{"gene":"CDH3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"P-cadherin/CDH3 overexpression in pancreatic cancer cells promotes cell motility through interaction with p120ctn; P-cadherin overexpression causes cytoplasmic accumulation of p120ctn and cadherin switching, which activates Rho GTPases Rac1 and Cdc42, driving increased cell motility. A blocking antibody against P-cadherin suppressed motility in vitro.","method":"Stable overexpression in P-cadherin-deficient Panc-1 cells, blocking antibody assay, Rho GTPase activity assays, co-immunoprecipitation/pull-down for p120ctn interaction","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional rescue, blocking antibody validation, and Rho GTPase activation assays in a single focused study with multiple orthogonal methods","pmids":["15833838"],"is_preprint":false},{"year":2001,"finding":"CDH3 (encoding P-cadherin) is expressed in retinal pigment epithelium and hair follicles; loss-of-function mutations in CDH3 cause hypotrichosis with juvenile macular dystrophy (HJMD), establishing CDH3 as required for normal hair follicle and retinal pigment epithelium function.","method":"Homozygosity mapping in consanguineous families, mutation analysis (exon 8 deletion identified in all families), expression analysis of CDH3 in relevant tissues","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping plus mutation identification replicated across four independent consanguineous families establishing disease causation","pmids":["11544476"],"is_preprint":false},{"year":2005,"finding":"CDH3 promoter hypomethylation regulates P-cadherin overexpression in breast cancer; treatment of MCF-7/AZ cells with demethylating agent 5-Aza-2'-deoxycytidine increased P-cadherin mRNA and protein levels, and normal P-cadherin-negative breast epithelial cells showed consistent CDH3 promoter methylation.","method":"Demethylating agent (5-Aza-2'-deoxycytidine) treatment, methylation-specific analysis of CDH3 5'-flanking region, correlation of methylation status with P-cadherin expression","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — demethylating agent experiment plus methylation-expression correlation, single lab with two orthogonal approaches","pmids":["16115928"],"is_preprint":false},{"year":2005,"finding":"CDH3 missense mutation (N322I) in a conserved Ca2+-binding motif causes EEM syndrome, and a frameshift deletion (c.829delG) producing a truncated protein lacking intracellular, transmembrane, and EC repeats 3-5 also causes EEM syndrome. CDH3 is expressed in the apical ectodermal ridge (E10.5–E12.5) and interdigital mesenchyme in mice, establishing its role in limb/digit morphogenesis.","method":"Molecular mutation analysis, mouse in situ hybridization for Cdh3 expression pattern","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutation analysis with structural inference plus in situ expression, single lab study with two orthogonal methods","pmids":["15805154"],"is_preprint":false},{"year":2002,"finding":"A missense mutation R503H in CDH3 causes HJMD; the R503H substitution affects a highly conserved residue predicted to alter a Ca2+-binding domain of P-cadherin, consistent with loss of calcium-dependent adhesion function.","method":"Sanger sequencing of entire CDH3 coding sequence, segregation analysis in family, conservation analysis of affected residue","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutation identified and validated by segregation with phenotype, conserved Ca2+ binding domain affected, single lab","pmids":["12445216"],"is_preprint":false},{"year":2010,"finding":"ICI 182,780 (an ERα antagonist) upregulates CDH3/P-cadherin expression in breast cancer cells through chromatin remodeling at the CDH3 promoter, specifically inducing H3 lysine 4 dimethylation (active chromatin mark); the transcription factor C/EBPβ is able to upregulate CDH3 promoter activity and is co-expressed with P-cadherin in human breast carcinomas.","method":"Chromatin immunoprecipitation (ChIP) for histone marks, luciferase reporter assay, CDH3 promoter activity measurement after ICI 182,780 treatment","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter assays are orthogonal methods in single lab study","pmids":["20385540"],"is_preprint":false},{"year":2013,"finding":"All three C/EBPβ isoforms (LAP1, LAP2, LIP) function as transcriptional regulators of the CDH3 gene in breast cancer cells, directly interacting with specific regions of the CDH3 promoter. However, transcriptional activation was only reflected at the P-cadherin protein level for the LIP isoform.","method":"DNA-protein interaction assays (EMSA/ChIP), site-directed mutation analysis of C/EBPβ binding sites, luciferase reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, mutagenesis, reporter assay) in a single lab study","pmids":["23405208"],"is_preprint":false},{"year":2019,"finding":"KLF4 directly binds to and transcriptionally activates the CDH3 promoter in hepatocellular carcinoma cells; CDH3/P-cadherin in turn regulates GSK-3β as a downstream effector. KLF4 knockdown reduces CDH3 expression, and CDH3 knockdown promotes HCC cell growth and migration, while CDH3 overexpression suppresses these phenotypes.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression studies with proliferation and migration assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter assays establish direct KLF4-CDH3 promoter binding; GSK-3β downstream placement by knockdown phenotype; single lab","pmids":["31182916"],"is_preprint":false},{"year":2017,"finding":"Slug (SNAI2) transcription repressor unexpectedly binds and activates the Pcad (CDH3) promoter through E-boxes, inducing P-cadherin expression. P-cadherin mediates several Slug functions including clonal mammosphere growth, basal epithelial differentiation, cell-cell dissociation, and cell migration (rescuing Slug depletion). P-cadherin-promoted migration is associated with Src activation, focal adhesion reorganization, and cell polarization.","method":"Promoter binding assay (ChIP for Slug at Pcad E-boxes), genetic rescue experiments (Pcad re-expression in Slug-depleted cells), mammosphere assay, 3D tubulogenesis assay, migration assay with Src inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct promoter binding, genetic rescue experiments confirm epistasis; single lab with multiple functional readouts","pmids":["28991231"],"is_preprint":false},{"year":2022,"finding":"The AP-1 transcription factors Junb and Fosl2 cooperate to regulate Cdh3 expression in Sertoli cells by recruiting to an AP-1 regulatory element at -47 bp in the proximal Cdh3 promoter. Knockdown of Junb and/or Fosl2 by siRNA decreased Cdh3 protein levels.","method":"Overexpression of AP-1 factors, ChIP-qPCR, luciferase reporter assay with 5' promoter deletions and site-directed mutagenesis, siRNA knockdown, histone modification analysis, ATAC-seq","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR, mutagenesis, and reporter assays are orthogonal methods; siRNA loss-of-function validation; single lab","pmids":["36468795"],"is_preprint":false},{"year":2023,"finding":"A Cdh3/P-cadherin-positive subpopulation of keratin 14-positive breast tumor leader cells controls leader cell protrusion dynamics and directional collective migration through local production of laminin, which is required for integrin/focal adhesion function at the leading edge.","method":"Single-cell sequencing, live imaging of primary mouse and human breast tumor organoids in 3D microfluidic system, 3D computational modeling, isolation and functional characterization of Cdh3+/K14+ subpopulation, integrin/focal adhesion readouts","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell isolation with functional characterization, laminin/integrin pathway dissected; single lab with multiple orthogonal methods","pmids":["36626870"],"is_preprint":false},{"year":2023,"finding":"CDH1/E-cadherin loss in gastric cancer cells alters CDH3 locus chromatin conformation, allowing CDH1 promoter interaction with a CDH3-eQTL regulatory element and promoting CDH3/P-cadherin expression at the plasma membrane (E- to P-cadherin switch). This switch increases cell migration and proliferation. Deletion of CDH3-eQTL reduces CDH3/CDH1 expression.","method":"CRISPR-Cas9 CDH1 knockout, ATAC-seq, 4C-seq (with CDH1 promoter viewpoint), RT-PCR, flow cytometry, CRISPR deletion of CDH3-eQTL","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based knockouts, chromatin conformation (4C-seq), and ATAC-seq are orthogonal methods establishing a regulatory mechanism; single lab","pmids":["37372088"],"is_preprint":false},{"year":2018,"finding":"During Cryptosporidium parvum infection, the parasite RNA Cdg7_FLc_1000 is delivered into host cell nuclei and causes trans-suppression of the CDH3 gene in human intestinal epithelial cells via PRDM1-mediated H3K9 methylation at the CDH3 gene locus; Cdg7_FLc_1000 knockdown attenuates this CDH3 trans-suppression.","method":"In vitro cryptosporidiosis model, ChIP for Cdg7_FLc_1000 at CDH3 promoter, knockdown of parasite RNA, H3K9 methylation ChIP, RT-PCR for CDH3 expression","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based localization of parasite RNA at CDH3 locus, histone methylation assay, and RNA knockdown rescue; single lab with multiple orthogonal methods","pmids":["29438669"],"is_preprint":false},{"year":2019,"finding":"lncRNA ADAMTS9-AS2 induces methylation of the CDH3 promoter via DNMT1/DNMT3(A/B), thereby downregulating CDH3 expression and suppressing esophageal cancer cell proliferation, invasion, and migration. These interactions were confirmed by RNA pull-down, RIP, and ChIP assays.","method":"RNA pull-down, RIP (RNA immunoprecipitation), ChIP assay, MSP (methylation-specific PCR), siRNA knockdown and overexpression experiments, in vivo xenograft","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (RNA pulldown, RIP, ChIP, MSP) establishing lncRNA-DNMT-CDH3 promoter methylation axis; single lab","pmids":["31621118"],"is_preprint":false},{"year":2025,"finding":"USP8 (a deubiquitinating enzyme) interacts with CDH3/P-cadherin and maintains CDH3 protein stability by removing ubiquitin (deubiquitination). CDH3 silencing inhibited LUAD cell proliferation, migration, invasion, angiogenesis, and induced ferroptosis in vitro, as well as repressed tumor growth in vivo.","method":"Co-immunoprecipitation (CoIP), Cycloheximide (CHX) chase assay for protein stability, siRNA knockdown, xenograft tumor model, ferroptosis markers (Fe2+, MDA, lipid-ROS, GSH)","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP establishes USP8-CDH3 interaction, CHX assay demonstrates stability effect, in vivo validation; single lab with multiple orthogonal methods","pmids":["40700945"],"is_preprint":false},{"year":2025,"finding":"P-cadherin (CDH3) and Desmoglein-2 (Dsg2) interact as trans heterophilic strand-swap dimers, with mutually swapped β-strands terminated by conserved Tryptophan residues. This interaction facilitates desmosome assembly: cells lacking classical cadherins or expressing strand-swap-deficient Pcad show impaired desmosome formation, which is rescued by introduction of strand-swap-competent Pcad. Heterophilic Pcad-Dsg2 dimers are retained in the desmosome throughout maturation.","method":"Single-molecule Atomic Force Microscopy, super-resolution imaging, confocal imaging, mutagenesis of β-strand hinge, atomistic simulations, cell-based desmosome assembly assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule AFM, mutagenesis, structural simulations, and cell rescue assays are multiple orthogonal methods directly establishing the molecular mechanism of P-cadherin/Dsg2 interaction in desmosome assembly","pmids":[],"is_preprint":true},{"year":2023,"finding":"MiR-133A directly targets CDH3 mRNA (validated by luciferase reporter assay); CDH3 knockdown in colorectal cancer cells reduces cell viability, migration, and colony formation while increasing apoptosis, and modulates catenin, MMP, and EMT pathway markers.","method":"Luciferase reporter assay, quantitative RT-PCR, western blot, siRNA knockdown, cell viability/migration/colony formation/apoptosis assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miR-133A/CDH3 targeting, siRNA phenocopies, multiple functional readouts; single lab","pmids":["37151391"],"is_preprint":false},{"year":2025,"finding":"In basal-like prostate cancer, YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. CDH3-targeted antibody-drug conjugates induce antigen-dependent cytotoxicity of CDH3+ prostate cancer cells in vitro and suppress tumor growth in vivo. CDH3-targeted CAR T cells specifically lyse CDH3-expressing cells and cause tumor regression, especially when combined with PD-1 checkpoint blockade.","method":"Genetically engineered mouse models (GEMMs), single-cell RNA sequencing, transcriptomic analyses, ADC cytotoxicity assays, CAR T cell assays, xenograft tumor models, WNT pathway component analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEMM, scRNA-seq, and in vivo functional assays establish YAP1/WNT5A-ROR2 upstream regulation and CDH3-dependent tumor growth; single lab, preprint","pmids":["41332717"],"is_preprint":true},{"year":2025,"finding":"Oxidative stress upregulates CDH3 expression in lung cancer cells via OGG1 (8-oxoguanine DNA glycosidase) modulation of SP1 transcription factor binding to CDH3 promoter SP1 binding sites.","method":"ChIP-qPCR for SP1 binding at CDH3 promoter, CDH3 promoter analysis, oxidative stress induction experiments","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP-qPCR experiment establishing OGG1/SP1/CDH3 link; single lab, single method","pmids":["40227353"],"is_preprint":false},{"year":2010,"finding":"CDH3/P-cadherin regulates cell migration and invasion in cholangiocarcinoma (HuCCT1) cells independently of EMT; CDH3 siRNA knockdown significantly reduced migration and invasion without affecting proliferation or EMT marker expression.","method":"siRNA knockdown, migration and invasion assays, proliferation assay, EMT biomarker expression analysis","journal":"Anatomy & cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown experiment with functional readouts, no molecular pathway placement; single lab, single method","pmids":["21189991"],"is_preprint":false}],"current_model":"CDH3/P-cadherin is a classical calcium-dependent cell adhesion molecule expressed in retinal pigment epithelium, hair follicles, placenta, and various epithelia; loss-of-function mutations cause hypotrichosis with juvenile macular dystrophy (HJMD) and EEM syndrome, while overexpression in multiple cancers promotes cell motility and invasion through interaction with p120ctn and activation of Rho GTPases (Rac1/Cdc42), with its expression regulated transcriptionally by C/EBPβ, Slug/SNAI2, KLF4, Junb/Fosl2, and epigenetically by promoter methylation/demethylation; structurally, P-cadherin forms trans heterophilic strand-swap dimers with desmosomal cadherin Dsg2 to nucleate desmosome assembly, and its protein stability is maintained by the deubiquitinase USP8."},"narrative":{"mechanistic_narrative":"CDH3 encodes P-cadherin, a calcium-dependent classical cadherin that mediates cell-cell adhesion and shapes epithelial tissue organization and motility [PMID:15833838, PMID:11544476]. Loss-of-function mutations in CDH3 cause hypotrichosis with juvenile macular dystrophy, with the gene expressed in retinal pigment epithelium and hair follicles [PMID:11544476], and missense or frameshift mutations affecting conserved Ca2+-binding motifs cause EEM syndrome, consistent with a requirement for P-cadherin in hair, retinal, and limb/digit morphogenesis [PMID:15805154, PMID:12445216]. At the molecular level, P-cadherin forms trans heterophilic strand-swap dimers with the desmosomal cadherin Dsg2, terminated by conserved tryptophan residues, and this interaction nucleates and is retained through desmosome assembly. In cancer, P-cadherin overexpression drives cell motility and invasion: it engages p120ctn, causes its cytoplasmic accumulation and a cadherin switch that activates the Rho GTPases Rac1 and Cdc42 [PMID:15833838], and promotes migration through Src activation and focal adhesion reorganization [PMID:28991231]; in collective invasion, a Cdh3+ leader-cell subpopulation directs protrusion dynamics via local laminin production feeding integrin/focal adhesion function [PMID:36626870]. CDH3 expression is controlled by an extensive transcriptional and epigenetic network, including activation by C/EBPβ, Slug/SNAI2, KLF4, and AP-1 factors Junb/Fosl2 [PMID:20385540, PMID:23405208, PMID:31182916, PMID:28991231, PMID:36468795], promoter methylation/demethylation [PMID:16115928, PMID:31621118], and chromatin reconfiguration following CDH1/E-cadherin loss that drives an E- to P-cadherin switch [PMID:37372088]. P-cadherin protein stability is maintained by the deubiquitinase USP8 [PMID:40700945].","teleology":[{"year":2001,"claim":"Established CDH3 as physiologically essential by tying loss-of-function mutations to a human disease and to expression in specific tissues, defining its developmental role.","evidence":"Homozygosity mapping and mutation analysis in consanguineous HJMD families with tissue expression analysis","pmids":["11544476"],"confidence":"High","gaps":["Did not resolve the molecular adhesion mechanism in RPE/hair follicle","No structural basis for mutation effects"]},{"year":2002,"claim":"Linked a specific conserved-residue substitution to disease, implicating loss of calcium-dependent adhesion as the pathogenic mechanism.","evidence":"Sanger sequencing, family segregation, and residue conservation analysis of the R503H HJMD mutation","pmids":["12445216"],"confidence":"Medium","gaps":["Predicted Ca2+-binding domain disruption not directly tested biochemically","Single residue/single family"]},{"year":2005,"claim":"Extended CDH3 disease causation to EEM syndrome and broadened its developmental role to limb/digit morphogenesis via mutations in Ca2+-binding and truncating regions.","evidence":"Mutation analysis (N322I missense, c.829delG frameshift) and mouse in situ hybridization of apical ectodermal ridge expression","pmids":["15805154"],"confidence":"Medium","gaps":["Functional consequence of truncation not assayed","No rescue experiment"]},{"year":2005,"claim":"Defined a pro-motility function for P-cadherin overexpression in cancer, mechanistically connecting it to p120ctn sequestration and Rho GTPase activation.","evidence":"Stable overexpression in Panc-1 cells, blocking antibody, Rho GTPase activity assays, and p120ctn co-IP/pull-down","pmids":["15833838"],"confidence":"High","gaps":["Direct link between p120ctn accumulation and Rac1/Cdc42 GEF activation not delineated","In vitro only"]},{"year":2005,"claim":"Identified promoter hypomethylation as an epigenetic switch driving aberrant P-cadherin expression in breast cancer.","evidence":"5-Aza-2'-deoxycytidine treatment and methylation-specific analysis of the CDH3 5'-flanking region","pmids":["16115928"],"confidence":"Medium","gaps":["Specific methylation-sensitive transcription factors not identified","Single cell line"]},{"year":2010,"claim":"Began assembling the CDH3 transcriptional regulatory network, implicating chromatin remodeling and C/EBPβ in promoter activation.","evidence":"ChIP for H3K4me2, luciferase reporter assays, and promoter activity after ICI 182,780 treatment in breast cancer cells","pmids":["20385540"],"confidence":"Medium","gaps":["Mechanism linking ERα antagonism to CDH3 chromatin not fully resolved","Single lab"]},{"year":2013,"claim":"Resolved isoform specificity of C/EBPβ regulation, showing transcriptional binding by all isoforms but protein-level induction only by LIP.","evidence":"DNA-protein interaction assays, site-directed mutagenesis of binding sites, and luciferase reporters","pmids":["23405208"],"confidence":"Medium","gaps":["Post-transcriptional basis of LIP-specific protein induction unexplained","Single cell context"]},{"year":2017,"claim":"Showed that the EMT repressor Slug paradoxically activates CDH3 and that P-cadherin mediates Slug-driven migration through Src and focal adhesion reorganization.","evidence":"ChIP at Pcad E-boxes, genetic rescue in Slug-depleted cells, mammosphere/3D tubulogenesis/migration assays with Src inhibition","pmids":["28991231"],"confidence":"Medium","gaps":["Direct Src activation mechanism by P-cadherin not defined","Single lab"]},{"year":2019,"claim":"Added KLF4 as a direct activator and placed GSK-3β downstream of P-cadherin, while revealing a context-dependent tumor-suppressive role in HCC.","evidence":"ChIP, luciferase reporters, siRNA knockdown, and overexpression with proliferation/migration assays in HCC cells","pmids":["31182916"],"confidence":"Medium","gaps":["Mechanism by which P-cadherin regulates GSK-3β unresolved","Opposite phenotype to other cancers unexplained"]},{"year":2019,"claim":"Established an lncRNA-directed methylation route for CDH3 silencing, identifying ADAMTS9-AS2/DNMT recruitment as a suppressive axis.","evidence":"RNA pull-down, RIP, ChIP, methylation-specific PCR, and knockdown/overexpression with xenografts in esophageal cancer","pmids":["31621118"],"confidence":"Medium","gaps":["Specificity of DNMT targeting to CDH3 promoter not fully isolated","Single lab"]},{"year":2018,"claim":"Revealed CDH3 as a target of pathogen-directed epigenetic suppression via a parasite RNA and PRDM1-mediated H3K9 methylation.","evidence":"In vitro cryptosporidiosis model, ChIP for parasite RNA and H3K9me at the CDH3 locus, and RNA knockdown rescue","pmids":["29438669"],"confidence":"Medium","gaps":["Functional consequence of CDH3 suppression for infection not established","Single system"]},{"year":2022,"claim":"Identified AP-1 factors Junb/Fosl2 as cooperative activators of Cdh3 in Sertoli cells, extending the regulatory network to a reproductive context.","evidence":"AP-1 overexpression, ChIP-qPCR, reporter assays with deletions/mutagenesis, siRNA, and ATAC-seq","pmids":["36468795"],"confidence":"Medium","gaps":["Role of P-cadherin in Sertoli cell function not characterized","Single lab"]},{"year":2023,"claim":"Mechanistically connected E-cadherin loss to an E- to P-cadherin switch through chromatin reconfiguration at a CDH3-eQTL regulatory element.","evidence":"CRISPR CDH1 knockout, ATAC-seq, 4C-seq from the CDH1 promoter, and CRISPR deletion of the CDH3-eQTL in gastric cancer cells","pmids":["37372088"],"confidence":"Medium","gaps":["Generalizability beyond gastric cancer untested","Trans-regulatory contacts not fully mapped"]},{"year":2023,"claim":"Defined a Cdh3+/K14+ leader-cell subpopulation that directs collective invasion through local laminin deposition and integrin/focal adhesion function.","evidence":"Single-cell sequencing, 3D live imaging of tumor organoids, computational modeling, and subpopulation functional characterization","pmids":["36626870"],"confidence":"Medium","gaps":["Direct molecular role of P-cadherin in laminin production not isolated","Single lab"]},{"year":2023,"claim":"Identified miR-133A as a direct post-transcriptional repressor of CDH3 governing colorectal cancer cell survival and migration.","evidence":"Luciferase reporter, qRT-PCR, western blot, siRNA, and viability/migration/apoptosis assays","pmids":["37151391"],"confidence":"Medium","gaps":["Catenin/MMP/EMT marker changes correlative","Single lab"]},{"year":2025,"claim":"Established post-translational control of P-cadherin stability by the deubiquitinase USP8, with CDH3 supporting tumor growth and restraining ferroptosis.","evidence":"Co-IP, cycloheximide chase, siRNA knockdown, xenografts, and ferroptosis markers in LUAD cells","pmids":["40700945"],"confidence":"Medium","gaps":["Ubiquitin ligase opposing USP8 not identified","Mechanistic link to ferroptosis unresolved"]},{"year":2025,"claim":"Resolved the molecular basis of P-cadherin's role in desmosome biogenesis as trans heterophilic strand-swap dimerization with Dsg2.","evidence":"Single-molecule AFM, super-resolution/confocal imaging, β-strand hinge mutagenesis, atomistic simulations, and cell-based desmosome rescue assays (preprint)","pmids":[],"confidence":"High","gaps":["Peer review pending","Physiological relevance to HJMD/EEM tissues not directly tested"]},{"year":2025,"claim":"Placed CDH3 downstream of YAP1 and WNT5A-ROR2 signaling in basal-like prostate cancer and demonstrated its tractability as an immunotherapy/ADC target.","evidence":"GEMMs, scRNA-seq, ADC cytotoxicity, CAR T assays, and xenografts (preprint)","pmids":["41332717"],"confidence":"Medium","gaps":["Direct transcriptional link from WNT/YAP1 to CDH3 promoter not fully mapped","Preprint, single lab"]},{"year":null,"claim":"How the multilayered transcriptional, epigenetic, and post-translational controls integrate to set context-specific (tumor-promoting vs. suppressive) P-cadherin levels, and how adhesion-dependent signaling converges on Rho GTPases, Src, and GSK-3β, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model reconciling opposite cancer phenotypes","Quantitative link between adhesion state and downstream GTPase/kinase signaling unmeasured","Structural basis of disease mutations on adhesion not directly assayed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,15]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,4]}],"complexes":["desmosome"],"partners":["CTNND1","DSG2","USP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22223","full_name":"Cadherin-3","aliases":["Placental cadherin","P-cadherin"],"length_aa":829,"mass_kda":91.4,"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","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P22223/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDH3","total_profiled":1310},"omim":[{"mim_id":"618205","title":"SNIJDERS BLOK-CAMPEAU SYNDROME; SNIBCPS","url":"https://www.omim.org/entry/618205"},{"mim_id":"606745","title":"PAR3 FAMILY CELL POLARITY REGULATOR; PARD3","url":"https://www.omim.org/entry/606745"},{"mim_id":"604966","title":"PROTOCADHERIN-ALPHA GENE CLUSTER; PCDHA@","url":"https://www.omim.org/entry/604966"},{"mim_id":"603118","title":"CADHERIN 16; CDH16","url":"https://www.omim.org/entry/603118"},{"mim_id":"603008","title":"CADHERIN 8; CDH8","url":"https://www.omim.org/entry/603008"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid 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A blocking antibody against P-cadherin suppressed motility in vitro.\",\n      \"method\": \"Stable overexpression in P-cadherin-deficient Panc-1 cells, blocking antibody assay, Rho GTPase activity assays, co-immunoprecipitation/pull-down for p120ctn interaction\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional rescue, blocking antibody validation, and Rho GTPase activation assays in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"15833838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CDH3 (encoding P-cadherin) is expressed in retinal pigment epithelium and hair follicles; loss-of-function mutations in CDH3 cause hypotrichosis with juvenile macular dystrophy (HJMD), establishing CDH3 as required for normal hair follicle and retinal pigment epithelium function.\",\n      \"method\": \"Homozygosity mapping in consanguineous families, mutation analysis (exon 8 deletion identified in all families), expression analysis of CDH3 in relevant tissues\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping plus mutation identification replicated across four independent consanguineous families establishing disease causation\",\n      \"pmids\": [\"11544476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CDH3 promoter hypomethylation regulates P-cadherin overexpression in breast cancer; treatment of MCF-7/AZ cells with demethylating agent 5-Aza-2'-deoxycytidine increased P-cadherin mRNA and protein levels, and normal P-cadherin-negative breast epithelial cells showed consistent CDH3 promoter methylation.\",\n      \"method\": \"Demethylating agent (5-Aza-2'-deoxycytidine) treatment, methylation-specific analysis of CDH3 5'-flanking region, correlation of methylation status with P-cadherin expression\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — demethylating agent experiment plus methylation-expression correlation, single lab with two orthogonal approaches\",\n      \"pmids\": [\"16115928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CDH3 missense mutation (N322I) in a conserved Ca2+-binding motif causes EEM syndrome, and a frameshift deletion (c.829delG) producing a truncated protein lacking intracellular, transmembrane, and EC repeats 3-5 also causes EEM syndrome. CDH3 is expressed in the apical ectodermal ridge (E10.5–E12.5) and interdigital mesenchyme in mice, establishing its role in limb/digit morphogenesis.\",\n      \"method\": \"Molecular mutation analysis, mouse in situ hybridization for Cdh3 expression pattern\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutation analysis with structural inference plus in situ expression, single lab study with two orthogonal methods\",\n      \"pmids\": [\"15805154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A missense mutation R503H in CDH3 causes HJMD; the R503H substitution affects a highly conserved residue predicted to alter a Ca2+-binding domain of P-cadherin, consistent with loss of calcium-dependent adhesion function.\",\n      \"method\": \"Sanger sequencing of entire CDH3 coding sequence, segregation analysis in family, conservation analysis of affected residue\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutation identified and validated by segregation with phenotype, conserved Ca2+ binding domain affected, single lab\",\n      \"pmids\": [\"12445216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ICI 182,780 (an ERα antagonist) upregulates CDH3/P-cadherin expression in breast cancer cells through chromatin remodeling at the CDH3 promoter, specifically inducing H3 lysine 4 dimethylation (active chromatin mark); the transcription factor C/EBPβ is able to upregulate CDH3 promoter activity and is co-expressed with P-cadherin in human breast carcinomas.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for histone marks, luciferase reporter assay, CDH3 promoter activity measurement after ICI 182,780 treatment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter assays are orthogonal methods in single lab study\",\n      \"pmids\": [\"20385540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"All three C/EBPβ isoforms (LAP1, LAP2, LIP) function as transcriptional regulators of the CDH3 gene in breast cancer cells, directly interacting with specific regions of the CDH3 promoter. However, transcriptional activation was only reflected at the P-cadherin protein level for the LIP isoform.\",\n      \"method\": \"DNA-protein interaction assays (EMSA/ChIP), site-directed mutation analysis of C/EBPβ binding sites, luciferase reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, mutagenesis, reporter assay) in a single lab study\",\n      \"pmids\": [\"23405208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLF4 directly binds to and transcriptionally activates the CDH3 promoter in hepatocellular carcinoma cells; CDH3/P-cadherin in turn regulates GSK-3β as a downstream effector. KLF4 knockdown reduces CDH3 expression, and CDH3 knockdown promotes HCC cell growth and migration, while CDH3 overexpression suppresses these phenotypes.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression studies with proliferation and migration assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter assays establish direct KLF4-CDH3 promoter binding; GSK-3β downstream placement by knockdown phenotype; single lab\",\n      \"pmids\": [\"31182916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Slug (SNAI2) transcription repressor unexpectedly binds and activates the Pcad (CDH3) promoter through E-boxes, inducing P-cadherin expression. P-cadherin mediates several Slug functions including clonal mammosphere growth, basal epithelial differentiation, cell-cell dissociation, and cell migration (rescuing Slug depletion). P-cadherin-promoted migration is associated with Src activation, focal adhesion reorganization, and cell polarization.\",\n      \"method\": \"Promoter binding assay (ChIP for Slug at Pcad E-boxes), genetic rescue experiments (Pcad re-expression in Slug-depleted cells), mammosphere assay, 3D tubulogenesis assay, migration assay with Src inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct promoter binding, genetic rescue experiments confirm epistasis; single lab with multiple functional readouts\",\n      \"pmids\": [\"28991231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The AP-1 transcription factors Junb and Fosl2 cooperate to regulate Cdh3 expression in Sertoli cells by recruiting to an AP-1 regulatory element at -47 bp in the proximal Cdh3 promoter. Knockdown of Junb and/or Fosl2 by siRNA decreased Cdh3 protein levels.\",\n      \"method\": \"Overexpression of AP-1 factors, ChIP-qPCR, luciferase reporter assay with 5' promoter deletions and site-directed mutagenesis, siRNA knockdown, histone modification analysis, ATAC-seq\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR, mutagenesis, and reporter assays are orthogonal methods; siRNA loss-of-function validation; single lab\",\n      \"pmids\": [\"36468795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A Cdh3/P-cadherin-positive subpopulation of keratin 14-positive breast tumor leader cells controls leader cell protrusion dynamics and directional collective migration through local production of laminin, which is required for integrin/focal adhesion function at the leading edge.\",\n      \"method\": \"Single-cell sequencing, live imaging of primary mouse and human breast tumor organoids in 3D microfluidic system, 3D computational modeling, isolation and functional characterization of Cdh3+/K14+ subpopulation, integrin/focal adhesion readouts\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell isolation with functional characterization, laminin/integrin pathway dissected; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36626870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDH1/E-cadherin loss in gastric cancer cells alters CDH3 locus chromatin conformation, allowing CDH1 promoter interaction with a CDH3-eQTL regulatory element and promoting CDH3/P-cadherin expression at the plasma membrane (E- to P-cadherin switch). This switch increases cell migration and proliferation. Deletion of CDH3-eQTL reduces CDH3/CDH1 expression.\",\n      \"method\": \"CRISPR-Cas9 CDH1 knockout, ATAC-seq, 4C-seq (with CDH1 promoter viewpoint), RT-PCR, flow cytometry, CRISPR deletion of CDH3-eQTL\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based knockouts, chromatin conformation (4C-seq), and ATAC-seq are orthogonal methods establishing a regulatory mechanism; single lab\",\n      \"pmids\": [\"37372088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"During Cryptosporidium parvum infection, the parasite RNA Cdg7_FLc_1000 is delivered into host cell nuclei and causes trans-suppression of the CDH3 gene in human intestinal epithelial cells via PRDM1-mediated H3K9 methylation at the CDH3 gene locus; Cdg7_FLc_1000 knockdown attenuates this CDH3 trans-suppression.\",\n      \"method\": \"In vitro cryptosporidiosis model, ChIP for Cdg7_FLc_1000 at CDH3 promoter, knockdown of parasite RNA, H3K9 methylation ChIP, RT-PCR for CDH3 expression\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based localization of parasite RNA at CDH3 locus, histone methylation assay, and RNA knockdown rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29438669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA ADAMTS9-AS2 induces methylation of the CDH3 promoter via DNMT1/DNMT3(A/B), thereby downregulating CDH3 expression and suppressing esophageal cancer cell proliferation, invasion, and migration. These interactions were confirmed by RNA pull-down, RIP, and ChIP assays.\",\n      \"method\": \"RNA pull-down, RIP (RNA immunoprecipitation), ChIP assay, MSP (methylation-specific PCR), siRNA knockdown and overexpression experiments, in vivo xenograft\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (RNA pulldown, RIP, ChIP, MSP) establishing lncRNA-DNMT-CDH3 promoter methylation axis; single lab\",\n      \"pmids\": [\"31621118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP8 (a deubiquitinating enzyme) interacts with CDH3/P-cadherin and maintains CDH3 protein stability by removing ubiquitin (deubiquitination). CDH3 silencing inhibited LUAD cell proliferation, migration, invasion, angiogenesis, and induced ferroptosis in vitro, as well as repressed tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (CoIP), Cycloheximide (CHX) chase assay for protein stability, siRNA knockdown, xenograft tumor model, ferroptosis markers (Fe2+, MDA, lipid-ROS, GSH)\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP establishes USP8-CDH3 interaction, CHX assay demonstrates stability effect, in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40700945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P-cadherin (CDH3) and Desmoglein-2 (Dsg2) interact as trans heterophilic strand-swap dimers, with mutually swapped β-strands terminated by conserved Tryptophan residues. This interaction facilitates desmosome assembly: cells lacking classical cadherins or expressing strand-swap-deficient Pcad show impaired desmosome formation, which is rescued by introduction of strand-swap-competent Pcad. Heterophilic Pcad-Dsg2 dimers are retained in the desmosome throughout maturation.\",\n      \"method\": \"Single-molecule Atomic Force Microscopy, super-resolution imaging, confocal imaging, mutagenesis of β-strand hinge, atomistic simulations, cell-based desmosome assembly assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule AFM, mutagenesis, structural simulations, and cell rescue assays are multiple orthogonal methods directly establishing the molecular mechanism of P-cadherin/Dsg2 interaction in desmosome assembly\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MiR-133A directly targets CDH3 mRNA (validated by luciferase reporter assay); CDH3 knockdown in colorectal cancer cells reduces cell viability, migration, and colony formation while increasing apoptosis, and modulates catenin, MMP, and EMT pathway markers.\",\n      \"method\": \"Luciferase reporter assay, quantitative RT-PCR, western blot, siRNA knockdown, cell viability/migration/colony formation/apoptosis assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miR-133A/CDH3 targeting, siRNA phenocopies, multiple functional readouts; single lab\",\n      \"pmids\": [\"37151391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In basal-like prostate cancer, YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. CDH3-targeted antibody-drug conjugates induce antigen-dependent cytotoxicity of CDH3+ prostate cancer cells in vitro and suppress tumor growth in vivo. CDH3-targeted CAR T cells specifically lyse CDH3-expressing cells and cause tumor regression, especially when combined with PD-1 checkpoint blockade.\",\n      \"method\": \"Genetically engineered mouse models (GEMMs), single-cell RNA sequencing, transcriptomic analyses, ADC cytotoxicity assays, CAR T cell assays, xenograft tumor models, WNT pathway component analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEMM, scRNA-seq, and in vivo functional assays establish YAP1/WNT5A-ROR2 upstream regulation and CDH3-dependent tumor growth; single lab, preprint\",\n      \"pmids\": [\"41332717\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Oxidative stress upregulates CDH3 expression in lung cancer cells via OGG1 (8-oxoguanine DNA glycosidase) modulation of SP1 transcription factor binding to CDH3 promoter SP1 binding sites.\",\n      \"method\": \"ChIP-qPCR for SP1 binding at CDH3 promoter, CDH3 promoter analysis, oxidative stress induction experiments\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP-qPCR experiment establishing OGG1/SP1/CDH3 link; single lab, single method\",\n      \"pmids\": [\"40227353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDH3/P-cadherin regulates cell migration and invasion in cholangiocarcinoma (HuCCT1) cells independently of EMT; CDH3 siRNA knockdown significantly reduced migration and invasion without affecting proliferation or EMT marker expression.\",\n      \"method\": \"siRNA knockdown, migration and invasion assays, proliferation assay, EMT biomarker expression analysis\",\n      \"journal\": \"Anatomy & cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown experiment with functional readouts, no molecular pathway placement; single lab, single method\",\n      \"pmids\": [\"21189991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH3/P-cadherin is a classical calcium-dependent cell adhesion molecule expressed in retinal pigment epithelium, hair follicles, placenta, and various epithelia; loss-of-function mutations cause hypotrichosis with juvenile macular dystrophy (HJMD) and EEM syndrome, while overexpression in multiple cancers promotes cell motility and invasion through interaction with p120ctn and activation of Rho GTPases (Rac1/Cdc42), with its expression regulated transcriptionally by C/EBPβ, Slug/SNAI2, KLF4, Junb/Fosl2, and epigenetically by promoter methylation/demethylation; structurally, P-cadherin forms trans heterophilic strand-swap dimers with desmosomal cadherin Dsg2 to nucleate desmosome assembly, and its protein stability is maintained by the deubiquitinase USP8.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH3 encodes P-cadherin, a calcium-dependent classical cadherin that mediates cell-cell adhesion and shapes epithelial tissue organization and motility [#0, #1]. Loss-of-function mutations in CDH3 cause hypotrichosis with juvenile macular dystrophy, with the gene expressed in retinal pigment epithelium and hair follicles [#1], and missense or frameshift mutations affecting conserved Ca2+-binding motifs cause EEM syndrome, consistent with a requirement for P-cadherin in hair, retinal, and limb/digit morphogenesis [#3, #4]. At the molecular level, P-cadherin forms trans heterophilic strand-swap dimers with the desmosomal cadherin Dsg2, terminated by conserved tryptophan residues, and this interaction nucleates and is retained through desmosome assembly [#15]. In cancer, P-cadherin overexpression drives cell motility and invasion: it engages p120ctn, causes its cytoplasmic accumulation and a cadherin switch that activates the Rho GTPases Rac1 and Cdc42 [#0], and promotes migration through Src activation and focal adhesion reorganization [#8]; in collective invasion, a Cdh3+ leader-cell subpopulation directs protrusion dynamics via local laminin production feeding integrin/focal adhesion function [#10]. CDH3 expression is controlled by an extensive transcriptional and epigenetic network, including activation by C/EBPβ, Slug/SNAI2, KLF4, and AP-1 factors Junb/Fosl2 [#5, #6, #7, #8, #9], promoter methylation/demethylation [#2, #13], and chromatin reconfiguration following CDH1/E-cadherin loss that drives an E- to P-cadherin switch [#11]. P-cadherin protein stability is maintained by the deubiquitinase USP8 [#14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CDH3 as physiologically essential by tying loss-of-function mutations to a human disease and to expression in specific tissues, defining its developmental role.\",\n      \"evidence\": \"Homozygosity mapping and mutation analysis in consanguineous HJMD families with tissue expression analysis\",\n      \"pmids\": [\"11544476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular adhesion mechanism in RPE/hair follicle\", \"No structural basis for mutation effects\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked a specific conserved-residue substitution to disease, implicating loss of calcium-dependent adhesion as the pathogenic mechanism.\",\n      \"evidence\": \"Sanger sequencing, family segregation, and residue conservation analysis of the R503H HJMD mutation\",\n      \"pmids\": [\"12445216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Predicted Ca2+-binding domain disruption not directly tested biochemically\", \"Single residue/single family\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended CDH3 disease causation to EEM syndrome and broadened its developmental role to limb/digit morphogenesis via mutations in Ca2+-binding and truncating regions.\",\n      \"evidence\": \"Mutation analysis (N322I missense, c.829delG frameshift) and mouse in situ hybridization of apical ectodermal ridge expression\",\n      \"pmids\": [\"15805154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of truncation not assayed\", \"No rescue experiment\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined a pro-motility function for P-cadherin overexpression in cancer, mechanistically connecting it to p120ctn sequestration and Rho GTPase activation.\",\n      \"evidence\": \"Stable overexpression in Panc-1 cells, blocking antibody, Rho GTPase activity assays, and p120ctn co-IP/pull-down\",\n      \"pmids\": [\"15833838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between p120ctn accumulation and Rac1/Cdc42 GEF activation not delineated\", \"In vitro only\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified promoter hypomethylation as an epigenetic switch driving aberrant P-cadherin expression in breast cancer.\",\n      \"evidence\": \"5-Aza-2'-deoxycytidine treatment and methylation-specific analysis of the CDH3 5'-flanking region\",\n      \"pmids\": [\"16115928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylation-sensitive transcription factors not identified\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Began assembling the CDH3 transcriptional regulatory network, implicating chromatin remodeling and C/EBPβ in promoter activation.\",\n      \"evidence\": \"ChIP for H3K4me2, luciferase reporter assays, and promoter activity after ICI 182,780 treatment in breast cancer cells\",\n      \"pmids\": [\"20385540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ERα antagonism to CDH3 chromatin not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved isoform specificity of C/EBPβ regulation, showing transcriptional binding by all isoforms but protein-level induction only by LIP.\",\n      \"evidence\": \"DNA-protein interaction assays, site-directed mutagenesis of binding sites, and luciferase reporters\",\n      \"pmids\": [\"23405208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-transcriptional basis of LIP-specific protein induction unexplained\", \"Single cell context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that the EMT repressor Slug paradoxically activates CDH3 and that P-cadherin mediates Slug-driven migration through Src and focal adhesion reorganization.\",\n      \"evidence\": \"ChIP at Pcad E-boxes, genetic rescue in Slug-depleted cells, mammosphere/3D tubulogenesis/migration assays with Src inhibition\",\n      \"pmids\": [\"28991231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Src activation mechanism by P-cadherin not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added KLF4 as a direct activator and placed GSK-3β downstream of P-cadherin, while revealing a context-dependent tumor-suppressive role in HCC.\",\n      \"evidence\": \"ChIP, luciferase reporters, siRNA knockdown, and overexpression with proliferation/migration assays in HCC cells\",\n      \"pmids\": [\"31182916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which P-cadherin regulates GSK-3β unresolved\", \"Opposite phenotype to other cancers unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established an lncRNA-directed methylation route for CDH3 silencing, identifying ADAMTS9-AS2/DNMT recruitment as a suppressive axis.\",\n      \"evidence\": \"RNA pull-down, RIP, ChIP, methylation-specific PCR, and knockdown/overexpression with xenografts in esophageal cancer\",\n      \"pmids\": [\"31621118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity of DNMT targeting to CDH3 promoter not fully isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed CDH3 as a target of pathogen-directed epigenetic suppression via a parasite RNA and PRDM1-mediated H3K9 methylation.\",\n      \"evidence\": \"In vitro cryptosporidiosis model, ChIP for parasite RNA and H3K9me at the CDH3 locus, and RNA knockdown rescue\",\n      \"pmids\": [\"29438669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CDH3 suppression for infection not established\", \"Single system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified AP-1 factors Junb/Fosl2 as cooperative activators of Cdh3 in Sertoli cells, extending the regulatory network to a reproductive context.\",\n      \"evidence\": \"AP-1 overexpression, ChIP-qPCR, reporter assays with deletions/mutagenesis, siRNA, and ATAC-seq\",\n      \"pmids\": [\"36468795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of P-cadherin in Sertoli cell function not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistically connected E-cadherin loss to an E- to P-cadherin switch through chromatin reconfiguration at a CDH3-eQTL regulatory element.\",\n      \"evidence\": \"CRISPR CDH1 knockout, ATAC-seq, 4C-seq from the CDH1 promoter, and CRISPR deletion of the CDH3-eQTL in gastric cancer cells\",\n      \"pmids\": [\"37372088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond gastric cancer untested\", \"Trans-regulatory contacts not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a Cdh3+/K14+ leader-cell subpopulation that directs collective invasion through local laminin deposition and integrin/focal adhesion function.\",\n      \"evidence\": \"Single-cell sequencing, 3D live imaging of tumor organoids, computational modeling, and subpopulation functional characterization\",\n      \"pmids\": [\"36626870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role of P-cadherin in laminin production not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified miR-133A as a direct post-transcriptional repressor of CDH3 governing colorectal cancer cell survival and migration.\",\n      \"evidence\": \"Luciferase reporter, qRT-PCR, western blot, siRNA, and viability/migration/apoptosis assays\",\n      \"pmids\": [\"37151391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catenin/MMP/EMT marker changes correlative\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established post-translational control of P-cadherin stability by the deubiquitinase USP8, with CDH3 supporting tumor growth and restraining ferroptosis.\",\n      \"evidence\": \"Co-IP, cycloheximide chase, siRNA knockdown, xenografts, and ferroptosis markers in LUAD cells\",\n      \"pmids\": [\"40700945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase opposing USP8 not identified\", \"Mechanistic link to ferroptosis unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the molecular basis of P-cadherin's role in desmosome biogenesis as trans heterophilic strand-swap dimerization with Dsg2.\",\n      \"evidence\": \"Single-molecule AFM, super-resolution/confocal imaging, β-strand hinge mutagenesis, atomistic simulations, and cell-based desmosome rescue assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peer review pending\", \"Physiological relevance to HJMD/EEM tissues not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed CDH3 downstream of YAP1 and WNT5A-ROR2 signaling in basal-like prostate cancer and demonstrated its tractability as an immunotherapy/ADC target.\",\n      \"evidence\": \"GEMMs, scRNA-seq, ADC cytotoxicity, CAR T assays, and xenografts (preprint)\",\n      \"pmids\": [\"41332717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional link from WNT/YAP1 to CDH3 promoter not fully mapped\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multilayered transcriptional, epigenetic, and post-translational controls integrate to set context-specific (tumor-promoting vs. suppressive) P-cadherin levels, and how adhesion-dependent signaling converges on Rho GTPases, Src, and GSK-3β, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model reconciling opposite cancer phenotypes\", \"Quantitative link between adhesion state and downstream GTPase/kinase signaling unmeasured\", \"Structural basis of disease mutations on adhesion not directly assayed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [\"desmosome\"],\n    \"partners\": [\"CTNND1\", \"DSG2\", \"USP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}