{"gene":"CDH13","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2000,"finding":"CDH13 (T-cadherin) functions as a negative regulator of EGF-induced mitogenic proliferation in neuroblastoma cells: T-cadherin-negative TGW and NH-12 neuroblastoma cells transfected with T-cadherin cDNA lost their mitogenic proliferative response to epidermal growth factor.","method":"Stable transfection of T-cadherin cDNA into T-cadherin-negative neuroblastoma cell lines, proliferation assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function/gain-of-function in cell lines with defined proliferative phenotype, single lab, single method","pmids":["10737605"],"is_preprint":false},{"year":2001,"finding":"CDH13 (T-cadherin) expression downregulates surfactant protein D (SP-D) gene expression in human bronchioloalveolar type-II cells: A549 cells transfected with T-cadherin cDNA lost SP-D mRNA and protein expression, while control-transfected cells retained SP-D expression.","method":"Stable transfection of T-cadherin expression vector into A549 cells; RT-PCR and Western blot for SP-D","journal":"Virchows Archiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function experiment with two orthogonal readouts (RT-PCR + Western blot), single lab","pmids":["11355171"],"is_preprint":false},{"year":2001,"finding":"CDH13 (T-cadherin) is a GPI-anchored cadherin lacking a cytoplasmic domain and transmembrane region, anchored to the cell surface membrane through a glycosyl phosphatidyl inositol moiety.","method":"Biochemical characterization, structural analysis reviewed","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — structural feature established by multiple prior biochemical studies and reviewed; GPI anchor confirmed by multiple labs","pmids":["11642747"],"is_preprint":false},{"year":2001,"finding":"CDH13 promoter methylation causes biallelic silencing of CDH13 expression in breast and lung cancer cell lines; demethylation with 5-aza-2-deoxycytidine restores CDH13 mRNA expression, confirming that promoter hypermethylation is a direct mechanism of CDH13 gene silencing.","method":"Methylation-specific PCR, RT-PCR, 5-aza-2-deoxycytidine demethylation treatment in cancer cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — demethylation rescue confirmed in multiple cell lines, replicated across multiple cancer types and labs","pmids":["11389090"],"is_preprint":false},{"year":2002,"finding":"CDH13 promoter methylation combined with loss of heterozygosity causes loss of CDH13 expression in invasive cutaneous squamous cell carcinoma; demethylation with 5-aza-2-deoxycytidine restores T-cadherin expression in A431 cells with aberrant methylation.","method":"LOH analysis, methylation-specific PCR, sequence analysis, 5-aza-2-deoxycytidine treatment, immunohistochemistry, Western blot","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (LOH, MSP, demethylation rescue, IHC, Western blot), consistent with findings in multiple cancer types","pmids":["12177241"],"is_preprint":false},{"year":2012,"finding":"BRN2 (POU3F2/N-Oct-3) is a direct transcriptional repressor of CDH13 in melanoma cells: BRN2 binds to the CDH13 promoter at a regulatory element (-219 bp, sequence 5'-CATGCAAAA-3') and represses CDH13 promoter activity; BRN2 overexpression suppresses CDH13, while BRN2 knockdown restores T-cadherin expression.","method":"Reporter gene (luciferase) assay, electrophoretic mobility shift assay (EMSA), ectopic expression and siRNA knockdown of BRN2 in melanoma cells, RT-PCR, Western blot","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reconstitution via reporter assay and EMSA with direct binding demonstration, plus gain- and loss-of-function experiments, single lab with multiple orthogonal methods","pmids":["23069940"],"is_preprint":false},{"year":2013,"finding":"CDH13 (T-cadherin) functions as a pro-apoptotic tumor suppressor in melanoma by antagonizing AKT/CREB/AP-1/FoxO3a signaling: T-cadherin expression induces AKT and FoxO3a hypophosphorylation, downregulates BCL-2, BCL-xL, and Clusterin, and reduces CREB and AP-1 transcriptional activity, sensitizing cells to CD95/Fas-mediated apoptosis. NFκB, TCF/LEF, and mTOR are not part of T-cadherin signaling.","method":"Stable CDH13 expression in melanoma cells, tumor xenograft in nude mice, Western blot (pAKT, pFoxO3a, BCL-2, BCL-xL, Clusterin), reporter gene assay (CREB, AP-1, NFκB, TCF/LEF, mTOR), apoptosis assay with CD95/Fas antibody","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft plus multiple molecular pathway readouts with defined epistasis (NFκB, mTOR ruled out), single lab with multiple orthogonal methods","pmids":["23625515"],"is_preprint":false},{"year":2011,"finding":"CDH13 (T-cadherin) associates with insulin granules in pancreatic β-cells and is required for second-phase glucose-induced insulin secretion: T-cadherin was found on insulin granules by immunohistochemistry and electron microscopy; T-cadherin-deficient (Tcad-KO) mice showed impaired glucose-induced but not KCl-mediated insulin secretion in vitro, and defective second-phase insulin release during hyperglycemic clamp in vivo, leading to progressive glucose intolerance.","method":"Immunohistochemistry, electron microscopy, RFP-tagged T-cadherin colocalization with GFP-labeled insulin granules, Tcad-KO mouse phenotyping, in vitro islet insulin secretion assay, in vivo hyperglycemic clamp","journal":"Islets","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, live imaging, KO in vitro and in vivo), clear mechanistic dissection (second phase vs first phase), single lab","pmids":["21975561"],"is_preprint":false},{"year":2011,"finding":"T-cadherin deficiency (T-cad KO) protects against OVA-induced allergic airway hyperresponsiveness and inflammation; the protective effect requires adiponectin, as combined adiponectin/T-cad bideficiency reverses it; T-cad KO elevates circulating adiponectin levels because adiponectin normally sequestered by endothelial T-cad remains free in circulation.","method":"T-cad KO and adiponectin/T-cad bideficient mouse models, OVA sensitization and challenge, airway hyperresponsiveness measurement, BAL cell counting, cytokine/eotaxin mRNA, lung histology, serum adiponectin ELISA","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double KO rescue, multiple phenotypic readouts, mechanistic dissection of adiponectin sequestration by T-cad","pmids":["22815927"],"is_preprint":false},{"year":2013,"finding":"T-cadherin binding to adiponectin (specifically HMW isoforms) via endothelial T-cadherin is required for suppression of ozone-induced IL-17A expression and pulmonary inflammation: T-cad KO mice showed augmented IL-17A induction by ozone, and T-cad/Adipo double-KO showed no further increase compared to T-cad KO alone, establishing T-cad as required mediator of adiponectin's suppression of IL-17A in the lung.","method":"Genetic epistasis with T-cad KO, Adipo KO, and T-cad/Adipo double-KO mice; ozone exposure; pulmonary IL-17A, saa3 mRNA; BAL neutrophils; G-CSF; lung histology","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — three genotypes with double-KO epistasis clearly resolves pathway, multiple molecular readouts, single lab","pmids":["23755285"],"is_preprint":false},{"year":2013,"finding":"CDH13 missense variants found in ADHD patients are processed canonically as GPI-anchored proteins; wild-type and mutant CDH13 proteins showed similar expression levels and subcellular distribution in CHO and HEK293 cells, indicating no significant functional difference in processing or localization for these rare variants.","method":"Sequencing of CDH13 in ADHD patients and controls; GFP-tagged and native protein expression in CHO/HEK293 cells; immunofluorescence localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — protein localization and expression confirmed canonical GPI processing, but negative result for functional difference; single lab, single study","pmids":["23936508"],"is_preprint":false},{"year":2012,"finding":"CDH13 knockdown in bladder TCC 5637 cells promotes cell migration, invasion, adhesion, and upregulates MMP2 expression, establishing CDH13 as a suppressor of invasiveness in bladder cancer acting via MMP2 regulation.","method":"siRNA knockdown of CDH13 in 5637 bladder cancer cells; migration/invasion/adhesion assays; RT-PCR and Western blot for MMP2; IHC in primary tumor tissues","journal":"Urologia internationalis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple cellular assays and molecular readout (MMP2), single lab, consistent with tissue data","pmids":["23235385"],"is_preprint":false},{"year":2015,"finding":"The UHRF1/PRMT5 complex contributes to CDH13 promoter methylation in endometrial carcinoma: Co-immunoprecipitation demonstrated PRMT5 binds UHRF1; combined 5-Aza-CdR and TSA treatment completely reversed CDH13 methylation and restored expression, while either agent alone only partially reversed it.","method":"Co-immunoprecipitation (UHRF1-PRMT5 interaction), methylation-specific PCR, qRT-PCR, 5-Aza-CdR and TSA treatment of endometrial carcinoma cell lines","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for UHRF1/PRMT5 interaction and demethylation rescue, but mechanistic link between complex and CDH13 methylation inferred rather than directly reconstituted; single lab","pmids":["26597461"],"is_preprint":false},{"year":2018,"finding":"microRNA-377 directly targets CDH13 mRNA: dual-luciferase reporter assay confirmed miR-377 binds the CDH13 3'-UTR; miR-377 knockdown in an Alzheimer's disease cell model increased CDH13 expression and reduced cell viability, while CDH13 knockdown reversed these effects.","method":"Dual-luciferase reporter gene assay, qRT-PCR, Western blot, CCK-8 viability assay, flow cytometry apoptosis assay in SH-SY5Y cells","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase reporter validates direct miRNA-CDH13 interaction, functional rescue confirms pathway; single lab, single study","pmids":["29771432"],"is_preprint":false},{"year":2018,"finding":"CDH13 modulates lipid metabolism during adipogenesis but not in mature adipocytes: CDH13 knockdown during adipogenesis reduced fatty acid uptake, lipid content, and blunted induction of PPARγ and C/EBPα expression in 3T3-L1 adipocytes.","method":"CDH13 knockdown in 3T3-L1 adipocytes during differentiation; fatty acid uptake assay; lipid content measurement; RT-PCR/Western blot for PPARγ and C/EBPα","journal":"International journal of obesity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple orthogonal readouts (fatty acid uptake, lipid content, transcription factor expression), single lab","pmids":["29467502"],"is_preprint":false},{"year":2020,"finding":"DNA polymerase β (Pol β) promotes CDH13 expression through demethylation of the CDH13 promoter via its role in base excision repair; CDH13 mediates the anti-migratory and anti-invasive effects of Pol β in breast and lung cancer cells, as CDH13 knockdown rescues migration, invasion, and angiogenesis suppressed by Pol β overexpression.","method":"Pol β overexpression and knockdown in breast/lung cancer cells; CDH13 mRNA/protein measurement; CDH13 promoter methylation analysis; migration/invasion assays; mouse xenograft tumor model; CDH13 siRNA rescue experiment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by CDH13 knockdown rescue plus in vivo xenograft, multiple assays; indirect mechanism (BER-dependent demethylation) inferred but not reconstituted in vitro; single lab","pmids":["32641859"],"is_preprint":false},{"year":2018,"finding":"CDH13 deficiency in mice leads to increased inhibitory drive onto hippocampal CA1 pyramidal neurons, a shift in excitatory/inhibitory balance, and moderates migration of serotonergic neurons in the dorsal raphe nucleus preferentially projecting to thalamus and cerebellum; CDH13 knockout mice show impaired fear extinction and increased stress-related behavioral phenotypes.","method":"Cdh13 knockout (KO, heterozygous, homozygous) mice; behavioral battery (Barnes maze, fear conditioning, light-dark test, locomotor); hippocampal transcriptome analysis; inference from electrophysiology data cited in abstract","journal":"Progress in neuro-psychopharmacology & biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined behavioral and transcriptomic phenotypes; electrophysiology claims referenced but not directly described in this abstract; single lab","pmids":["30165120"],"is_preprint":false},{"year":2024,"finding":"CDH13 (T-cadherin) interacts with MyD88 as shown by molecular docking simulations and co-immunoprecipitation; pharmacological treatment with PDA upregulates MyD88 in smooth muscle cells and interacts with CDH13, augmenting SMC proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling.","method":"Molecular docking, co-immunoprecipitation, smooth muscle cell proliferation assay (BrdU), Boyden chamber migration assay, spheroid sprouting assay, Matrigel tube formation, carotid artery ligation mouse model","journal":"Chinese journal of natural medicines","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP confirms CDH13-MyD88 interaction, supported by in vivo and in vitro functional assays; single lab, single study","pmids":["38278560"],"is_preprint":false},{"year":2024,"finding":"CDH13 expression promotes melanoma cell sensitivity to garcinol-induced apoptosis: garcinol reduced proliferation and induced apoptosis more effectively in CDH13-positive melanoma cells; siRNA knockdown of CDH13 reduced garcinol sensitivity and restored proliferation and anti-apoptotic behavior.","method":"siRNA knockdown of CDH13 in melanoma cell lines; proliferation assay; apoptosis assay; garcinol treatment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNAi rescue experiment demonstrating CDH13-dependent drug sensitivity, single lab, single study","pmids":["38791932"],"is_preprint":false},{"year":2024,"finding":"CDH13 activation via small activating RNA (saRNA) in imatinib-resistant CML cells inhibits NF-κB signaling pathway and induces apoptosis, overcoming BCR-ABL1-independent imatinib resistance; LNP-delivered saRNA also limited K562-IMR tumor growth in vivo.","method":"saRNA design targeting CDH13 promoter; qPCR and Western blot for CDH13 expression; cell viability and colony formation assays; NF-κB pathway activity measurement; mouse xenograft model with LNP-saRNA","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function via saRNA with in vitro and in vivo validation; NF-κB pathway identified as downstream effector; single lab","pmids":["39179585"],"is_preprint":false},{"year":2025,"finding":"CDH13 mRNA stability is regulated by the lncRNA CDH13-AS2, which binds CDH13 mRNA in endothelial cells and protects it from miRNA-mediated degradation; miRNAs miR-19b-3p, miR-125b-2-3p, miR-433-3p, and miR-7b-5p accelerate CDH13 mRNA degradation, an effect neutralized by CRISPRa activation of CDH13-AS2. CDH13 loss of function increases atherosclerotic plaque size in Cdh13/Apoe double-KO mice on a Western diet.","method":"dCas13-mediated RNA immunoprecipitation (CDH13-AS2 binding to CDH13 mRNA), CRISPR/Cas9 KO and CRISPRa of CDH13-AS2 in human endothelial cells, miRNA screen, Cdh13/Apoe double-KO mouse model with Western diet, UK Biobank LoF variant analysis","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation confirms direct lncRNA-mRNA binding, genetic rescue via CRISPRa, in vivo atherosclerosis model; preprint, not yet peer-reviewed","pmids":["40894025"],"is_preprint":true},{"year":2026,"finding":"CDH13 is expressed in endothelial cells of pathological neovascular membranes; CDH13 knockdown inhibits pathological vessel growth and promotes vascular normalization in OIR and CNV mouse models; mechanistically, hypoxia suppresses NR2F2, de-repressing CDH13 transcription and activating NF-κB to drive vascular dysfunction; CDH13 inhibition with LXR agonist GW3965 reduced LDL deposition and pathological neovascularization.","method":"CDH13 knockdown in OIR/CNV mouse models; in vitro transwell, wound healing, EdU assays; dual-luciferase reporter assay (NR2F2-CDH13 axis); RT-PCR, Western blot; fundus fluorescein angiography; isolectin B4 staining; bioinformatics of human nAMD FVMs","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO models with multiple phenotypic readouts and reporter assay defining upstream transcriptional regulation; single lab, single study","pmids":["41814412"],"is_preprint":false}],"current_model":"CDH13 (T-cadherin/H-cadherin) is an atypical GPI-anchored cadherin that lacks both transmembrane and cytoplasmic domains and signals through its extracellular domain to regulate cell proliferation, adhesion, migration, apoptosis, insulin secretion, adipogenesis, and vascular biology; it acts as a negative regulator of EGF-driven neuronal proliferation, a pro-apoptotic tumor suppressor that antagonizes AKT/CREB/AP-1/FoxO3a signaling in melanoma, a component of pancreatic β-cell insulin granules required for second-phase glucose-stimulated insulin secretion, a vascular endothelial receptor that sequesters HMW adiponectin and mediates its anti-inflammatory effects (including ozone-induced IL-17A suppression), a modulator of lipid metabolism and PPARγ/C/EBPα induction during adipogenesis, and a suppressor of cancer cell invasiveness partly via MMP2 downregulation; its expression is silenced in numerous cancers primarily by promoter CpG hypermethylation (regulated by UHRF1/PRMT5 and Pol β-dependent demethylation) and also by direct transcriptional repression via BRN2 and post-transcriptional regulation via miRNAs (including miR-377) and the lncRNA CDH13-AS2."},"narrative":{"mechanistic_narrative":"CDH13 (T-cadherin/H-cadherin) is an atypical GPI-anchored cadherin that lacks transmembrane and cytoplasmic domains and signals from the cell surface to control proliferation, adhesion, apoptosis, metabolism, and vascular biology [PMID:11642747]. In tumor cells it behaves as a pro-apoptotic suppressor: re-expression antagonizes AKT/CREB/AP-1/FoxO3a signaling, downregulates BCL-2, BCL-xL, and Clusterin, and sensitizes melanoma cells to CD95/Fas-mediated apoptosis [PMID:23625515], while in bladder carcinoma loss of CDH13 promotes migration, invasion, and adhesion through upregulation of MMP2 [PMID:23235385]. Consistent with a tumor-suppressor role, CDH13 is silenced across breast, lung, and squamous cancers primarily by promoter CpG hypermethylation, reversible with demethylating agents [PMID:11389090, PMID:12177241], reinforced by combined methylation/histone-deacetylation through a UHRF1/PRMT5 axis [PMID:26597461] and opposed by Pol β-dependent promoter demethylation that restores its anti-migratory activity [PMID:32641859]; expression is further controlled by direct transcriptional repression via BRN2 [PMID:23069940] and by post-transcriptional regulation through miR-377 and the lncRNA CDH13-AS2 [PMID:29771432]. As an endothelial receptor, CDH13 sequesters HMW adiponectin and is required for adiponectin-dependent suppression of airway and ozone-induced IL-17A inflammation [PMID:22815927, PMID:23755285], and it participates in pathological vascular remodeling and neovascularization via NF-κB and MyD88 signaling [PMID:38278560, PMID:41814412]. CDH13 also localizes to pancreatic β-cell insulin granules and is required for second-phase glucose-stimulated insulin secretion [PMID:21975561], and supports adipogenesis by promoting fatty acid uptake and PPARγ/C/EBPα induction [PMID:29467502]. In the nervous system CDH13 negatively regulates EGF-driven neuronal proliferation [PMID:10737605] and shapes excitatory/inhibitory balance and serotonergic neuron migration relevant to fear and stress behavior [PMID:30165120].","teleology":[{"year":2000,"claim":"Established the first functional role for CDH13, showing it restrains growth-factor-driven proliferation rather than acting purely as an adhesion molecule.","evidence":"Gain-of-function transfection of T-cadherin into negative neuroblastoma cells with EGF proliferation assay","pmids":["10737605"],"confidence":"Medium","gaps":["Mechanism by which the GPI-anchored ectodomain blocks EGF mitogenic signaling not defined","Single cell-line context"]},{"year":2001,"claim":"Defined the defining structural feature — a GPI anchor with no transmembrane or cytoplasmic domain — framing CDH13 as a signaling receptor that must act through partners.","evidence":"Biochemical/structural characterization reviewed","pmids":["11642747"],"confidence":"Medium","gaps":["Does not identify the transmembrane co-receptors that transduce CDH13 signals"]},{"year":2001,"claim":"Identified promoter CpG hypermethylation as a direct, reversible silencing mechanism for CDH13 in cancer, explaining its frequent loss.","evidence":"Methylation-specific PCR and 5-aza-2-deoxycytidine demethylation rescue in breast and lung cancer cell lines","pmids":["11389090"],"confidence":"High","gaps":["Enzymes establishing the methylation not identified here","Causal link to tumor phenotype not yet shown"]},{"year":2002,"claim":"Showed that methylation cooperates with loss of heterozygosity to fully inactivate CDH13 in invasive squamous carcinoma, supporting a two-hit tumor-suppressor model.","evidence":"LOH, MSP, demethylation rescue, IHC and Western blot in cutaneous SCC and A431 cells","pmids":["12177241"],"confidence":"High","gaps":["Functional consequence of biallelic loss for invasion not directly tested"]},{"year":2011,"claim":"Revealed an unexpected metabolic role: CDH13 resides on insulin granules and is specifically required for second-phase glucose-stimulated insulin secretion.","evidence":"EM, live-cell colocalization, Tcad-KO mouse islet secretion assays and in vivo hyperglycemic clamp","pmids":["21975561"],"confidence":"High","gaps":["Molecular role on the granule (docking vs trafficking) unresolved","Binding partner on granules not identified"]},{"year":2011,"claim":"Established CDH13 as the endothelial receptor that sequesters adiponectin, defining how it controls circulating adiponectin levels and allergic airway inflammation.","evidence":"T-cad KO and adiponectin/T-cad double-KO epistasis in OVA airway model with serum adiponectin ELISA","pmids":["22815927"],"confidence":"High","gaps":["Downstream signaling from the CDH13-adiponectin complex not mapped"]},{"year":2012,"claim":"Identified BRN2 as a direct transcriptional repressor of CDH13, adding a methylation-independent silencing route in melanoma.","evidence":"Luciferase reporter, EMSA, BRN2 overexpression and knockdown in melanoma cells","pmids":["23069940"],"confidence":"High","gaps":["Interplay between BRN2 repression and promoter methylation not resolved"]},{"year":2012,"claim":"Provided functional evidence that CDH13 suppresses cancer cell invasiveness through MMP2 regulation.","evidence":"siRNA knockdown in bladder TCC 5637 cells with migration/invasion/adhesion assays and MMP2 readout","pmids":["23235385"],"confidence":"Medium","gaps":["Mechanism linking CDH13 loss to MMP2 induction unknown","Single cell line"]},{"year":2013,"claim":"Mapped the pro-apoptotic tumor-suppressor signaling of CDH13, showing it antagonizes AKT/CREB/AP-1/FoxO3a survival signaling and ruling out NFκB/mTOR involvement.","evidence":"Stable expression in melanoma, xenografts, pathway Western blots, reporter assays, CD95/Fas apoptosis assay","pmids":["23625515"],"confidence":"High","gaps":["How the GPI-anchored ectodomain reaches intracellular AKT signaling is not defined"]},{"year":2013,"claim":"Demonstrated that CDH13 is the obligate mediator of adiponectin's suppression of ozone-induced IL-17A pulmonary inflammation.","evidence":"T-cad KO, Adipo KO, and double-KO epistasis with ozone exposure and IL-17A readouts","pmids":["23755285"],"confidence":"High","gaps":["Cell type and signaling cascade linking endothelial CDH13 to IL-17A suppression not detailed"]},{"year":2013,"claim":"Tested whether ADHD-associated CDH13 missense variants disrupt protein processing, finding canonical GPI anchoring and localization unaffected.","evidence":"Expression of WT and mutant CDH13 in CHO/HEK293 with immunofluorescence","pmids":["23936508"],"confidence":"Medium","gaps":["Negative result; functional consequence of variants on signaling not addressed"]},{"year":2015,"claim":"Linked a UHRF1/PRMT5 complex to CDH13 promoter methylation, indicating coordinated DNA and histone modification silences the gene.","evidence":"Co-IP of UHRF1-PRMT5 and combined 5-Aza-CdR/TSA rescue in endometrial carcinoma cells","pmids":["26597461"],"confidence":"Medium","gaps":["Direct recruitment of UHRF1/PRMT5 to the CDH13 promoter inferred, not reconstituted"]},{"year":2018,"claim":"Showed CDH13 promotes adipocyte differentiation by enabling fatty acid uptake and PPARγ/C/EBPα induction, extending its metabolic function to lipid handling.","evidence":"CDH13 knockdown during 3T3-L1 differentiation with fatty acid uptake, lipid, and transcription factor readouts","pmids":["29467502"],"confidence":"Medium","gaps":["No effect in mature adipocytes; receptor-level mechanism for lipid uptake unknown"]},{"year":2018,"claim":"Identified miR-377 as a direct post-transcriptional regulator of CDH13 in a neuronal disease model.","evidence":"Dual-luciferase 3'-UTR reporter and rescue assays in SH-SY5Y cells","pmids":["29771432"],"confidence":"Medium","gaps":["Physiological relevance beyond the cell model unestablished","Single study"]},{"year":2018,"claim":"Defined CNS functions for CDH13 in excitatory/inhibitory balance, serotonergic neuron migration, and fear/stress behavior.","evidence":"Cdh13 KO mouse behavioral battery, hippocampal transcriptomics, cited electrophysiology","pmids":["30165120"],"confidence":"Medium","gaps":["Electrophysiology not directly described","Molecular pathway in neurons not defined"]},{"year":2020,"claim":"Established that Pol β-driven base-excision-repair demethylation reactivates CDH13, with CDH13 mediating Pol β's anti-migratory and anti-angiogenic effects.","evidence":"Pol β overexpression/knockdown, methylation analysis, CDH13 siRNA rescue, xenografts in breast/lung cancer","pmids":["32641859"],"confidence":"Medium","gaps":["BER-dependent demethylation inferred but not reconstituted in vitro"]},{"year":2024,"claim":"Implicated CDH13 in pathological vascular remodeling through interaction with MyD88, augmenting smooth muscle cell proliferation and ECM deposition.","evidence":"Molecular docking, Co-IP, SMC proliferation/migration/sprouting assays, carotid ligation mouse model","pmids":["38278560"],"confidence":"Medium","gaps":["CDH13-MyD88 interaction from docking and single Co-IP without reciprocal validation","Single study"]},{"year":2024,"claim":"Showed CDH13 expression confers melanoma sensitivity to garcinol-induced apoptosis, linking its tumor-suppressor function to drug response.","evidence":"siRNA knockdown and garcinol treatment in melanoma cell lines with proliferation/apoptosis assays","pmids":["38791932"],"confidence":"Medium","gaps":["Mechanism connecting CDH13 to garcinol response not defined","Single study"]},{"year":2024,"claim":"Demonstrated that restoring CDH13 via small activating RNA overcomes BCR-ABL1-independent imatinib resistance by inhibiting NF-κB and inducing apoptosis.","evidence":"saRNA targeting CDH13 promoter, viability/colony assays, NF-κB readout, LNP-saRNA xenograft in CML cells","pmids":["39179585"],"confidence":"Medium","gaps":["How surface CDH13 modulates NF-κB not mechanistically resolved"]},{"year":2025,"claim":"Identified the lncRNA CDH13-AS2 as a stabilizer of CDH13 mRNA against miRNA-mediated decay and linked CDH13 loss to atherosclerosis.","evidence":"dCas13 RNA-IP, CRISPRa/KO in endothelial cells, miRNA screen, Cdh13/Apoe double-KO atherosclerosis model (preprint)","pmids":["40894025"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism of CDH13-AS2 protection of mRNA not detailed"]},{"year":2026,"claim":"Placed CDH13 in a hypoxia-NR2F2-NFκB axis driving pathological neovascularization, defining an upstream transcriptional regulator and therapeutic angle.","evidence":"CDH13 knockdown in OIR/CNV models, dual-luciferase NR2F2-CDH13 reporter, LXR agonist treatment, human FVM bioinformatics","pmids":["41814412"],"confidence":"Medium","gaps":["How surface CDH13 activates NF-κB in endothelium not defined","Single study"]},{"year":null,"claim":"How a GPI-anchored cadherin lacking a cytoplasmic domain transduces signals to intracellular pathways (AKT/FoxO3a, NFκB, MyD88) across its many contexts remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Transmembrane co-receptor(s) for CDH13 not identified","Unified signaling mechanism across cancer, metabolic, vascular, and neural roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,8,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,17,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,18,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,15]}],"complexes":[],"partners":["ADIPOQ","MYD88"],"other_free_text":[]}},"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. 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methylation of CDH13, TFPI2, and FSTL1 in squamous cell carcinoma of the esophagus in vivo.","date":"2016","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/27400374","citation_count":6,"is_preprint":false},{"pmid":"16133358","id":"PMC_16133358","title":"T-/H-cadherin (CDH13): a new marker for differentiating podocytes.","date":"2005","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16133358","citation_count":6,"is_preprint":false},{"pmid":"24688318","id":"PMC_24688318","title":"Association study of ARL15 and CDH13 with T2DM in a Han Chinese population.","date":"2014","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24688318","citation_count":6,"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":5,"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":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":"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":"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":"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":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":"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":"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 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Herzegovina)","url":"https://pubmed.ncbi.nlm.nih.gov/34759445","citation_count":0,"is_preprint":false},{"pmid":"41388436","id":"PMC_41388436","title":"Multimodal analysis reveals potential association of CDH13 with endothelial cells and its overexpression in hepatocellular carcinoma.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41388436","citation_count":0,"is_preprint":false},{"pmid":"19199263","id":"PMC_19199263","title":"[Expression of the CDH13 gene and BCR/ABL fusion gene in chronic myeloid leukemia patients and their relationship].","date":"2009","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19199263","citation_count":0,"is_preprint":false},{"pmid":"41814412","id":"PMC_41814412","title":"Targeting CDH13 as a therapeutic strategy to mitigate pathological ocular angiogenesis.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41814412","citation_count":0,"is_preprint":false},{"pmid":"29419874","id":"PMC_29419874","title":"[Association of single nucleotide polymorphisms of CDH13 gene with metabolic syndrome among ethnic Han Chinese].","date":"2018","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29419874","citation_count":0,"is_preprint":false},{"pmid":"41898868","id":"PMC_41898868","title":"Association Between CDH13 rs12596316 and Adiponectin Levels According to Fasting Glucose Status in a Korean Population.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41898868","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54272,"output_tokens":6173,"usd":0.127705,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14943,"output_tokens":5601,"usd":0.10737,"stage2_stop_reason":"end_turn"},"total_usd":0.235075,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CDH13 (T-cadherin) functions as a negative regulator of EGF-induced mitogenic proliferation in neuroblastoma cells: T-cadherin-negative TGW and NH-12 neuroblastoma cells transfected with T-cadherin cDNA lost their mitogenic proliferative response to epidermal growth factor.\",\n      \"method\": \"Stable transfection of T-cadherin cDNA into T-cadherin-negative neuroblastoma cell lines, proliferation assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function/gain-of-function in cell lines with defined proliferative phenotype, single lab, single method\",\n      \"pmids\": [\"10737605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDH13 (T-cadherin) expression downregulates surfactant protein D (SP-D) gene expression in human bronchioloalveolar type-II cells: A549 cells transfected with T-cadherin cDNA lost SP-D mRNA and protein expression, while control-transfected cells retained SP-D expression.\",\n      \"method\": \"Stable transfection of T-cadherin expression vector into A549 cells; RT-PCR and Western blot for SP-D\",\n      \"journal\": \"Virchows Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function experiment with two orthogonal readouts (RT-PCR + Western blot), single lab\",\n      \"pmids\": [\"11355171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDH13 (T-cadherin) is a GPI-anchored cadherin lacking a cytoplasmic domain and transmembrane region, anchored to the cell surface membrane through a glycosyl phosphatidyl inositol moiety.\",\n      \"method\": \"Biochemical characterization, structural analysis reviewed\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — structural feature established by multiple prior biochemical studies and reviewed; GPI anchor confirmed by multiple labs\",\n      \"pmids\": [\"11642747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDH13 promoter methylation causes biallelic silencing of CDH13 expression in breast and lung cancer cell lines; demethylation with 5-aza-2-deoxycytidine restores CDH13 mRNA expression, confirming that promoter hypermethylation is a direct mechanism of CDH13 gene silencing.\",\n      \"method\": \"Methylation-specific PCR, RT-PCR, 5-aza-2-deoxycytidine demethylation treatment in cancer cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — demethylation rescue confirmed in multiple cell lines, replicated across multiple cancer types and labs\",\n      \"pmids\": [\"11389090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CDH13 promoter methylation combined with loss of heterozygosity causes loss of CDH13 expression in invasive cutaneous squamous cell carcinoma; demethylation with 5-aza-2-deoxycytidine restores T-cadherin expression in A431 cells with aberrant methylation.\",\n      \"method\": \"LOH analysis, methylation-specific PCR, sequence analysis, 5-aza-2-deoxycytidine treatment, immunohistochemistry, Western blot\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (LOH, MSP, demethylation rescue, IHC, Western blot), consistent with findings in multiple cancer types\",\n      \"pmids\": [\"12177241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BRN2 (POU3F2/N-Oct-3) is a direct transcriptional repressor of CDH13 in melanoma cells: BRN2 binds to the CDH13 promoter at a regulatory element (-219 bp, sequence 5'-CATGCAAAA-3') and represses CDH13 promoter activity; BRN2 overexpression suppresses CDH13, while BRN2 knockdown restores T-cadherin expression.\",\n      \"method\": \"Reporter gene (luciferase) assay, electrophoretic mobility shift assay (EMSA), ectopic expression and siRNA knockdown of BRN2 in melanoma cells, RT-PCR, Western blot\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution via reporter assay and EMSA with direct binding demonstration, plus gain- and loss-of-function experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23069940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDH13 (T-cadherin) functions as a pro-apoptotic tumor suppressor in melanoma by antagonizing AKT/CREB/AP-1/FoxO3a signaling: T-cadherin expression induces AKT and FoxO3a hypophosphorylation, downregulates BCL-2, BCL-xL, and Clusterin, and reduces CREB and AP-1 transcriptional activity, sensitizing cells to CD95/Fas-mediated apoptosis. NFκB, TCF/LEF, and mTOR are not part of T-cadherin signaling.\",\n      \"method\": \"Stable CDH13 expression in melanoma cells, tumor xenograft in nude mice, Western blot (pAKT, pFoxO3a, BCL-2, BCL-xL, Clusterin), reporter gene assay (CREB, AP-1, NFκB, TCF/LEF, mTOR), apoptosis assay with CD95/Fas antibody\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft plus multiple molecular pathway readouts with defined epistasis (NFκB, mTOR ruled out), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23625515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDH13 (T-cadherin) associates with insulin granules in pancreatic β-cells and is required for second-phase glucose-induced insulin secretion: T-cadherin was found on insulin granules by immunohistochemistry and electron microscopy; T-cadherin-deficient (Tcad-KO) mice showed impaired glucose-induced but not KCl-mediated insulin secretion in vitro, and defective second-phase insulin release during hyperglycemic clamp in vivo, leading to progressive glucose intolerance.\",\n      \"method\": \"Immunohistochemistry, electron microscopy, RFP-tagged T-cadherin colocalization with GFP-labeled insulin granules, Tcad-KO mouse phenotyping, in vitro islet insulin secretion assay, in vivo hyperglycemic clamp\",\n      \"journal\": \"Islets\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, live imaging, KO in vitro and in vivo), clear mechanistic dissection (second phase vs first phase), single lab\",\n      \"pmids\": [\"21975561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"T-cadherin deficiency (T-cad KO) protects against OVA-induced allergic airway hyperresponsiveness and inflammation; the protective effect requires adiponectin, as combined adiponectin/T-cad bideficiency reverses it; T-cad KO elevates circulating adiponectin levels because adiponectin normally sequestered by endothelial T-cad remains free in circulation.\",\n      \"method\": \"T-cad KO and adiponectin/T-cad bideficient mouse models, OVA sensitization and challenge, airway hyperresponsiveness measurement, BAL cell counting, cytokine/eotaxin mRNA, lung histology, serum adiponectin ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double KO rescue, multiple phenotypic readouts, mechanistic dissection of adiponectin sequestration by T-cad\",\n      \"pmids\": [\"22815927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T-cadherin binding to adiponectin (specifically HMW isoforms) via endothelial T-cadherin is required for suppression of ozone-induced IL-17A expression and pulmonary inflammation: T-cad KO mice showed augmented IL-17A induction by ozone, and T-cad/Adipo double-KO showed no further increase compared to T-cad KO alone, establishing T-cad as required mediator of adiponectin's suppression of IL-17A in the lung.\",\n      \"method\": \"Genetic epistasis with T-cad KO, Adipo KO, and T-cad/Adipo double-KO mice; ozone exposure; pulmonary IL-17A, saa3 mRNA; BAL neutrophils; G-CSF; lung histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three genotypes with double-KO epistasis clearly resolves pathway, multiple molecular readouts, single lab\",\n      \"pmids\": [\"23755285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDH13 missense variants found in ADHD patients are processed canonically as GPI-anchored proteins; wild-type and mutant CDH13 proteins showed similar expression levels and subcellular distribution in CHO and HEK293 cells, indicating no significant functional difference in processing or localization for these rare variants.\",\n      \"method\": \"Sequencing of CDH13 in ADHD patients and controls; GFP-tagged and native protein expression in CHO/HEK293 cells; immunofluorescence localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — protein localization and expression confirmed canonical GPI processing, but negative result for functional difference; single lab, single study\",\n      \"pmids\": [\"23936508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDH13 knockdown in bladder TCC 5637 cells promotes cell migration, invasion, adhesion, and upregulates MMP2 expression, establishing CDH13 as a suppressor of invasiveness in bladder cancer acting via MMP2 regulation.\",\n      \"method\": \"siRNA knockdown of CDH13 in 5637 bladder cancer cells; migration/invasion/adhesion assays; RT-PCR and Western blot for MMP2; IHC in primary tumor tissues\",\n      \"journal\": \"Urologia internationalis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple cellular assays and molecular readout (MMP2), single lab, consistent with tissue data\",\n      \"pmids\": [\"23235385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The UHRF1/PRMT5 complex contributes to CDH13 promoter methylation in endometrial carcinoma: Co-immunoprecipitation demonstrated PRMT5 binds UHRF1; combined 5-Aza-CdR and TSA treatment completely reversed CDH13 methylation and restored expression, while either agent alone only partially reversed it.\",\n      \"method\": \"Co-immunoprecipitation (UHRF1-PRMT5 interaction), methylation-specific PCR, qRT-PCR, 5-Aza-CdR and TSA treatment of endometrial carcinoma cell lines\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for UHRF1/PRMT5 interaction and demethylation rescue, but mechanistic link between complex and CDH13 methylation inferred rather than directly reconstituted; single lab\",\n      \"pmids\": [\"26597461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"microRNA-377 directly targets CDH13 mRNA: dual-luciferase reporter assay confirmed miR-377 binds the CDH13 3'-UTR; miR-377 knockdown in an Alzheimer's disease cell model increased CDH13 expression and reduced cell viability, while CDH13 knockdown reversed these effects.\",\n      \"method\": \"Dual-luciferase reporter gene assay, qRT-PCR, Western blot, CCK-8 viability assay, flow cytometry apoptosis assay in SH-SY5Y cells\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase reporter validates direct miRNA-CDH13 interaction, functional rescue confirms pathway; single lab, single study\",\n      \"pmids\": [\"29771432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH13 modulates lipid metabolism during adipogenesis but not in mature adipocytes: CDH13 knockdown during adipogenesis reduced fatty acid uptake, lipid content, and blunted induction of PPARγ and C/EBPα expression in 3T3-L1 adipocytes.\",\n      \"method\": \"CDH13 knockdown in 3T3-L1 adipocytes during differentiation; fatty acid uptake assay; lipid content measurement; RT-PCR/Western blot for PPARγ and C/EBPα\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple orthogonal readouts (fatty acid uptake, lipid content, transcription factor expression), single lab\",\n      \"pmids\": [\"29467502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNA polymerase β (Pol β) promotes CDH13 expression through demethylation of the CDH13 promoter via its role in base excision repair; CDH13 mediates the anti-migratory and anti-invasive effects of Pol β in breast and lung cancer cells, as CDH13 knockdown rescues migration, invasion, and angiogenesis suppressed by Pol β overexpression.\",\n      \"method\": \"Pol β overexpression and knockdown in breast/lung cancer cells; CDH13 mRNA/protein measurement; CDH13 promoter methylation analysis; migration/invasion assays; mouse xenograft tumor model; CDH13 siRNA rescue experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by CDH13 knockdown rescue plus in vivo xenograft, multiple assays; indirect mechanism (BER-dependent demethylation) inferred but not reconstituted in vitro; single lab\",\n      \"pmids\": [\"32641859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDH13 deficiency in mice leads to increased inhibitory drive onto hippocampal CA1 pyramidal neurons, a shift in excitatory/inhibitory balance, and moderates migration of serotonergic neurons in the dorsal raphe nucleus preferentially projecting to thalamus and cerebellum; CDH13 knockout mice show impaired fear extinction and increased stress-related behavioral phenotypes.\",\n      \"method\": \"Cdh13 knockout (KO, heterozygous, homozygous) mice; behavioral battery (Barnes maze, fear conditioning, light-dark test, locomotor); hippocampal transcriptome analysis; inference from electrophysiology data cited in abstract\",\n      \"journal\": \"Progress in neuro-psychopharmacology & biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined behavioral and transcriptomic phenotypes; electrophysiology claims referenced but not directly described in this abstract; single lab\",\n      \"pmids\": [\"30165120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDH13 (T-cadherin) interacts with MyD88 as shown by molecular docking simulations and co-immunoprecipitation; pharmacological treatment with PDA upregulates MyD88 in smooth muscle cells and interacts with CDH13, augmenting SMC proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling.\",\n      \"method\": \"Molecular docking, co-immunoprecipitation, smooth muscle cell proliferation assay (BrdU), Boyden chamber migration assay, spheroid sprouting assay, Matrigel tube formation, carotid artery ligation mouse model\",\n      \"journal\": \"Chinese journal of natural medicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP confirms CDH13-MyD88 interaction, supported by in vivo and in vitro functional assays; single lab, single study\",\n      \"pmids\": [\"38278560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDH13 expression promotes melanoma cell sensitivity to garcinol-induced apoptosis: garcinol reduced proliferation and induced apoptosis more effectively in CDH13-positive melanoma cells; siRNA knockdown of CDH13 reduced garcinol sensitivity and restored proliferation and anti-apoptotic behavior.\",\n      \"method\": \"siRNA knockdown of CDH13 in melanoma cell lines; proliferation assay; apoptosis assay; garcinol treatment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNAi rescue experiment demonstrating CDH13-dependent drug sensitivity, single lab, single study\",\n      \"pmids\": [\"38791932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDH13 activation via small activating RNA (saRNA) in imatinib-resistant CML cells inhibits NF-κB signaling pathway and induces apoptosis, overcoming BCR-ABL1-independent imatinib resistance; LNP-delivered saRNA also limited K562-IMR tumor growth in vivo.\",\n      \"method\": \"saRNA design targeting CDH13 promoter; qPCR and Western blot for CDH13 expression; cell viability and colony formation assays; NF-κB pathway activity measurement; mouse xenograft model with LNP-saRNA\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function via saRNA with in vitro and in vivo validation; NF-κB pathway identified as downstream effector; single lab\",\n      \"pmids\": [\"39179585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH13 mRNA stability is regulated by the lncRNA CDH13-AS2, which binds CDH13 mRNA in endothelial cells and protects it from miRNA-mediated degradation; miRNAs miR-19b-3p, miR-125b-2-3p, miR-433-3p, and miR-7b-5p accelerate CDH13 mRNA degradation, an effect neutralized by CRISPRa activation of CDH13-AS2. CDH13 loss of function increases atherosclerotic plaque size in Cdh13/Apoe double-KO mice on a Western diet.\",\n      \"method\": \"dCas13-mediated RNA immunoprecipitation (CDH13-AS2 binding to CDH13 mRNA), CRISPR/Cas9 KO and CRISPRa of CDH13-AS2 in human endothelial cells, miRNA screen, Cdh13/Apoe double-KO mouse model with Western diet, UK Biobank LoF variant analysis\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation confirms direct lncRNA-mRNA binding, genetic rescue via CRISPRa, in vivo atherosclerosis model; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40894025\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDH13 is expressed in endothelial cells of pathological neovascular membranes; CDH13 knockdown inhibits pathological vessel growth and promotes vascular normalization in OIR and CNV mouse models; mechanistically, hypoxia suppresses NR2F2, de-repressing CDH13 transcription and activating NF-κB to drive vascular dysfunction; CDH13 inhibition with LXR agonist GW3965 reduced LDL deposition and pathological neovascularization.\",\n      \"method\": \"CDH13 knockdown in OIR/CNV mouse models; in vitro transwell, wound healing, EdU assays; dual-luciferase reporter assay (NR2F2-CDH13 axis); RT-PCR, Western blot; fundus fluorescein angiography; isolectin B4 staining; bioinformatics of human nAMD FVMs\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO models with multiple phenotypic readouts and reporter assay defining upstream transcriptional regulation; single lab, single study\",\n      \"pmids\": [\"41814412\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH13 (T-cadherin/H-cadherin) is an atypical GPI-anchored cadherin that lacks both transmembrane and cytoplasmic domains and signals through its extracellular domain to regulate cell proliferation, adhesion, migration, apoptosis, insulin secretion, adipogenesis, and vascular biology; it acts as a negative regulator of EGF-driven neuronal proliferation, a pro-apoptotic tumor suppressor that antagonizes AKT/CREB/AP-1/FoxO3a signaling in melanoma, a component of pancreatic β-cell insulin granules required for second-phase glucose-stimulated insulin secretion, a vascular endothelial receptor that sequesters HMW adiponectin and mediates its anti-inflammatory effects (including ozone-induced IL-17A suppression), a modulator of lipid metabolism and PPARγ/C/EBPα induction during adipogenesis, and a suppressor of cancer cell invasiveness partly via MMP2 downregulation; its expression is silenced in numerous cancers primarily by promoter CpG hypermethylation (regulated by UHRF1/PRMT5 and Pol β-dependent demethylation) and also by direct transcriptional repression via BRN2 and post-transcriptional regulation via miRNAs (including miR-377) and the lncRNA CDH13-AS2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH13 (T-cadherin/H-cadherin) is an atypical GPI-anchored cadherin that lacks transmembrane and cytoplasmic domains and signals from the cell surface to control proliferation, adhesion, apoptosis, metabolism, and vascular biology [#2]. In tumor cells it behaves as a pro-apoptotic suppressor: re-expression antagonizes AKT/CREB/AP-1/FoxO3a signaling, downregulates BCL-2, BCL-xL, and Clusterin, and sensitizes melanoma cells to CD95/Fas-mediated apoptosis [#6], while in bladder carcinoma loss of CDH13 promotes migration, invasion, and adhesion through upregulation of MMP2 [#11]. Consistent with a tumor-suppressor role, CDH13 is silenced across breast, lung, and squamous cancers primarily by promoter CpG hypermethylation, reversible with demethylating agents [#3, #4], reinforced by combined methylation/histone-deacetylation through a UHRF1/PRMT5 axis [#12] and opposed by Pol \\u03b2-dependent promoter demethylation that restores its anti-migratory activity [#15]; expression is further controlled by direct transcriptional repression via BRN2 [#5] and by post-transcriptional regulation through miR-377 and the lncRNA CDH13-AS2 [#13]. As an endothelial receptor, CDH13 sequesters HMW adiponectin and is required for adiponectin-dependent suppression of airway and ozone-induced IL-17A inflammation [#8, #9], and it participates in pathological vascular remodeling and neovascularization via NF-\\u03baB and MyD88 signaling [#17, #21]. CDH13 also localizes to pancreatic \\u03b2-cell insulin granules and is required for second-phase glucose-stimulated insulin secretion [#7], and supports adipogenesis by promoting fatty acid uptake and PPAR\\u03b3/C/EBP\\u03b1 induction [#14]. In the nervous system CDH13 negatively regulates EGF-driven neuronal proliferation [#0] and shapes excitatory/inhibitory balance and serotonergic neuron migration relevant to fear and stress behavior [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first functional role for CDH13, showing it restrains growth-factor-driven proliferation rather than acting purely as an adhesion molecule.\",\n      \"evidence\": \"Gain-of-function transfection of T-cadherin into negative neuroblastoma cells with EGF proliferation assay\",\n      \"pmids\": [\"10737605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the GPI-anchored ectodomain blocks EGF mitogenic signaling not defined\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the defining structural feature \\u2014 a GPI anchor with no transmembrane or cytoplasmic domain \\u2014 framing CDH13 as a signaling receptor that must act through partners.\",\n      \"evidence\": \"Biochemical/structural characterization reviewed\",\n      \"pmids\": [\"11642747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the transmembrane co-receptors that transduce CDH13 signals\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified promoter CpG hypermethylation as a direct, reversible silencing mechanism for CDH13 in cancer, explaining its frequent loss.\",\n      \"evidence\": \"Methylation-specific PCR and 5-aza-2-deoxycytidine demethylation rescue in breast and lung cancer cell lines\",\n      \"pmids\": [\"11389090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes establishing the methylation not identified here\", \"Causal link to tumor phenotype not yet shown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that methylation cooperates with loss of heterozygosity to fully inactivate CDH13 in invasive squamous carcinoma, supporting a two-hit tumor-suppressor model.\",\n      \"evidence\": \"LOH, MSP, demethylation rescue, IHC and Western blot in cutaneous SCC and A431 cells\",\n      \"pmids\": [\"12177241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of biallelic loss for invasion not directly tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an unexpected metabolic role: CDH13 resides on insulin granules and is specifically required for second-phase glucose-stimulated insulin secretion.\",\n      \"evidence\": \"EM, live-cell colocalization, Tcad-KO mouse islet secretion assays and in vivo hyperglycemic clamp\",\n      \"pmids\": [\"21975561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role on the granule (docking vs trafficking) unresolved\", \"Binding partner on granules not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established CDH13 as the endothelial receptor that sequesters adiponectin, defining how it controls circulating adiponectin levels and allergic airway inflammation.\",\n      \"evidence\": \"T-cad KO and adiponectin/T-cad double-KO epistasis in OVA airway model with serum adiponectin ELISA\",\n      \"pmids\": [\"22815927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from the CDH13-adiponectin complex not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified BRN2 as a direct transcriptional repressor of CDH13, adding a methylation-independent silencing route in melanoma.\",\n      \"evidence\": \"Luciferase reporter, EMSA, BRN2 overexpression and knockdown in melanoma cells\",\n      \"pmids\": [\"23069940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between BRN2 repression and promoter methylation not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided functional evidence that CDH13 suppresses cancer cell invasiveness through MMP2 regulation.\",\n      \"evidence\": \"siRNA knockdown in bladder TCC 5637 cells with migration/invasion/adhesion assays and MMP2 readout\",\n      \"pmids\": [\"23235385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CDH13 loss to MMP2 induction unknown\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the pro-apoptotic tumor-suppressor signaling of CDH13, showing it antagonizes AKT/CREB/AP-1/FoxO3a survival signaling and ruling out NF\\u03baB/mTOR involvement.\",\n      \"evidence\": \"Stable expression in melanoma, xenografts, pathway Western blots, reporter assays, CD95/Fas apoptosis assay\",\n      \"pmids\": [\"23625515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the GPI-anchored ectodomain reaches intracellular AKT signaling is not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that CDH13 is the obligate mediator of adiponectin's suppression of ozone-induced IL-17A pulmonary inflammation.\",\n      \"evidence\": \"T-cad KO, Adipo KO, and double-KO epistasis with ozone exposure and IL-17A readouts\",\n      \"pmids\": [\"23755285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type and signaling cascade linking endothelial CDH13 to IL-17A suppression not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Tested whether ADHD-associated CDH13 missense variants disrupt protein processing, finding canonical GPI anchoring and localization unaffected.\",\n      \"evidence\": \"Expression of WT and mutant CDH13 in CHO/HEK293 with immunofluorescence\",\n      \"pmids\": [\"23936508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; functional consequence of variants on signaling not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked a UHRF1/PRMT5 complex to CDH13 promoter methylation, indicating coordinated DNA and histone modification silences the gene.\",\n      \"evidence\": \"Co-IP of UHRF1-PRMT5 and combined 5-Aza-CdR/TSA rescue in endometrial carcinoma cells\",\n      \"pmids\": [\"26597461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct recruitment of UHRF1/PRMT5 to the CDH13 promoter inferred, not reconstituted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CDH13 promotes adipocyte differentiation by enabling fatty acid uptake and PPAR\\u03b3/C/EBP\\u03b1 induction, extending its metabolic function to lipid handling.\",\n      \"evidence\": \"CDH13 knockdown during 3T3-L1 differentiation with fatty acid uptake, lipid, and transcription factor readouts\",\n      \"pmids\": [\"29467502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No effect in mature adipocytes; receptor-level mechanism for lipid uptake unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified miR-377 as a direct post-transcriptional regulator of CDH13 in a neuronal disease model.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter and rescue assays in SH-SY5Y cells\",\n      \"pmids\": [\"29771432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance beyond the cell model unestablished\", \"Single study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined CNS functions for CDH13 in excitatory/inhibitory balance, serotonergic neuron migration, and fear/stress behavior.\",\n      \"evidence\": \"Cdh13 KO mouse behavioral battery, hippocampal transcriptomics, cited electrophysiology\",\n      \"pmids\": [\"30165120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Electrophysiology not directly described\", \"Molecular pathway in neurons not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that Pol \\u03b2-driven base-excision-repair demethylation reactivates CDH13, with CDH13 mediating Pol \\u03b2's anti-migratory and anti-angiogenic effects.\",\n      \"evidence\": \"Pol \\u03b2 overexpression/knockdown, methylation analysis, CDH13 siRNA rescue, xenografts in breast/lung cancer\",\n      \"pmids\": [\"32641859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BER-dependent demethylation inferred but not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated CDH13 in pathological vascular remodeling through interaction with MyD88, augmenting smooth muscle cell proliferation and ECM deposition.\",\n      \"evidence\": \"Molecular docking, Co-IP, SMC proliferation/migration/sprouting assays, carotid ligation mouse model\",\n      \"pmids\": [\"38278560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDH13-MyD88 interaction from docking and single Co-IP without reciprocal validation\", \"Single study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed CDH13 expression confers melanoma sensitivity to garcinol-induced apoptosis, linking its tumor-suppressor function to drug response.\",\n      \"evidence\": \"siRNA knockdown and garcinol treatment in melanoma cell lines with proliferation/apoptosis assays\",\n      \"pmids\": [\"38791932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CDH13 to garcinol response not defined\", \"Single study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that restoring CDH13 via small activating RNA overcomes BCR-ABL1-independent imatinib resistance by inhibiting NF-\\u03baB and inducing apoptosis.\",\n      \"evidence\": \"saRNA targeting CDH13 promoter, viability/colony assays, NF-\\u03baB readout, LNP-saRNA xenograft in CML cells\",\n      \"pmids\": [\"39179585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How surface CDH13 modulates NF-\\u03baB not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the lncRNA CDH13-AS2 as a stabilizer of CDH13 mRNA against miRNA-mediated decay and linked CDH13 loss to atherosclerosis.\",\n      \"evidence\": \"dCas13 RNA-IP, CRISPRa/KO in endothelial cells, miRNA screen, Cdh13/Apoe double-KO atherosclerosis model (preprint)\",\n      \"pmids\": [\"40894025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mechanism of CDH13-AS2 protection of mRNA not detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed CDH13 in a hypoxia-NR2F2-NF\\u03baB axis driving pathological neovascularization, defining an upstream transcriptional regulator and therapeutic angle.\",\n      \"evidence\": \"CDH13 knockdown in OIR/CNV models, dual-luciferase NR2F2-CDH13 reporter, LXR agonist treatment, human FVM bioinformatics\",\n      \"pmids\": [\"41814412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How surface CDH13 activates NF-\\u03baB in endothelium not defined\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a GPI-anchored cadherin lacking a cytoplasmic domain transduces signals to intracellular pathways (AKT/FoxO3a, NF\\u03baB, MyD88) across its many contexts remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transmembrane co-receptor(s) for CDH13 not identified\", \"Unified signaling mechanism across cancer, metabolic, vascular, and neural roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 17, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 18, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADIPOQ\", \"MyD88\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}