{"gene":"CDH5","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1995,"finding":"VE-cadherin (CDH5/7B4) mediates homophilic, calcium-dependent cell aggregation and cell-to-cell adhesion when expressed in transfected CHO cells; it localizes to intercellular junctions where it co-distributes with alpha-catenin, decreases intercellular permeability to high-molecular-weight molecules, and reduces cell migration rate across a wounded area.","method":"Transfection of full-length CDH5 cDNA into CHO cells, cell aggregation assays, permeability assays, wound-healing migration assay, co-localization with alpha-catenin","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution in heterologous cells with multiple orthogonal assays (aggregation, permeability, migration, co-localization), foundational study replicated broadly","pmids":["7627717"],"is_preprint":false},{"year":1999,"finding":"Antibody blockade of VE-cadherin (CD144) in 3D collagen gel cultures impairs endothelial tube formation by inhibiting cell-cell association and reducing vacuole formation or vacuole fusion required for intercellular lumen formation, a role distinct from that of CD31.","method":"Monoclonal antibody inhibition in 3D type I collagen gel angiogenesis assay with morphological analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional blockade with defined morphological readout; single lab, single method but clear phenotypic specificity","pmids":["10487846"],"is_preprint":false},{"year":1999,"finding":"VE-cadherin (CD144) expression in transfected ECV304 cells (which lack endogenous VE-cadherin) recruits beta-catenin to junctional regions, reorganizes F-actin into parallel bundles, enables 3D tube formation, and enforces contact-inhibited monolayer growth with dramatic reduction of cell cycling after confluence — properties absent in CD31 transfectants and empty-vector controls.","method":"Stable transfection of VE-cadherin or CD31 cDNA into ECV304 cells, immunofluorescence for beta-catenin and F-actin, 3D collagen gel tube assay, cell proliferation analysis","journal":"International archives of allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous reconstitution with multiple functional readouts; single lab study","pmids":["10592470"],"is_preprint":false},{"year":2014,"finding":"Cdh5 (zebrafish ortholog of CDH5) organizes junctional and cortical actin cytoskeleton to support cell elongation during angiogenic sprouting; loss of cdh5 by null mutation impairs junctional remodeling and cell elongation associated with disorganized actin, and a truncated Cdh5 (lacking intracellular domain) fails to rescue these defects. Pharmacological inhibition of actin polymerization (but not actin-myosin contractility) phenocopies cdh5 mutation.","method":"Zebrafish cdh5 null mutant generation, in vivo live imaging of sprouting angiogenesis, rescue with truncated Cdh5 construct, pharmacological inhibition of actin polymerization vs. contractility","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null in vivo with domain-dissection rescue experiments and pharmacological epistasis, multiple orthogonal approaches in one study","pmids":["25373898"],"is_preprint":false},{"year":2013,"finding":"In glioblastoma stem-like cells (GSCs), both HIF1α and HIF2α transcriptionally activate CDH5 under hypoxia by directly binding its promoter (shown by ChIP), and CDH5 expression contributes to vasculogenic mimicry formation by GSCs, especially under hypoxic conditions (shown by CDH5 shRNA knockdown and tube formation assay).","method":"shRNA knockdown of CDH5, chromatin immunoprecipitation (ChIP) for HIF1α/HIF2α at CDH5 promoter, vasculogenic tube formation assay under normoxia and 1% O2","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown with defined phenotypic readout; single lab study","pmids":["23645533"],"is_preprint":false},{"year":2022,"finding":"VEGF-C/VEGFR3 signaling induces VE-cadherin (CDH5) endocytosis and loss of function via SRC-mediated phosphorylation, while VE-cadherin reciprocally prevents VEGFR3 endocytosis required for optimal receptor signaling. Mice with membrane-retained (non-endocytosable) VE-cadherin exhibit defects in sinusoidal and lymphatic vessel growth identical to loss of VEGFR3. Genetic loss of VE-cadherin rescues sinusoidal/lymphatic growth defects caused by VEGFR3 loss (but not VEGF-C loss) by potentiating VEGFR2 signaling.","method":"Mouse genetic models (membrane-retained CDH5 knock-in, conditional CDH5 knockout, VEGFR3 knockout, VEGF-C knockout, double mutants), genetic epistasis, mechanistic analysis of receptor endocytosis and SRC-mediated phosphorylation","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple mouse genetic models with epistasis, mechanistic dissection of phosphorylation and endocytosis, reciprocal regulatory axis established with orthogonal approaches","pmids":["36910472"],"is_preprint":false},{"year":2018,"finding":"IGFBP2 interacts with integrin α5β1 and activates the FAK/ERK pathway to upregulate CDH5 (CD144) expression in glioma cells, promoting vasculogenic mimicry formation. SP1, activated downstream of IGFBP2, binds directly to the CDH5 promoter (shown by luciferase reporter and ChIP assay).","method":"Co-immunoprecipitation of IGFBP2 with integrin α5/β1, IGFBP2 stable knockdown, luciferase reporter assay, ChIP assay for SP1 at CDH5 promoter, vasculogenic tube formation assay, orthotopic mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional assays; single lab but multiple orthogonal methods","pmids":["30368528"],"is_preprint":false},{"year":2016,"finding":"C1qr (CD93) and C1qrl (Clec14a) redundantly regulate angiogenesis in zebrafish by controlling Cdh5 expression; double mutation of c1qr/c1qrl abolishes Cdh5 from inter-segmental vessel endothelial junctions, and replenishment of Cdh5 rescues the angiogenic defects in double mutants.","method":"Zebrafish single and double mutant analysis, in vivo imaging of inter-segmental vessel formation, rescue by Cdh5 re-expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with rescue in vivo; single lab, zebrafish model","pmids":["28007601"],"is_preprint":false},{"year":2014,"finding":"IL-2 induces vascular leak syndrome through redistribution (altered membrane distribution) of CD144 (VE-cadherin) in primary human pulmonary microvascular endothelial cells, demonstrated by ex vivo studies using serum from IL-2-treated patients.","method":"Ex vivo primary human pulmonary microvascular endothelial cell model, in vitro IL-2 treatment, immunofluorescence-based analysis of CD144 distribution, patient serum studies","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization/redistribution assay in primary cells with both in vitro and ex vivo patient-serum validation; single lab","pmids":["24885155"],"is_preprint":false},{"year":2019,"finding":"miR-101 represses CDH5 expression by targeting its 3'-UTR in HUVECs, and this suppression mediates promotion of endothelial cell apoptosis and inhibition of cell migration; silencing CDH5 alone recapitulates the pro-apoptotic and anti-migratory effects of miR-101 overexpression.","method":"miR-101 overexpression in HUVECs, 3'-UTR luciferase reporter assay, CDH5 siRNA knockdown, apoptosis and migration assays","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter plus functional knockdown with defined phenotype; single lab","pmids":["31934175"],"is_preprint":false},{"year":2018,"finding":"TNFα induces hsa-miR-6086 in HUVECs, which in turn downregulates CDH5 expression by targeting it; inhibition of hsa-miR-6086 or exogenous CDH5 re-expression protects HUVECs from TNFα-induced apoptosis and growth inhibition, placing CDH5 as a downstream effector of TNFα/miR-6086 signaling in endothelial cells.","method":"miR-6086 mimic/inhibitor transfection in HUVECs, CDH5 cDNA re-expression (insensitive to miRNA), apoptosis and proliferation assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with miRNA-insensitive CDH5 construct plus functional readouts; single lab","pmids":["29605606"],"is_preprint":false},{"year":2024,"finding":"Notch1 directly transcriptionally activates CDH5 in gastric cancer cells, as demonstrated by ChIP assay showing Notch1 binding to the CDH5 gene promoter; CDH5 silencing attenuates the Notch1-driven enhancement of proliferation, migration, invasion, and vasculogenic mimicry.","method":"ChIP assay for Notch1 at CDH5 promoter, CDH5 shRNA knockdown with rescue, proliferation (EdU), migration, invasion, and tube formation assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional epistasis assays; single lab study","pmids":["39172098"],"is_preprint":false},{"year":2022,"finding":"ANGPTL4 upregulates ETV5 expression in ovarian cancer cells; ETV5 binds the CDH5 promoter region to activate CDH5 transcription; CDH5 in turn activates AKT phosphorylation and upregulates MMP9, promoting angiogenesis and metastasis. CDH5 expression is required for ANGPTL4-driven tumorigenic effects.","method":"shRNA knockdown of ANGPTL4 and ETV5, Western blotting for CDH5/p-AKT/MMP9, promoter binding by ETV5 (inferred by expression correlation and transcription factor binding analysis), in vivo xenograft model","journal":"Journal of ovarian research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ETV5-CDH5 promoter binding not directly demonstrated by ChIP; pathway placement based on expression changes and knockdown; single lab","pmids":["36517864"],"is_preprint":false},{"year":2026,"finding":"KAT14 (lysine acetyltransferase 14) acetylates histones H3K9 and H3K18 at the CDH5 locus, facilitating binding of serum response factor (SRF) to activate CDH5 expression in trophoblast/endothelial cells; CDH5 overexpression rescues placental vascular defects in KAT14-deficient mice, and CDH5-Cre; KAT14 KO mice show defective spiral artery remodeling.","method":"Co-immunoprecipitation, EMSA, luciferase reporter assay, ChIP for KAT14/SRF at CDH5 locus, conditional knockout mouse models (CYP19A1-Cre and CDH5-Cre), RNA sequencing, CDH5 overexpression rescue","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods (ChIP, EMSA, luciferase, Co-IP) plus in vivo genetic rescue; mechanistic chain from KAT14 acetylation to SRF binding to CDH5 activation established in one study","pmids":["41867034"],"is_preprint":false},{"year":2026,"finding":"MMP-2 promotes degradation of CDH5 (VE-cadherin), thereby increasing vascular permeability and facilitating inflammatory cell infiltration in heterotopic ossification; inhibition of MMP-2 preserves CDH5 and suppresses ectopic bone formation.","method":"In vitro and in vivo heterotopic ossification models, MMP-2 inhibition by Forsythoside A, assessment of CDH5 protein levels and vascular permeability","journal":"Materials today. Bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MMP-2 cleavage of CDH5 inferred from inhibitor studies; direct biochemical demonstration of cleavage not described in abstract; single lab","pmids":["42099999"],"is_preprint":false},{"year":2025,"finding":"CDH1 (E-cadherin) reduces endothelial cell permeability under chronic intermittent hypoxia by promoting CDH5 (VE-cadherin) membrane expression; loss of CDH1 from the cell membrane (caused by ox-LDL) correlates with reduced CDH5 membrane localization and increased permeability.","method":"Endothelial cell CIH model, immunofluorescence for CDH5 membrane localization, FITC-dextran permeability assay, CDH1 overexpression/knockdown","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract regarding how CDH1 promotes CDH5 membrane expression; single method approach","pmids":["41419959"],"is_preprint":false}],"current_model":"CDH5 (VE-cadherin/CD144) is an endothelial-specific type II classical cadherin that mediates homophilic, calcium-dependent cell-cell adhesion at endothelial junctions, where it co-assembles with beta-catenin and alpha-catenin to organize cortical F-actin, enforce contact-inhibited monolayer growth, reduce paracellular permeability, and support angiogenic sprouting by promoting cell elongation via actin polymerization; its membrane retention is regulated by SRC-mediated phosphorylation and endocytosis downstream of VEGF-C/VEGFR3 signaling, forming a reciprocal negative regulatory axis in which VE-cadherin opposes VEGFR3 endocytosis while VEGFR3 signaling promotes VE-cadherin endocytosis; at the transcriptional level, CDH5 is activated by HIF1α/HIF2α under hypoxia, by Notch1 and SP1 in cancer contexts, and by the KAT14–SRF epigenetic axis in vascular development, while being post-transcriptionally repressed by miR-101 and miR-6086."},"narrative":{"mechanistic_narrative":"CDH5 (VE-cadherin/CD144) is an endothelial cell-cell adhesion molecule that mediates homophilic, calcium-dependent adhesion at intercellular junctions, where it controls paracellular permeability, contact-inhibited monolayer growth, and angiogenic morphogenesis [PMID:7627717, PMID:10592470]. At junctions it recruits beta-catenin and co-distributes with alpha-catenin to reorganize cortical F-actin into parallel bundles, and this junctional/cortical actin organization drives endothelial cell elongation during sprouting angiogenesis [PMID:7627717, PMID:10592470, PMID:25373898]. The cytoplasmic domain is required for these functions: a truncated Cdh5 lacking the intracellular domain fails to rescue actin disorganization and elongation defects in vivo, and the phenotype is recapitulated by blocking actin polymerization rather than actomyosin contractility [PMID:25373898]. CDH5 also supports lumen and tube formation, acting through cell-cell association and vacuole fusion in a manner distinct from CD31 [PMID:10487846, PMID:10592470]. Membrane retention of CDH5 is dynamically regulated: VEGF-C/VEGFR3 signaling drives SRC-mediated phosphorylation and endocytosis of VE-cadherin, while VE-cadherin reciprocally restrains VEGFR3 endocytosis, establishing a reciprocal axis that tunes sinusoidal and lymphatic vessel growth [PMID:36910472]. CDH5 expression is transcriptionally activated under hypoxia by HIF1α and HIF2α and by the KAT14–SRF epigenetic axis through H3K9/H3K18 acetylation at the CDH5 locus, the latter being required for placental spiral artery remodeling in vivo [PMID:23645533, PMID:41867034]. In cancer, CDH5 is induced by Notch1 and by IGFBP2–SP1 signaling and contributes to vasculogenic mimicry, while it is post-transcriptionally repressed by miR-101 and TNFα-induced miR-6086 to promote endothelial apoptosis [PMID:30368528, PMID:31934175, PMID:29605606, PMID:39172098].","teleology":[{"year":1995,"claim":"Established that CDH5 is itself sufficient to confer endothelial-type cell-cell adhesion and junctional barrier function, defining its core molecular activity.","evidence":"Full-length CDH5 transfection into CHO cells with aggregation, permeability, migration, and alpha-catenin co-localization assays","pmids":["7627717"],"confidence":"High","gaps":["Did not resolve the cytoplasmic signaling partners beyond alpha-catenin","Heterologous cell context rather than native endothelium"]},{"year":1999,"claim":"Showed that CDH5 is required for endothelial morphogenesis (tube/lumen formation) and links junctional adhesion to beta-catenin recruitment, F-actin reorganization, and contact inhibition of growth.","evidence":"Antibody blockade in 3D collagen gels and CDH5 vs CD31 reconstitution in ECV304 cells with immunofluorescence and proliferation readouts","pmids":["10487846","10592470"],"confidence":"Medium","gaps":["Single-lab reconstitution systems","Did not define which cytoplasmic domain residues drive actin reorganization"]},{"year":2014,"claim":"Demonstrated in vivo that the CDH5 intracellular domain organizes junctional/cortical actin to drive cell elongation during sprouting, distinguishing actin polymerization from contractility as the relevant effector arm.","evidence":"Zebrafish cdh5 null mutants, domain-truncation rescue, live imaging, and pharmacological epistasis on actin polymerization vs contractility","pmids":["25373898"],"confidence":"High","gaps":["Specific actin regulators downstream of the cytoplasmic tail not identified","Connection to beta-catenin pool not directly tested"]},{"year":2013,"claim":"Identified hypoxia-driven transcriptional control of CDH5 by HIF1α/HIF2α and linked CDH5 to vasculogenic mimicry in tumor cells.","evidence":"ChIP for HIF1α/HIF2α at the CDH5 promoter plus shRNA knockdown and tube formation under hypoxia in glioblastoma stem-like cells","pmids":["23645533"],"confidence":"Medium","gaps":["Promoter binding shown but cooperating co-factors not mapped","Single tumor cell context"]},{"year":2016,"claim":"Placed CDH5 downstream of CD93/Clec14a in an in vivo angiogenic pathway, showing CDH5 junctional localization is a required effector.","evidence":"Zebrafish c1qr/c1qrl single and double mutants with Cdh5 re-expression rescue and ISV imaging","pmids":["28007601"],"confidence":"Medium","gaps":["Mechanism by which CD93/Clec14a control Cdh5 levels not defined","Transcriptional vs post-transcriptional control unresolved"]},{"year":2018,"claim":"Defined additional inputs to CDH5 regulation: TNFα/miR-6086 post-transcriptional repression promoting endothelial apoptosis, and IGFBP2–integrin–FAK/ERK–SP1 transcriptional activation in glioma vasculogenic mimicry.","evidence":"miRNA mimic/inhibitor with miRNA-insensitive CDH5 rescue in HUVECs; Co-IP, luciferase, and SP1 ChIP at CDH5 promoter with tube formation and orthotopic model","pmids":["29605606","30368528"],"confidence":"Medium","gaps":["Direct effect of CDH5 loss on barrier vs apoptosis pathways not separated","SP1 and miRNA inputs not tested in native endothelium together"]},{"year":2019,"claim":"Confirmed miR-101 as a direct 3'-UTR repressor of CDH5 controlling endothelial apoptosis and migration.","evidence":"miR-101 overexpression, 3'-UTR luciferase reporter, and CDH5 siRNA phenocopy in HUVECs","pmids":["31934175"],"confidence":"Medium","gaps":["In vivo relevance not established","Downstream pro-apoptotic effectors not defined"]},{"year":2022,"claim":"Established the reciprocal VE-cadherin–VEGFR3 endocytic axis, mechanistically linking SRC-mediated CDH5 phosphorylation and endocytosis to receptor signaling and vessel growth.","evidence":"Mouse genetic models (membrane-retained CDH5 knock-in, conditional knockouts, double mutants) with epistasis and endocytosis/phosphorylation analysis","pmids":["36910472"],"confidence":"High","gaps":["Identity of the SRC-targeted endocytic machinery not fully resolved","Whether the axis operates identically in blood vs lymphatic endothelium not separated"]},{"year":2026,"claim":"Defined an epigenetic activation mechanism in which KAT14-mediated H3K9/H3K18 acetylation enables SRF binding to drive CDH5 expression, with in vivo requirement for placental spiral artery remodeling.","evidence":"Co-IP, EMSA, luciferase, ChIP for KAT14/SRF at the CDH5 locus, conditional KO mice, and CDH5 overexpression rescue","pmids":["41867034"],"confidence":"High","gaps":["Whether KAT14–SRF control of CDH5 operates in mature vasculature beyond placenta not tested","Interplay with HIF-driven activation not addressed"]},{"year":2024,"claim":"Extended transcriptional control of CDH5 to Notch1, linking it to gastric cancer proliferation, invasion, and vasculogenic mimicry.","evidence":"Notch1 ChIP at the CDH5 promoter with CDH5 shRNA knockdown/rescue and functional assays","pmids":["39172098"],"confidence":"Medium","gaps":["Cooperating transcription factors not defined","Restricted to one cancer cell context"]},{"year":null,"claim":"How the multiple transcriptional (HIF, Notch1, SP1, KAT14–SRF), post-transcriptional (miR-101, miR-6086), and post-translational (SRC phosphorylation, proteolysis) inputs are integrated to set CDH5 levels and junctional localization in different vascular beds remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the regulatory inputs","Proteolytic regulation by MMP-2 and CDH1-dependent membrane retention rest on low-confidence inhibitor/correlation studies","Mechanism of CDH1-promoted CDH5 membrane expression undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,5,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]}],"complexes":["VE-cadherin–catenin junctional complex"],"partners":["CTNNB1","CTNNA1","VEGFR3","SRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P33151","full_name":"Cadherin-5","aliases":["7B4 antigen","Vascular endothelial cadherin","VE-cadherin"],"length_aa":784,"mass_kda":87.5,"function":"Cadherins are calcium-dependent cell adhesion proteins (By similarity). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types (PubMed:21269602). This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions (By similarity). It associates with alpha-catenin forming a link to the cytoskeleton (PubMed:10861224). Plays a role in coupling actin fibers to cell junctions in endothelial cells, via acting as a cell junctional complex anchor for AMOTL2 and MAGI1 (By similarity). Acts in concert with KRIT1 and PALS1 to establish and maintain correct endothelial cell polarity and vascular lumen (By similarity). These effects are mediated by recruitment and activation of the Par polarity complex and RAP1B (PubMed:20332120). Positively regulates reorientation of actin stress fibers and endothelial cell reorientation in response to cellular mechantransduction (PubMed:25795300). Required for activation of PRKCZ and for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction (PubMed:20332120). Associates with CTNND1/p120-catenin to control CADH5 endocytosis (By similarity)","subcellular_location":"Cell junction, adherens junction; Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P33151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH5","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDH5","total_profiled":1310},"omim":[{"mim_id":"620845","title":"TRANSMEMBRANE 4 L6 FAMILY, MEMBER 19; TM4SF19","url":"https://www.omim.org/entry/620845"},{"mim_id":"617721","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 9; HMND9","url":"https://www.omim.org/entry/617721"},{"mim_id":"616845","title":"C-TYPE LECTIN DOMAIN FAMILY 14, MEMBER A; CLEC14A","url":"https://www.omim.org/entry/616845"},{"mim_id":"615815","title":"SMOOTH MUSCLE- AND ENDOTHELIAL CELL-ENRICHED MIGRATION/DIFFERENTIATION-ASSOCIATED LONG NONCODING RNA; SENCR","url":"https://www.omim.org/entry/615815"},{"mim_id":"614398","title":"JUNCTIONAL CADHERIN 5-ASSOCIATED PROTEIN; JCAD","url":"https://www.omim.org/entry/614398"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":221.7}],"url":"https://www.proteinatlas.org/search/CDH5"},"hgnc":{"alias_symbol":["7B4","CD144"],"prev_symbol":[]},"alphafold":{"accession":"P33151","domains":[{"cath_id":"2.60.40.60","chopping":"54-143","consensus_level":"high","plddt":89.7437,"start":54,"end":143},{"cath_id":"2.60.40.60","chopping":"151-250","consensus_level":"medium","plddt":91.2284,"start":151,"end":250},{"cath_id":"2.60.40.60","chopping":"258-365","consensus_level":"medium","plddt":91.2095,"start":258,"end":365},{"cath_id":"2.60.40.60","chopping":"372-471","consensus_level":"high","plddt":92.6523,"start":372,"end":471},{"cath_id":"2.60.40.60","chopping":"479-589","consensus_level":"high","plddt":87.2305,"start":479,"end":589}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P33151","model_url":"https://alphafold.ebi.ac.uk/files/AF-P33151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P33151-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDH5","jax_strain_url":"https://www.jax.org/strain/search?query=CDH5"},"sequence":{"accession":"P33151","fasta_url":"https://rest.uniprot.org/uniprotkb/P33151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P33151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P33151"}},"corpus_meta":[{"pmid":"7627717","id":"PMC_7627717","title":"Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin.","date":"1995","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7627717","citation_count":243,"is_preprint":false},{"pmid":"10487846","id":"PMC_10487846","title":"Functional roles for PECAM-1 (CD31) and VE-cadherin (CD144) in tube assembly and lumen formation in three-dimensional collagen gels.","date":"1999","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10487846","citation_count":197,"is_preprint":false},{"pmid":"25373898","id":"PMC_25373898","title":"Cdh5/VE-cadherin promotes endothelial cell interface elongation via cortical actin polymerization during angiogenic sprouting.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25373898","citation_count":137,"is_preprint":false},{"pmid":"23645533","id":"PMC_23645533","title":"CDH5 is specifically activated in glioblastoma 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it localizes to intercellular junctions where it co-distributes with alpha-catenin, decreases intercellular permeability to high-molecular-weight molecules, and reduces cell migration rate across a wounded area.\",\n      \"method\": \"Transfection of full-length CDH5 cDNA into CHO cells, cell aggregation assays, permeability assays, wound-healing migration assay, co-localization with alpha-catenin\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution in heterologous cells with multiple orthogonal assays (aggregation, permeability, migration, co-localization), foundational study replicated broadly\",\n      \"pmids\": [\"7627717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Antibody blockade of VE-cadherin (CD144) in 3D collagen gel cultures impairs endothelial tube formation by inhibiting cell-cell association and reducing vacuole formation or vacuole fusion required for intercellular lumen formation, a role distinct from that of CD31.\",\n      \"method\": \"Monoclonal antibody inhibition in 3D type I collagen gel angiogenesis assay with morphological analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional blockade with defined morphological readout; single lab, single method but clear phenotypic specificity\",\n      \"pmids\": [\"10487846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"VE-cadherin (CD144) expression in transfected ECV304 cells (which lack endogenous VE-cadherin) recruits beta-catenin to junctional regions, reorganizes F-actin into parallel bundles, enables 3D tube formation, and enforces contact-inhibited monolayer growth with dramatic reduction of cell cycling after confluence — properties absent in CD31 transfectants and empty-vector controls.\",\n      \"method\": \"Stable transfection of VE-cadherin or CD31 cDNA into ECV304 cells, immunofluorescence for beta-catenin and F-actin, 3D collagen gel tube assay, cell proliferation analysis\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous reconstitution with multiple functional readouts; single lab study\",\n      \"pmids\": [\"10592470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cdh5 (zebrafish ortholog of CDH5) organizes junctional and cortical actin cytoskeleton to support cell elongation during angiogenic sprouting; loss of cdh5 by null mutation impairs junctional remodeling and cell elongation associated with disorganized actin, and a truncated Cdh5 (lacking intracellular domain) fails to rescue these defects. Pharmacological inhibition of actin polymerization (but not actin-myosin contractility) phenocopies cdh5 mutation.\",\n      \"method\": \"Zebrafish cdh5 null mutant generation, in vivo live imaging of sprouting angiogenesis, rescue with truncated Cdh5 construct, pharmacological inhibition of actin polymerization vs. contractility\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null in vivo with domain-dissection rescue experiments and pharmacological epistasis, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"25373898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In glioblastoma stem-like cells (GSCs), both HIF1α and HIF2α transcriptionally activate CDH5 under hypoxia by directly binding its promoter (shown by ChIP), and CDH5 expression contributes to vasculogenic mimicry formation by GSCs, especially under hypoxic conditions (shown by CDH5 shRNA knockdown and tube formation assay).\",\n      \"method\": \"shRNA knockdown of CDH5, chromatin immunoprecipitation (ChIP) for HIF1α/HIF2α at CDH5 promoter, vasculogenic tube formation assay under normoxia and 1% O2\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown with defined phenotypic readout; single lab study\",\n      \"pmids\": [\"23645533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VEGF-C/VEGFR3 signaling induces VE-cadherin (CDH5) endocytosis and loss of function via SRC-mediated phosphorylation, while VE-cadherin reciprocally prevents VEGFR3 endocytosis required for optimal receptor signaling. Mice with membrane-retained (non-endocytosable) VE-cadherin exhibit defects in sinusoidal and lymphatic vessel growth identical to loss of VEGFR3. Genetic loss of VE-cadherin rescues sinusoidal/lymphatic growth defects caused by VEGFR3 loss (but not VEGF-C loss) by potentiating VEGFR2 signaling.\",\n      \"method\": \"Mouse genetic models (membrane-retained CDH5 knock-in, conditional CDH5 knockout, VEGFR3 knockout, VEGF-C knockout, double mutants), genetic epistasis, mechanistic analysis of receptor endocytosis and SRC-mediated phosphorylation\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple mouse genetic models with epistasis, mechanistic dissection of phosphorylation and endocytosis, reciprocal regulatory axis established with orthogonal approaches\",\n      \"pmids\": [\"36910472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IGFBP2 interacts with integrin α5β1 and activates the FAK/ERK pathway to upregulate CDH5 (CD144) expression in glioma cells, promoting vasculogenic mimicry formation. SP1, activated downstream of IGFBP2, binds directly to the CDH5 promoter (shown by luciferase reporter and ChIP assay).\",\n      \"method\": \"Co-immunoprecipitation of IGFBP2 with integrin α5/β1, IGFBP2 stable knockdown, luciferase reporter assay, ChIP assay for SP1 at CDH5 promoter, vasculogenic tube formation assay, orthotopic mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30368528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C1qr (CD93) and C1qrl (Clec14a) redundantly regulate angiogenesis in zebrafish by controlling Cdh5 expression; double mutation of c1qr/c1qrl abolishes Cdh5 from inter-segmental vessel endothelial junctions, and replenishment of Cdh5 rescues the angiogenic defects in double mutants.\",\n      \"method\": \"Zebrafish single and double mutant analysis, in vivo imaging of inter-segmental vessel formation, rescue by Cdh5 re-expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with rescue in vivo; single lab, zebrafish model\",\n      \"pmids\": [\"28007601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-2 induces vascular leak syndrome through redistribution (altered membrane distribution) of CD144 (VE-cadherin) in primary human pulmonary microvascular endothelial cells, demonstrated by ex vivo studies using serum from IL-2-treated patients.\",\n      \"method\": \"Ex vivo primary human pulmonary microvascular endothelial cell model, in vitro IL-2 treatment, immunofluorescence-based analysis of CD144 distribution, patient serum studies\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization/redistribution assay in primary cells with both in vitro and ex vivo patient-serum validation; single lab\",\n      \"pmids\": [\"24885155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-101 represses CDH5 expression by targeting its 3'-UTR in HUVECs, and this suppression mediates promotion of endothelial cell apoptosis and inhibition of cell migration; silencing CDH5 alone recapitulates the pro-apoptotic and anti-migratory effects of miR-101 overexpression.\",\n      \"method\": \"miR-101 overexpression in HUVECs, 3'-UTR luciferase reporter assay, CDH5 siRNA knockdown, apoptosis and migration assays\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter plus functional knockdown with defined phenotype; single lab\",\n      \"pmids\": [\"31934175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TNFα induces hsa-miR-6086 in HUVECs, which in turn downregulates CDH5 expression by targeting it; inhibition of hsa-miR-6086 or exogenous CDH5 re-expression protects HUVECs from TNFα-induced apoptosis and growth inhibition, placing CDH5 as a downstream effector of TNFα/miR-6086 signaling in endothelial cells.\",\n      \"method\": \"miR-6086 mimic/inhibitor transfection in HUVECs, CDH5 cDNA re-expression (insensitive to miRNA), apoptosis and proliferation assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with miRNA-insensitive CDH5 construct plus functional readouts; single lab\",\n      \"pmids\": [\"29605606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Notch1 directly transcriptionally activates CDH5 in gastric cancer cells, as demonstrated by ChIP assay showing Notch1 binding to the CDH5 gene promoter; CDH5 silencing attenuates the Notch1-driven enhancement of proliferation, migration, invasion, and vasculogenic mimicry.\",\n      \"method\": \"ChIP assay for Notch1 at CDH5 promoter, CDH5 shRNA knockdown with rescue, proliferation (EdU), migration, invasion, and tube formation assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional epistasis assays; single lab study\",\n      \"pmids\": [\"39172098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANGPTL4 upregulates ETV5 expression in ovarian cancer cells; ETV5 binds the CDH5 promoter region to activate CDH5 transcription; CDH5 in turn activates AKT phosphorylation and upregulates MMP9, promoting angiogenesis and metastasis. CDH5 expression is required for ANGPTL4-driven tumorigenic effects.\",\n      \"method\": \"shRNA knockdown of ANGPTL4 and ETV5, Western blotting for CDH5/p-AKT/MMP9, promoter binding by ETV5 (inferred by expression correlation and transcription factor binding analysis), in vivo xenograft model\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ETV5-CDH5 promoter binding not directly demonstrated by ChIP; pathway placement based on expression changes and knockdown; single lab\",\n      \"pmids\": [\"36517864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KAT14 (lysine acetyltransferase 14) acetylates histones H3K9 and H3K18 at the CDH5 locus, facilitating binding of serum response factor (SRF) to activate CDH5 expression in trophoblast/endothelial cells; CDH5 overexpression rescues placental vascular defects in KAT14-deficient mice, and CDH5-Cre; KAT14 KO mice show defective spiral artery remodeling.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, luciferase reporter assay, ChIP for KAT14/SRF at CDH5 locus, conditional knockout mouse models (CYP19A1-Cre and CDH5-Cre), RNA sequencing, CDH5 overexpression rescue\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods (ChIP, EMSA, luciferase, Co-IP) plus in vivo genetic rescue; mechanistic chain from KAT14 acetylation to SRF binding to CDH5 activation established in one study\",\n      \"pmids\": [\"41867034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MMP-2 promotes degradation of CDH5 (VE-cadherin), thereby increasing vascular permeability and facilitating inflammatory cell infiltration in heterotopic ossification; inhibition of MMP-2 preserves CDH5 and suppresses ectopic bone formation.\",\n      \"method\": \"In vitro and in vivo heterotopic ossification models, MMP-2 inhibition by Forsythoside A, assessment of CDH5 protein levels and vascular permeability\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MMP-2 cleavage of CDH5 inferred from inhibitor studies; direct biochemical demonstration of cleavage not described in abstract; single lab\",\n      \"pmids\": [\"42099999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDH1 (E-cadherin) reduces endothelial cell permeability under chronic intermittent hypoxia by promoting CDH5 (VE-cadherin) membrane expression; loss of CDH1 from the cell membrane (caused by ox-LDL) correlates with reduced CDH5 membrane localization and increased permeability.\",\n      \"method\": \"Endothelial cell CIH model, immunofluorescence for CDH5 membrane localization, FITC-dextran permeability assay, CDH1 overexpression/knockdown\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract regarding how CDH1 promotes CDH5 membrane expression; single method approach\",\n      \"pmids\": [\"41419959\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH5 (VE-cadherin/CD144) is an endothelial-specific type II classical cadherin that mediates homophilic, calcium-dependent cell-cell adhesion at endothelial junctions, where it co-assembles with beta-catenin and alpha-catenin to organize cortical F-actin, enforce contact-inhibited monolayer growth, reduce paracellular permeability, and support angiogenic sprouting by promoting cell elongation via actin polymerization; its membrane retention is regulated by SRC-mediated phosphorylation and endocytosis downstream of VEGF-C/VEGFR3 signaling, forming a reciprocal negative regulatory axis in which VE-cadherin opposes VEGFR3 endocytosis while VEGFR3 signaling promotes VE-cadherin endocytosis; at the transcriptional level, CDH5 is activated by HIF1α/HIF2α under hypoxia, by Notch1 and SP1 in cancer contexts, and by the KAT14–SRF epigenetic axis in vascular development, while being post-transcriptionally repressed by miR-101 and miR-6086.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH5 (VE-cadherin/CD144) is an endothelial cell-cell adhesion molecule that mediates homophilic, calcium-dependent adhesion at intercellular junctions, where it controls paracellular permeability, contact-inhibited monolayer growth, and angiogenic morphogenesis [#0, #2]. At junctions it recruits beta-catenin and co-distributes with alpha-catenin to reorganize cortical F-actin into parallel bundles, and this junctional/cortical actin organization drives endothelial cell elongation during sprouting angiogenesis [#0, #2, #3]. The cytoplasmic domain is required for these functions: a truncated Cdh5 lacking the intracellular domain fails to rescue actin disorganization and elongation defects in vivo, and the phenotype is recapitulated by blocking actin polymerization rather than actomyosin contractility [#3]. CDH5 also supports lumen and tube formation, acting through cell-cell association and vacuole fusion in a manner distinct from CD31 [#1, #2]. Membrane retention of CDH5 is dynamically regulated: VEGF-C/VEGFR3 signaling drives SRC-mediated phosphorylation and endocytosis of VE-cadherin, while VE-cadherin reciprocally restrains VEGFR3 endocytosis, establishing a reciprocal axis that tunes sinusoidal and lymphatic vessel growth [#5]. CDH5 expression is transcriptionally activated under hypoxia by HIF1\\u03b1 and HIF2\\u03b1 and by the KAT14\\u2013SRF epigenetic axis through H3K9/H3K18 acetylation at the CDH5 locus, the latter being required for placental spiral artery remodeling in vivo [#4, #13]. In cancer, CDH5 is induced by Notch1 and by IGFBP2\\u2013SP1 signaling and contributes to vasculogenic mimicry, while it is post-transcriptionally repressed by miR-101 and TNF\\u03b1-induced miR-6086 to promote endothelial apoptosis [#6, #9, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that CDH5 is itself sufficient to confer endothelial-type cell-cell adhesion and junctional barrier function, defining its core molecular activity.\",\n      \"evidence\": \"Full-length CDH5 transfection into CHO cells with aggregation, permeability, migration, and alpha-catenin co-localization assays\",\n      \"pmids\": [\"7627717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the cytoplasmic signaling partners beyond alpha-catenin\", \"Heterologous cell context rather than native endothelium\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that CDH5 is required for endothelial morphogenesis (tube/lumen formation) and links junctional adhesion to beta-catenin recruitment, F-actin reorganization, and contact inhibition of growth.\",\n      \"evidence\": \"Antibody blockade in 3D collagen gels and CDH5 vs CD31 reconstitution in ECV304 cells with immunofluorescence and proliferation readouts\",\n      \"pmids\": [\"10487846\", \"10592470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reconstitution systems\", \"Did not define which cytoplasmic domain residues drive actin reorganization\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in vivo that the CDH5 intracellular domain organizes junctional/cortical actin to drive cell elongation during sprouting, distinguishing actin polymerization from contractility as the relevant effector arm.\",\n      \"evidence\": \"Zebrafish cdh5 null mutants, domain-truncation rescue, live imaging, and pharmacological epistasis on actin polymerization vs contractility\",\n      \"pmids\": [\"25373898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific actin regulators downstream of the cytoplasmic tail not identified\", \"Connection to beta-catenin pool not directly tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified hypoxia-driven transcriptional control of CDH5 by HIF1\\u03b1/HIF2\\u03b1 and linked CDH5 to vasculogenic mimicry in tumor cells.\",\n      \"evidence\": \"ChIP for HIF1\\u03b1/HIF2\\u03b1 at the CDH5 promoter plus shRNA knockdown and tube formation under hypoxia in glioblastoma stem-like cells\",\n      \"pmids\": [\"23645533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter binding shown but cooperating co-factors not mapped\", \"Single tumor cell context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CDH5 downstream of CD93/Clec14a in an in vivo angiogenic pathway, showing CDH5 junctional localization is a required effector.\",\n      \"evidence\": \"Zebrafish c1qr/c1qrl single and double mutants with Cdh5 re-expression rescue and ISV imaging\",\n      \"pmids\": [\"28007601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD93/Clec14a control Cdh5 levels not defined\", \"Transcriptional vs post-transcriptional control unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined additional inputs to CDH5 regulation: TNF\\u03b1/miR-6086 post-transcriptional repression promoting endothelial apoptosis, and IGFBP2\\u2013integrin\\u2013FAK/ERK\\u2013SP1 transcriptional activation in glioma vasculogenic mimicry.\",\n      \"evidence\": \"miRNA mimic/inhibitor with miRNA-insensitive CDH5 rescue in HUVECs; Co-IP, luciferase, and SP1 ChIP at CDH5 promoter with tube formation and orthotopic model\",\n      \"pmids\": [\"29605606\", \"30368528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of CDH5 loss on barrier vs apoptosis pathways not separated\", \"SP1 and miRNA inputs not tested in native endothelium together\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed miR-101 as a direct 3'-UTR repressor of CDH5 controlling endothelial apoptosis and migration.\",\n      \"evidence\": \"miR-101 overexpression, 3'-UTR luciferase reporter, and CDH5 siRNA phenocopy in HUVECs\",\n      \"pmids\": [\"31934175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance not established\", \"Downstream pro-apoptotic effectors not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the reciprocal VE-cadherin\\u2013VEGFR3 endocytic axis, mechanistically linking SRC-mediated CDH5 phosphorylation and endocytosis to receptor signaling and vessel growth.\",\n      \"evidence\": \"Mouse genetic models (membrane-retained CDH5 knock-in, conditional knockouts, double mutants) with epistasis and endocytosis/phosphorylation analysis\",\n      \"pmids\": [\"36910472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the SRC-targeted endocytic machinery not fully resolved\", \"Whether the axis operates identically in blood vs lymphatic endothelium not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an epigenetic activation mechanism in which KAT14-mediated H3K9/H3K18 acetylation enables SRF binding to drive CDH5 expression, with in vivo requirement for placental spiral artery remodeling.\",\n      \"evidence\": \"Co-IP, EMSA, luciferase, ChIP for KAT14/SRF at the CDH5 locus, conditional KO mice, and CDH5 overexpression rescue\",\n      \"pmids\": [\"41867034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KAT14\\u2013SRF control of CDH5 operates in mature vasculature beyond placenta not tested\", \"Interplay with HIF-driven activation not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended transcriptional control of CDH5 to Notch1, linking it to gastric cancer proliferation, invasion, and vasculogenic mimicry.\",\n      \"evidence\": \"Notch1 ChIP at the CDH5 promoter with CDH5 shRNA knockdown/rescue and functional assays\",\n      \"pmids\": [\"39172098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cooperating transcription factors not defined\", \"Restricted to one cancer cell context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional (HIF, Notch1, SP1, KAT14\\u2013SRF), post-transcriptional (miR-101, miR-6086), and post-translational (SRC phosphorylation, proteolysis) inputs are integrated to set CDH5 levels and junctional localization in different vascular beds remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the regulatory inputs\", \"Proteolytic regulation by MMP-2 and CDH1-dependent membrane retention rest on low-confidence inhibitor/correlation studies\", \"Mechanism of CDH1-promoted CDH5 membrane expression undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 5, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"VE-cadherin\\u2013catenin junctional complex\"],\n    \"partners\": [\"CTNNB1\", \"CTNNA1\", \"VEGFR3\", \"SRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}