for CDH13 was discovered: DNA polymerase β promotes CDH13 expression through BER-dependent demethylation of its promoter, and CDH13 is the functional effector of Pol β's anti-migratory and anti-angiogenic activity.","evidence":"Pol β overexpression/knockdown in cancer cells and xenografts; CDH13 KD rescue; CDH13 promoter methylation analysis; migration, invasion, and tube formation assays","pmids":["32641859"],"confidence":"Medium","gaps":["Whether Pol β acts directly at the CDH13 locus via TET-BER or passive demethylation not distinguished","Single lab finding"]},{"year":2024,"claim":"CDH13 re-expression was shown to overcome drug resistance in imatinib-resistant CML by inhibiting NF-κB signaling and inducing apoptosis, expanding CDH13's tumor-suppressive role to hematological malignancies.","evidence":"saRNA-mediated CDH13 activation in BCR-ABL1-independent resistant CML cells; NF-κB pathway analysis; apoptosis and colony assays; LNP-saRNA xenograft","pmids":["39179585"],"confidence":"Medium","gaps":["Mechanism by which CDH13 inhibits NF-κB (direct vs indirect) not resolved","Contrast with earlier melanoma finding excluding NF-κB suggests context-dependence that is unexplained"]},{"year":null,"claim":"How a GPI-anchored protein lacking a cytoplasmic domain transduces intracellular signals to inhibit AKT, regulate NF-κB, and modulate synaptic function remains the central unresolved question; no co-receptor, lipid-raft partner, or signaling intermediary has been identified.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-receptor or transmembrane partner identified","No structural model of the CDH13 ectodomain at atomic resolution","Tissue-specific signaling outputs (endothelium vs neuron vs β-cell) not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,9,20]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,12,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,16]}],"complexes":[],"partners":["ADIPOQ","BRN2","UHRF1","PRMT5","POLB"],"other_free_text":[]},"mechanistic_narrative":"CDH13 (T-cadherin) is a GPI-anchored atypical cadherin that functions as a vascular sequestration receptor for high-molecular-weight adiponectin, a tumor suppressor silenced by promoter hypermethylation in diverse cancers, and a modulator of inhibitory synaptic transmission in the brain [PMID:11642747, PMID:22815927, PMID:30165120]. On vascular endothelium, CDH13 sequesters circulating adiponectin, as demonstrated by markedly elevated serum adiponectin in Cdh13-knockout mice that is reversed by combined adiponectin/Cdh13 bideficiency [PMID:22815927]; in pancreatic β-cells, CDH13 localizes to insulin secretory granules and is required for normal second-phase glucose-stimulated insulin secretion [PMID:21975561]. CDH13 suppresses tumor growth by promoting apoptosis through AKT/FoxO3a hypophosphorylation and downregulation of BCL-2 family anti-apoptotic proteins, and its expression is frequently extinguished by promoter CpG methylation maintained by a UHRF1/PRMT5 complex and counteracted by Pol β-mediated base excision repair demethylation [PMID:23625515, PMID:11389090, PMID:26597461, PMID:32641859]. In the hippocampus, CDH13 is restricted to presynaptic terminals of GABAergic inhibitory synapses, and its loss increases inhibitory drive onto CA1 pyramidal neurons, shifting excitatory/inhibitory balance [PMID:30165120]."},"prefetch_data":{"uniprot":{"accession":"P55290","full_name":"Cadherin-13","aliases":["Heart cadherin","H-cadherin","P105","Truncated cadherin","T-cad","T-cadherin"],"length_aa":713,"mass_kda":78.3,"function":"Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. May act as a negative regulator of neural cell growth","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P55290/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH13","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDH13","total_profiled":1310},"omim":[{"mim_id":"613836","title":"ADIPONECTIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 5; ADIPQTL5","url":"https://www.omim.org/entry/613836"},{"mim_id":"613547","title":"STATURE QUANTITATIVE TRAIT LOCUS 22; STQTL22","url":"https://www.omim.org/entry/613547"},{"mim_id":"611731","title":"APC REGULATOR OF WNT SIGNALING PATHWAY; APC","url":"https://www.omim.org/entry/611731"},{"mim_id":"608462","title":"HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 8; HSCR8","url":"https://www.omim.org/entry/608462"},{"mim_id":"605082","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 1; RASSF1","url":"https://www.omim.org/entry/605082"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood 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biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/25388841","citation_count":5,"is_preprint":false},{"pmid":"38926485","id":"PMC_38926485","title":"Droplet digital PCR analysis of CDH13 methylation status in Slovak women with invasive ductal breast cancer.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38926485","citation_count":5,"is_preprint":false},{"pmid":"20364027","id":"PMC_20364027","title":"Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in essential thrombocythaemia.","date":"2010","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20364027","citation_count":4,"is_preprint":false},{"pmid":"26600672","id":"PMC_26600672","title":"Differential Associations between CDH13 Genotypes, Adiponectin Levels, and Circulating Levels of Cellular Adhesive Molecules.","date":"2015","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26600672","citation_count":4,"is_preprint":false},{"pmid":"38278560","id":"PMC_38278560","title":"Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injury-induced pathological vascular remodeling.","date":"2024","source":"Chinese journal of natural medicines","url":"https://pubmed.ncbi.nlm.nih.gov/38278560","citation_count":4,"is_preprint":false},{"pmid":"27771748","id":"PMC_27771748","title":"Pharmacogenetics of stimulant abuse liability: association of CDH13 variant with amphetamine response in a racially-heterogeneous sample of healthy young adults.","date":"2016","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27771748","citation_count":4,"is_preprint":false},{"pmid":"38732110","id":"PMC_38732110","title":"Analysis of CDO1, PITX2, and CDH13 Gene Methylation in Early Endometrial Cancer for Prediction of Medical Treatment Outcomes.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38732110","citation_count":3,"is_preprint":false},{"pmid":"33407434","id":"PMC_33407434","title":"Interactive association between dietary fat and sex on CDH13 cg02263260 methylation.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33407434","citation_count":3,"is_preprint":false},{"pmid":"29416663","id":"PMC_29416663","title":"Genetic variation in CDH13 gene was associated with non-small cell lung cancer (NSCLC): A population-based case-control study.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29416663","citation_count":3,"is_preprint":false},{"pmid":"34680977","id":"PMC_34680977","title":"Genome-Wide Association Study on Adiponectin-Mediated Suppression of HDL-C Levels in Taiwanese Individuals Identifies Functional Haplotypes in CDH13.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34680977","citation_count":3,"is_preprint":false},{"pmid":"22490847","id":"PMC_22490847","title":"[5-aza-2'-deoxycytidine-induced inhibition of CDH13 expression and its inhibitory effect on methylation status in human colon cancer cells in vitro and on growth of xenograft in nude mice].","date":"2012","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/22490847","citation_count":3,"is_preprint":false},{"pmid":"38074818","id":"PMC_38074818","title":"Association of the CDH13 gene variant rs9940180 with schizophrenia risk in North Indian population.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/38074818","citation_count":2,"is_preprint":false},{"pmid":"28562572","id":"PMC_28562572","title":"The association of six single nucleotide polymorphisms and their haplotypes in CDH13 with T2DM in a Han Chinese population.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28562572","citation_count":2,"is_preprint":false},{"pmid":"39179585","id":"PMC_39179585","title":"Small RNA activation of CDH13 expression overcome BCR-ABL1-independent imatinib-resistance and their signaling pathway studies in chronic myeloid leukemia.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39179585","citation_count":2,"is_preprint":false},{"pmid":"31854260","id":"PMC_31854260","title":"A potential role for the CDH13/CDH15 gene in repeat revascularization after first percutaneous coronary intervention.","date":"2019","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/31854260","citation_count":1,"is_preprint":false},{"pmid":"40894025","id":"PMC_40894025","title":"An interplay of non-coding RNAs regulates CDH13 expression and affects endothelial function and coronary artery disease risk.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/40894025","citation_count":1,"is_preprint":false},{"pmid":"27125099","id":"PMC_27125099","title":"[Single Nucleotide Polymorphisms in T-Cadherin Gene (CDH13) Have Cumulative Effect on Body Mass in Patients With Ischemic Heart Disease].","date":"2015","source":"Kardiologiia","url":"https://pubmed.ncbi.nlm.nih.gov/27125099","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53344,"output_tokens":5870,"usd":0.124041},"stage2":{"model":"claude-opus-4-6","input_tokens":9507,"output_tokens":3224,"usd":0.192202},"total_usd":0.316243,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CDH13/T-cadherin, when transfected into T-cadherin-negative neuroblastoma cells (TGW and NH-12), abolished the mitogenic proliferative response to epidermal growth factor, identifying it as a negative regulator of EGF-driven neural cell growth.\",\n      \"method\": \"Transfection of CDH13 cDNA expression vector into neuroblastoma cells, proliferation assay with EGF stimulation\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"10737605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDH13/T-cadherin is anchored to the cell surface membrane exclusively through a glycosyl phosphatidylinositol (GPI) moiety, lacking a cytoplasmic domain and transmembrane region, distinguishing it structurally from classical cadherins.\",\n      \"method\": \"Structural/biochemical characterization reviewed; GPI-anchor confirmed by domain analysis\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural feature established by biochemical characterization, replicated across multiple labs\",\n      \"pmids\": [\"11642747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Forced expression of T-cadherin (CDH13) in A549 human lung cancer cells (alveolar type-II characteristics) suppressed surfactant protein D (SP-D) mRNA and protein expression, demonstrating CDH13-mediated transcriptional downregulation of SP-D in bronchioloalveolar cells.\",\n      \"method\": \"Transfection of T-cadherin expression vector into A549 cells; RT-PCR and Western immunoblotting for SP-D\",\n      \"journal\": \"Virchows Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular phenotype with two orthogonal detection methods, single lab\",\n      \"pmids\": [\"11355171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Aberrant promoter methylation of the CDH13 gene causes transcriptional silencing; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores CDH13 expression in methylated breast and lung cancer cell lines, confirming promoter methylation as the epigenetic mechanism of silencing.\",\n      \"method\": \"Methylation-specific PCR, RT-PCR, 5-aza-2'-deoxycytidine demethylation rescue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — demethylation rescue with expression restoration, replicated across multiple cancer types and labs\",\n      \"pmids\": [\"11389090\", \"12067979\", \"9737784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CDH13 promoter activity was confirmed by luciferase reporter assay, establishing that the 5' region of CDH13 functions as an active promoter susceptible to epigenetic silencing.\",\n      \"method\": \"Luciferase reporter assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct reporter assay, single lab\",\n      \"pmids\": [\"12067979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDH13 expression is a direct transcriptional target of the repressor BRN2 in melanoma cells; BRN2 binds the CDH13 promoter at a defined element (-219 bp upstream of start codon, sequence 5'-CATGCAAAA-3') and suppresses CDH13 transcription, contributing to loss of T-cadherin and increased melanoma invasion.\",\n      \"method\": \"Reporter gene assay, electrophoretic mobility shift assay (EMSA), BRN2 overexpression and siRNA knockdown with CDH13 mRNA/protein measurement\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — EMSA identifies binding element, reporter assay and reciprocal OE/KD experiments with multiple readouts, single lab\",\n      \"pmids\": [\"23069940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of T-cadherin (CDH13) in melanoma promotes tumor growth by desensitizing cells to apoptosis; restoration of T-cadherin expression causes AKT and FoxO3a hypophosphorylation, downregulation of anti-apoptotic molecules BCL-2, BCL-x and Clusterin, and sensitization to CD95/Fas-induced apoptosis, while NFκB, TCF/LEF and mTOR signaling are not part of this pathway.\",\n      \"method\": \"T-cadherin expression in melanoma cells; in vivo xenograft tumor growth; Western blot for AKT, FoxO3a, BCL-2, BCL-x, Clusterin; transcriptional activity assays for CREB, AP-1, NFκB, TCF/LEF, mTOR; CD95/Fas apoptosis assay\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, in vivo and in vitro, with pathway exclusions tested\",\n      \"pmids\": [\"23625515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"T-cadherin (Cdh13) localizes to insulin secretory granules in mouse and human pancreatic β-cells, and Cdh13-knockout mice exhibit impaired glucose-induced second-phase insulin secretion in vivo and in vitro without altered islet architecture, first-phase release, or insulin content, demonstrating a role for CDH13 in insulin granule function independent of adiponectin interaction.\",\n      \"method\": \"Immunohistochemistry, electron microscopy, RFP/GFP co-targeting in isolated β-cells, glucose-stimulated insulin secretion from primary islets, hyperglycemic clamp in Tcad-KO mice, glucose tolerance testing\",\n      \"journal\": \"Islets\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution-level localization with electron microscopy, KO with multiple in vivo and in vitro functional readouts\",\n      \"pmids\": [\"21975561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T-cadherin (Cdh13) deficiency in mice leads to markedly elevated serum adiponectin, because adiponectin normally sequestered by endothelial T-cadherin remains free in circulation; combined adiponectin/T-cad bideficiency reverses the phenotype, demonstrating that T-cadherin acts as a vascular sequestration receptor for high-molecular-weight adiponectin rather than mediating its downstream signaling.\",\n      \"method\": \"T-cad-/-, adiponectin/T-cad bideficient mice; OVA-challenge allergic airways model; serum adiponectin ELISA; BAL cell counts; histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with bideficient rescue, functional phenotype, replicated in pulmonary ozone model\",\n      \"pmids\": [\"22815927\", \"23755285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDH13 knockdown in bladder TCC 5637 cells increases cell migration, invasion, adhesion, and MMP2 expression, demonstrating that CDH13 suppresses invasiveness partly by limiting matrix metalloproteinase-2 upregulation.\",\n      \"method\": \"RNA interference knockdown of CDH13; Boyden chamber migration/invasion assay; adhesion assay; MMP2 expression by Western blot/RT-PCR\",\n      \"journal\": \"Urologia internationalis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined loss-of-function phenotype with molecular readout, single lab\",\n      \"pmids\": [\"23235385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T-cadherin (CDH13) wild-type and missense variant proteins are processed via the canonical GPI-anchor processing pathway; protein expression and cell-surface localization are similar for wild-type and ADHD-associated missense variants, as shown in CHO and HEK293 cells.\",\n      \"method\": \"Expression of GFP-tagged wild-type and mutant CDH13 in CHO and HEK293 cells; protein expression levels and subcellular distribution imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implication for variant biology, single lab\",\n      \"pmids\": [\"23936508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDH13 promoter methylation is regulated by a UHRF1/PRMT5 epigenetic complex; co-immunoprecipitation demonstrated PRMT5 binding to UHRF1, and combined treatment with 5-Aza-CdR and TSA completely reversed CDH13 promoter methylation and restored expression, indicating that both DNA methylation and histone modification cooperate in CDH13 silencing in endometrial carcinoma.\",\n      \"method\": \"Co-immunoprecipitation of UHRF1 and PRMT5; methylation-specific PCR; qRT-PCR; 5-Aza-CdR and TSA treatment\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP identifies complex, functional rescue with two agents, single lab\",\n      \"pmids\": [\"26597461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH13 promoter methylation in cisplatin-resistant lung cancer cells (A549/DDP) suppresses CDH13 expression; demethylation with 5-Aza-CdR restores CDH13 expression, increases apoptosis, and reverses cisplatin resistance by 3.35-fold, demonstrating a causal link between CDH13 methylation and drug resistance.\",\n      \"method\": \"RT-PCR, methylation-specific PCR, MTT assay, flow cytometry apoptosis assay, 5-Aza-CdR treatment in A549 vs A549/DDP cells\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts with mechanistic molecular explanation, single lab\",\n      \"pmids\": [\"30344726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MicroRNA-377 directly targets CDH13 mRNA 3'-UTR to regulate its expression; in an Alzheimer's disease cell model, CDH13 is upregulated and miR-377 is downregulated; CDH13 knockdown rescues the cell viability reduction and apoptosis increase caused by miR-377 knockdown, placing CDH13 downstream of miR-377.\",\n      \"method\": \"Dual-luciferase reporter gene assay, qRT-PCR, Western blot, CCK-8 viability assay, flow cytometry apoptosis in SH-SY5Y AD model\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase confirms direct miRNA-UTR interaction, epistasis by CDH13 KD rescue, single lab\",\n      \"pmids\": [\"29771432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH13 knockdown during adipogenesis in 3T3-L1 cells reduces fatty acid uptake, lipid content, and induction of the adipogenic transcription factors PPARγ and C/EBPα, demonstrating that CDH13 is required for normal adipocyte differentiation at the lipid metabolism and transcription factor level.\",\n      \"method\": \"CDH13 siRNA knockdown in 3T3-L1 adipocytes; fatty acid uptake assay; lipid staining; PPARγ and C/EBPα mRNA/protein quantification\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined loss-of-function in differentiation model with molecular readouts, single lab\",\n      \"pmids\": [\"29467502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNA polymerase β (Pol β) suppresses cancer cell migration and invasion by promoting CDH13 expression through active DNA demethylation of the CDH13 promoter via base excision repair; CDH13 knockdown restores migratory, invasive capabilities and angiogenesis that were impaired by Pol β overexpression, placing CDH13 downstream of Pol β in the BER-demethylation pathway.\",\n      \"method\": \"Pol β overexpression and knockdown in breast/lung cancer cells and xenografts; CDH13 KD rescue; CDH13 promoter methylation assay; migration/invasion assays; tube formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via CDH13 KD rescue, in vivo and in vitro with multiple readouts, single lab\",\n      \"pmids\": [\"32641859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hsa_circ_0000119 acts as a sponge for miR-142-5p to increase DNMT1 expression, which then promotes CDH13 promoter methylation and silences CDH13; CDH13 re-expression or miR-142-5p overexpression reversed the pro-tumorigenic effects of hsa_circ_0000119 in ovarian cancer cells.\",\n      \"method\": \"circRNA overexpression/silencing, luciferase reporter assay for miR-142-5p binding, DNMT1 expression, CDH13 promoter methylation assay, CDH13 rescue experiments, proliferation/migration/invasion assays\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase confirms miRNA-circ interaction, methylation measured, rescue experiments performed, single lab\",\n      \"pmids\": [\"36482494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The lncRNA CDH13-AS2 physically binds CDH13 mRNA in human endothelial cells (confirmed by dCas13-mediated RNA immunoprecipitation); CDH13-AS2 knockout is atherogenic and CDH13-AS2 CRISPRa activation is atheroprotective, effects mediated by CDH13 mRNA stability. Four miRNAs (miR-19b-3p, miR-125b-2-3p, miR-433-3p, miR-7b-5p) bind CDH13 3'UTR and accelerate mRNA degradation; CDH13-AS2 CRISPRa neutralizes this miRNA-mediated degradation.\",\n      \"method\": \"dCas13-RNA immunoprecipitation, CRISPR/Cas9 KO and CRISPRa of CDH13-AS2, in vitro miRNA binding assay, CDH13 mRNA stability measurements, atherosclerosis plaque assay in Cdh13/Apoe double-KO mice\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct RNA-RNA binding confirmed by RIP, CRISPR functional validation in cells and mice; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40894025\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Potassium dehydroandrographolide succinate (PDA) upregulates MyD88 in smooth muscle cells, which physically interacts with T-cadherin (CDH13) as demonstrated by molecular docking and co-immunoprecipitation; this MyD88/CDH13 interaction augments SMC proliferation, migration, and extracellular matrix deposition, exacerbating pathological vascular remodeling.\",\n      \"method\": \"Molecular docking simulation, co-immunoprecipitation, SMC proliferation (BrdU), Boyden chamber migration, spheroid sprouting, tube formation assays, carotid ligation mouse model\",\n      \"journal\": \"Chinese journal of natural medicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with molecular docking, mechanistic interpretation limited, single lab\",\n      \"pmids\": [\"38278560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDH13 loss-of-function increases atherosclerotic plaque size in Cdh13/Apoe double-knockout mice on a Western diet compared to Apoe single-knockout mice, demonstrating an atheroprotective role for CDH13 in vascular biology.\",\n      \"method\": \"Cdh13/Apoe double-KO mouse model on Western diet; atherosclerotic plaque quantification\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined in vivo phenotype; preprint status limits confidence\",\n      \"pmids\": [\"40894025\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"saRNA-mediated activation of CDH13 expression in BCR-ABL1-independent imatinib-resistant CML cells inhibits the NF-κB signaling pathway and induces apoptosis, overcoming drug resistance both in vitro and in a xenograft model.\",\n      \"method\": \"saRNA targeting CDH13 promoter; qPCR and Western blot for CDH13; NF-κB pathway analysis; apoptosis assay; clone formation assay; LNP-saRNA xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with molecular pathway readout, in vivo validation, single lab\",\n      \"pmids\": [\"39179585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH13 expression is restricted to the presynaptic compartment of inhibitory GABAergic synapses in the adult hippocampus; Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, causing a shift in excitatory/inhibitory balance, and CDH13 moderates the migration of serotonergic neurons in the dorsal raphe nucleus during brain development.\",\n      \"method\": \"Cdh13 KO mouse behavioral battery, transcriptome analysis of hippocampus, electrophysiology implied by description of inhibitory drive; expression localization in brain\",\n      \"journal\": \"Progress in neuro-psychopharmacology & biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with electrophysiology-based circuit phenotype and localization data, referenced from prior work; single lab\",\n      \"pmids\": [\"30165120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cdh13 knockout rats show increased cue-induced reinstatement of cocaine seeking (instrumental conditioning) compared to wild-type, while Cdh13 deficiency does not alter conditioned place preference or locomotor response to cocaine, establishing Cdh13 as a modulator of drug-cue associative learning.\",\n      \"method\": \"Cdh13 KO rat intravenous cocaine self-administration, cue-induced reinstatement, conditioned place preference, locomotor assay\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with specific behavioral paradigms discriminating different conditioning types, single lab\",\n      \"pmids\": [\"28387990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CDH13/T-cadherin is expressed on the apical membrane of differentiating podocytes in fetal human glomeruli and becomes restricted to foot processes at the advanced capillary loop stage, implicating CDH13 in podocyte differentiation and formation of the glomerular filtration barrier.\",\n      \"method\": \"Immunohistochemistry with anti-T-/H-cadherin antiserum on human fetal kidney tissue sections; developmental staging\",\n      \"journal\": \"Virchows Archiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by IHC with developmental context, no functional loss-of-function\",\n      \"pmids\": [\"16133358\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH13/T-cadherin is a GPI-anchored cell-adhesion glycoprotein that functions as a receptor/sequestration site for high-molecular-weight adiponectin on vascular endothelium and as a component of insulin secretory granules in β-cells; it acts as a tumor suppressor by promoting apoptosis and suppressing AKT/CREB/AP-1 signaling, and its expression is silenced in many cancers through promoter hypermethylation (regulated by UHRF1/PRMT5 and counteracted by Pol β-mediated BER-dependent demethylation), transcriptional repression by BRN2, and post-transcriptional regulation by miRNAs (including miR-377 and miR-19b/125b/433/7b) whose activity is buffered by the lncRNA CDH13-AS2; in the nervous system CDH13 localizes to presynaptic GABAergic terminals in hippocampus, and its loss shifts the excitatory/inhibitory balance and impairs inhibitory neurotransmission.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDH13 (T-cadherin) is a GPI-anchored atypical cadherin that functions as a vascular sequestration receptor for high-molecular-weight adiponectin, a tumor suppressor silenced by promoter hypermethylation in diverse cancers, and a modulator of inhibitory synaptic transmission in the brain [PMID:11642747, PMID:22815927, PMID:30165120]. On vascular endothelium, CDH13 sequesters circulating adiponectin, as demonstrated by markedly elevated serum adiponectin in Cdh13-knockout mice that is reversed by combined adiponectin/Cdh13 bideficiency [PMID:22815927]; in pancreatic β-cells, CDH13 localizes to insulin secretory granules and is required for normal second-phase glucose-stimulated insulin secretion [PMID:21975561]. CDH13 suppresses tumor growth by promoting apoptosis through AKT/FoxO3a hypophosphorylation and downregulation of BCL-2 family anti-apoptotic proteins, and its expression is frequently extinguished by promoter CpG methylation maintained by a UHRF1/PRMT5 complex and counteracted by Pol β-mediated base excision repair demethylation [PMID:23625515, PMID:11389090, PMID:26597461, PMID:32641859]. In the hippocampus, CDH13 is restricted to presynaptic terminals of GABAergic inhibitory synapses, and its loss increases inhibitory drive onto CA1 pyramidal neurons, shifting excitatory/inhibitory balance [PMID:30165120].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Whether CDH13 influences cell proliferation was unknown; forced expression in neuroblastoma cells abolished the mitogenic response to EGF, establishing CDH13 as a growth-suppressive molecule.\",\n      \"evidence\": \"CDH13 cDNA transfection into T-cadherin-negative neuroblastoma lines with EGF proliferation assay\",\n      \"pmids\": [\"10737605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GPI-anchored CDH13 to intracellular EGF signaling not defined\", \"No loss-of-function complement\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The structural basis of CDH13's unusual biology was clarified: unlike classical cadherins, CDH13 is anchored exclusively by a GPI moiety and lacks a cytoplasmic domain, explaining its inability to directly engage catenin signaling.\",\n      \"evidence\": \"Biochemical/structural characterization of GPI anchor, replicated across multiple labs\",\n      \"pmids\": [\"11642747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GPI-anchored CDH13 transduces signals intracellularly remains unresolved\", \"No crystal structure of the full extracellular domain\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Epigenetic silencing of CDH13 was established as a general cancer mechanism when promoter hypermethylation was shown to cause transcriptional shutdown in breast and lung cancers, reversible by 5-aza-2′-deoxycytidine.\",\n      \"evidence\": \"Methylation-specific PCR, RT-PCR, and demethylation rescue across multiple cancer cell lines\",\n      \"pmids\": [\"11389090\", \"12067979\", \"9737784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the methyltransferases responsible was unknown at this stage\", \"Whether methylation is a driver or passenger in tumorigenesis was unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"CDH13's metabolic role was expanded beyond vasculature: CDH13 localizes to insulin secretory granules in β-cells and is required for second-phase glucose-stimulated insulin secretion, independent of adiponectin.\",\n      \"evidence\": \"Immunohistochemistry, electron microscopy, hyperglycemic clamp, and glucose-stimulated insulin secretion in Cdh13-KO mice and isolated islets\",\n      \"pmids\": [\"21975561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CDH13 facilitates granule exocytosis is unknown\", \"Whether GPI-anchor cleavage releases CDH13 into the granule lumen was not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The long-debated question of whether CDH13 is a signaling receptor or a sequestration site for adiponectin was resolved: genetic epistasis in bideficient mice showed CDH13 sequesters high-molecular-weight adiponectin on vascular endothelium rather than transducing its signal.\",\n      \"evidence\": \"T-cad−/−, adiponectin/T-cad double-KO mice; serum adiponectin ELISA; OVA-challenge and ozone pulmonary models\",\n      \"pmids\": [\"22815927\", \"23755285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate of sequestered adiponectin (internalization vs surface retention) not determined\", \"Tissue-specific contribution of endothelial vs other cell CDH13 pools not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CDH13's tumor-suppressive signaling was mechanistically delineated: re-expression in melanoma causes AKT/FoxO3a hypophosphorylation, loss of BCL-2/BCL-x/Clusterin, and apoptosis sensitization, while NF-κB, TCF/LEF, and mTOR pathways are excluded.\",\n      \"evidence\": \"CDH13 expression in melanoma cells; xenograft growth; Western blot for AKT, FoxO3a, BCL-2 family; transcriptional reporter assays; CD95/Fas apoptosis assay\",\n      \"pmids\": [\"23625515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signal transduction from GPI-anchored CDH13 to AKT inhibition unknown\", \"No identification of a co-receptor or lipid-raft partner mediating signal relay\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Transcriptional repression of CDH13 was linked to a specific transcription factor: BRN2 directly binds the CDH13 promoter at −219 bp and suppresses transcription, promoting melanoma invasion.\",\n      \"evidence\": \"EMSA for BRN2 binding element, reporter assay, reciprocal BRN2 overexpression/siRNA with CDH13 measurement\",\n      \"pmids\": [\"23069940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRN2-mediated repression cooperates with DNA methylation was not tested\", \"Relevance beyond melanoma undetermined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The epigenetic machinery responsible for CDH13 methylation was identified: UHRF1 and PRMT5 form a complex that maintains CDH13 promoter methylation, and combined DNA methylation plus histone modification inhibition fully restores expression.\",\n      \"evidence\": \"Co-immunoprecipitation of UHRF1/PRMT5; methylation-specific PCR; 5-Aza-CdR + TSA dual treatment in endometrial carcinoma cells\",\n      \"pmids\": [\"26597461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal IP or endogenous complex validation\", \"Whether PRMT5 acts via histone arginine methylation at CDH13 locus specifically was not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CDH13's role in addiction-relevant behavior was established: Cdh13-KO rats show enhanced cue-induced reinstatement of cocaine seeking without altered conditioned place preference, dissociating CDH13 from drug reward per se and linking it to drug-cue associative learning.\",\n      \"evidence\": \"Cdh13-KO rat; intravenous cocaine self-administration, cue-induced reinstatement, conditioned place preference, locomotor assays\",\n      \"pmids\": [\"28387990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circuit-level mechanism (which brain region and synapse type) not identified\", \"Whether the phenotype maps to GABAergic synapse dysfunction was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CDH13's neural circuit function was defined: in adult hippocampus CDH13 is restricted to presynaptic GABAergic terminals, and its loss increases inhibitory drive onto CA1 pyramidal neurons, shifting excitatory/inhibitory balance.\",\n      \"evidence\": \"Cdh13-KO mouse; hippocampal expression localization; electrophysiology-derived inhibitory drive measurement; serotonergic neuron migration analysis\",\n      \"pmids\": [\"30165120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDH13 acts as a synapse-organizing molecule or modulates GABA release probability is unknown\", \"Causal link between hippocampal E/I shift and behavioral phenotypes not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An active demethylation pathway for CDH13 was discovered: DNA polymerase β promotes CDH13 expression through BER-dependent demethylation of its promoter, and CDH13 is the functional effector of Pol β's anti-migratory and anti-angiogenic activity.\",\n      \"evidence\": \"Pol β overexpression/knockdown in cancer cells and xenografts; CDH13 KD rescue; CDH13 promoter methylation analysis; migration, invasion, and tube formation assays\",\n      \"pmids\": [\"32641859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Pol β acts directly at the CDH13 locus via TET-BER or passive demethylation not distinguished\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CDH13 re-expression was shown to overcome drug resistance in imatinib-resistant CML by inhibiting NF-κB signaling and inducing apoptosis, expanding CDH13's tumor-suppressive role to hematological malignancies.\",\n      \"evidence\": \"saRNA-mediated CDH13 activation in BCR-ABL1-independent resistant CML cells; NF-κB pathway analysis; apoptosis and colony assays; LNP-saRNA xenograft\",\n      \"pmids\": [\"39179585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CDH13 inhibits NF-κB (direct vs indirect) not resolved\", \"Contrast with earlier melanoma finding excluding NF-κB suggests context-dependence that is unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a GPI-anchored protein lacking a cytoplasmic domain transduces intracellular signals to inhibit AKT, regulate NF-κB, and modulate synaptic function remains the central unresolved question; no co-receptor, lipid-raft partner, or signaling intermediary has been identified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-receptor or transmembrane partner identified\", \"No structural model of the CDH13 ectodomain at atomic resolution\", \"Tissue-specific signaling outputs (endothelium vs neuron vs β-cell) not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 9, 20]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 12, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ADIPOQ\",\n      \"BRN2\",\n      \"UHRF1\",\n      \"PRMT5\",\n      \"POLB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}