Affinage

CDH5

Cadherin-5 · UniProt P33151

Round 2 corrected
Length
784 aa
Mass
87.5 kDa
Annotated
2026-04-28
74 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDH5 (VE-cadherin) is an endothelial-specific classical cadherin that mediates homophilic, calcium-dependent cell-cell adhesion at adherens junctions and serves as a master regulator of vascular integrity, permeability, angiogenesis, and endothelial survival signaling. Its cytoplasmic tail recruits β-catenin, p120-catenin, and plakoglobin to connect to the actin cytoskeleton, and is required for VEGF-A–mediated survival signaling through a VEGFR-2/β-catenin/PI3K-Akt complex, as demonstrated by embryonic lethality (E9.5) in cytoplasmic-truncation knock-in mice (PMID:10428027); site-specific tyrosine phosphorylation of Tyr685 controls vascular permeability while Tyr731 controls leukocyte extravasation via SHP-2-mediated dephosphorylation and AP-2-dependent endocytosis (PMID:24487320), and VEGF triggers PAK-mediated serine phosphorylation leading to β-arrestin2-dependent clathrin-mediated VE-cadherin internalization (PMID:17060906). VE-cadherin's transmembrane domain directly binds VEGFR2 and VEGFR3 to assemble the endothelial mechanosensory complex transducing shear stress signals (PMID:25800053), while at junctions it retains VEGFR-2 at the plasma membrane to limit proliferative signaling (PMID:16893970) and reciprocally inhibits VEGF-C/VEGFR3 signaling by preventing VEGFR3 endocytosis (PMID:36910472). Barrier function is reinforced by cAMP-Epac1-Rap1 signaling that requires VE-cadherin for cortical actin reorganization (PMID:15601837), and VE-cadherin organizes cortical F-actin through Rac/Tiam-1 to drive endothelial cell elongation during angiogenic sprouting (PMID:11950930, PMID:25373898).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1991 High

    Establishing the molecular identity of CDH5 as a new cadherin family member resolved the question of whether endothelium expresses a tissue-specific cadherin and placed VE-cadherin within the classical cadherin superfamily.

    Evidence PCR-based cDNA cloning from brain/retina libraries with sequence analysis and Northern blot

    PMID:2059658

    Open questions at the time
    • No functional characterization performed
    • Endothelial specificity not yet demonstrated
  2. 1992 High

    Discovery that VE-cadherin is an endothelial junction-specific glycoprotein whose antibody blockade increases monolayer permeability established its function as the principal adhesion molecule controlling endothelial barrier integrity.

    Evidence Monoclonal antibody generation, immunofluorescence, immunoprecipitation, NH2-terminal sequencing, and permeability assays in endothelial monolayers

    PMID:1522121

    Open questions at the time
    • Homophilic binding not yet formally demonstrated
    • Cytoplasmic partners unknown
  3. 1995 High

    Reconstitution of VE-cadherin in non-endothelial CHO cells demonstrated its sufficiency for homophilic calcium-dependent adhesion, junction formation, co-distribution with α-catenin, permeability reduction, and migration inhibition, confirming it as a bona fide adhesion receptor.

    Evidence cDNA transfection into CHO cells with cell aggregation, permeability, wound-healing, and immunofluorescence assays

    PMID:7627717

    Open questions at the time
    • Identity of all catenin partners at endothelial junctions not mapped
    • In vivo requirement not tested
  4. 1997 High

    Identification of junction maturity-dependent tyrosine phosphorylation of VE-cadherin, β-catenin, and p120, and the dynamic exchange of p120/β-catenin for plakoglobin during junction maturation, revealed that VE-cadherin complexes are actively regulated by phosphorylation state and confluence.

    Evidence Co-immunoprecipitation, phosphotyrosine immunofluorescence across cell density conditions, transfection mapping in CHO cells

    PMID:9378757

    Open questions at the time
    • Specific phosphorylation sites on VE-cadherin not identified
    • Kinases and phosphatases responsible unknown
  5. 1999 High

    Genetic ablation and cytoplasmic truncation of VE-cadherin in mice causing E9.5 lethality from endothelial apoptosis, together with biochemical demonstration of a VEGFR-2/β-catenin/PI3K complex on VE-cadherin's tail, established that VE-cadherin is essential for vascular development and transmits VEGF survival signals in vivo.

    Evidence Gene targeting and cytoplasmic truncation knock-in mice, co-immunoprecipitation with VEGFR-2/β-catenin/PI3K, Akt phosphorylation and Bcl2 expression assays

    PMID:10428027

    Open questions at the time
    • Relative contributions of adhesion vs. signaling functions not separated
    • Whether VEGFR-2 binding is direct or catenin-mediated was unclear
  6. 2002 High

    Two parallel advances defined upstream regulators and downstream effectors: VE-cadherin activates Rac via Tiam-1 upregulation to reorganize actin, and VE-PTP associates with VE-cadherin through ectodomains to dephosphorylate it and reduce permeability, establishing a phosphorylation-dephosphorylation regulatory circuit.

    Evidence Rac/Rho pull-down assays with VE-cadherin reconstitution, Tiam-1 expression analysis, subcellular fractionation, dominant-negative Rac; reciprocal co-IP of VE-PTP with domain mapping, catalytic-dead mutant, and permeability assays

    PMID:11950930 PMID:12234928

    Open questions at the time
    • Structural basis of VE-PTP–VE-cadherin ectodomain interaction unknown
    • Whether Tiam-1 upregulation is transcriptional or post-transcriptional not resolved
  7. 2005 High

    Site-specific mutagenesis identified Tyr658 as the p120-binding switch and Tyr731 as the β-catenin-binding switch on VE-cadherin, while cAMP-Epac1-Rap1 signaling was shown to reinforce VE-cadherin-dependent barrier function through cortical actin reorganization that absolutely requires VE-cadherin, defining both phosphorylation-based destabilization and cAMP-based stabilization pathways.

    Evidence Phosphomimetic Y658E/Y731E mutagenesis with co-IP and barrier/migration assays; Epac-specific cAMP analogue, dominant-negative Rap1, siRNA, VE-cadherin KO/rescue, permeability assays

    PMID:15601837 PMID:16027153 PMID:16115630

    Open questions at the time
    • In vivo contribution of each tyrosine site not yet separated
    • How Rap1 physically acts on VE-cadherin complexes unknown
  8. 2006 High

    The VEGF-induced VE-cadherin endocytosis pathway was mapped (VEGFR-2→Src→Vav2→Rac→PAK→serine phosphorylation→β-arrestin2→clathrin), and VE-cadherin at junctions was shown to restrain VEGFR-2 internalization via DEP-1 phosphatase, revealing a reciprocal feedback between adhesion and receptor trafficking that controls proliferation versus quiescence.

    Evidence PAK-dependent serine mutagenesis, β-arrestin2 co-IP, clathrin inhibition, pathway epistasis; VEGFR-2 endocytosis assays in VE-cadherin KO/rescue cells, DEP-1 siRNA, ERK/PLCγ phosphorylation

    PMID:16893970 PMID:17060906

    Open questions at the time
    • Exact serine residues on VE-cadherin phosphorylated by PAK debated
    • Whether DEP-1 dephosphorylates VE-cadherin or VEGFR-2 directly unclear
  9. 2008 High

    ADAM10-mediated ectodomain shedding followed by γ-secretase cleavage was identified as a proteolytic mechanism for VE-cadherin removal, induced by Ca²⁺ influx and thrombin, required in both endothelial cells and T cells for T-cell transmigration; separately, the ETS factor Erg was placed upstream of CDH5 transcription via ChIP-verified promoter binding.

    Evidence ADAM10 RNAi and metalloprotease inhibitors with shedding/permeability/transmigration assays; Erg siRNA, ChIP, luciferase reporter, VE-cadherin rescue overexpression

    PMID:18195090 PMID:18420943

    Open questions at the time
    • ADAM10 cleavage site on VE-cadherin not mapped
    • Whether Erg cooperates with other transcription factors at the CDH5 promoter not resolved
  10. 2012 High

    Live imaging with FRET-based tension sensors revealed that VE-cadherin forms mechanically loaded focal adherens junctions (FAJs) to which Vinculin is recruited via Rho-ROCK-actomyosin contractility, protecting junctions from force-dependent opening; S1PR1 signaling was shown to stabilize VE-cadherin at junctions and oppose VEGF-driven sprouting.

    Evidence VE-cadherin FRET tension sensor, α-catenin Vinculin-binding mutant, ROCK inhibition, live imaging; S1PR1 loss-of-function in zebrafish and mice with VE-cadherin localization analysis

    PMID:22391038 PMID:22975327

    Open questions at the time
    • How S1PR1 signaling mechanistically stabilizes VE-cadherin (direct or indirect) not defined
    • Vinculin recruitment dynamics in vivo not measured
  11. 2014 High

    Knock-in mice separating Tyr685 and Tyr731 functions in vivo demonstrated that Tyr685 phosphorylation controls permeability while Tyr731 dephosphorylation (by SHP-2) permits AP-2 binding and endocytosis during neutrophil extravasation, definitively separating the two major phosphotyrosine regulatory arms of VE-cadherin in physiological settings.

    Evidence Y685F and Y731F knock-in mice, intravital microscopy, phospho-specific antibodies, SHP-2 interaction studies, AP-2 co-immunoprecipitation

    PMID:24487320

    Open questions at the time
    • Kinase(s) responsible for Tyr685 phosphorylation in vivo not definitively identified
    • Whether other tyrosine sites contribute in vivo not tested
  12. 2014 High

    Zebrafish cdh5 null mutants revealed that VE-cadherin organizes cortical F-actin polymerization to drive endothelial cell elongation during sprouting angiogenesis, with the cytoplasmic domain essential for this function, and actin polymerization (not contractility) as the critical downstream effector.

    Evidence Zebrafish cdh5 null mutants (TALEN/CRISPR), truncated Cdh5 rescue constructs, latrunculin vs blebbistatin treatment, live imaging

    PMID:25373898

    Open questions at the time
    • Which cytoplasmic domain residues or catenin interactions drive actin polymerization not mapped
    • Applicability to mammalian sprouting not directly shown in this study
  13. 2015 High

    The transmembrane domain of VE-cadherin was shown to directly bind VEGFR2 and VEGFR3 transmembrane domains, assembling the mechanosensory complex for shear stress responses, with VEGFR2 and VEGFR3 acting redundantly downstream; ZO-1 was found to regulate tension on VE-cadherin junctions through JACOP-p114RhoGEF-mediated Rho activity.

    Evidence Transmembrane domain mutant constructs with co-IP and shear stress signaling; ZO-1 siRNA with VE-cadherin FRET tension sensor, myosin activity assays, in vivo angiogenesis

    PMID:25753039 PMID:25800053

    Open questions at the time
    • Structural model of the VE-cadherin–VEGFR2/3 transmembrane complex not available
    • Whether ZO-1 tension regulation feeds back to mechanosensory signaling not tested
  14. 2016 High

    VE-cadherin was found to form polarized 'cadherin finger' protrusions that guide collective endothelial migration through Arp2/3-dependent actin polymerization and catenin-complex engagement, revealing a previously unknown morphogenetic signaling function beyond static adhesion.

    Evidence TIRF and lattice light-sheet live imaging, VE-cadherin/GFP constructs, Arp2/3 and actin inhibitors, catenin-binding mutants

    PMID:27842057

    Open questions at the time
    • How cadherin finger initiation is triggered at the rear of leader cells unknown
    • In vivo relevance of cadherin fingers not demonstrated
  15. 2022 High

    A reciprocal inhibitory axis between VE-cadherin and VEGF-C/VEGFR3 was genetically dissected: VE-cadherin prevents VEGFR3 endocytosis to dampen signaling, while VEGF-C/VEGFR3 triggers SRC-mediated VE-cadherin phosphorylation and internalization, controlling sinusoidal and lymphatic vessel growth.

    Evidence Conditional mouse knockouts, membrane-retained VE-cadherin knock-in, genetic epistasis, SRC inhibition, endocytosis assays

    PMID:36910472

    Open questions at the time
    • Whether VE-cadherin–VEGFR3 interaction is direct at the ectodomain or only transmembrane-mediated not resolved
    • Relevance to pathological lymphangiogenesis not tested
  16. 2025 High

    KAT14-mediated histone acetylation (H3K9, H3K18) at the CDH5 locus in cooperation with SRF was identified as a transcriptional activation mechanism; trophoblast-specific KAT14 knockout reduces CDH5 expression and impairs spiral artery remodeling, linking CDH5 epigenetic regulation to placental vascular development.

    Evidence Trophoblast-specific conditional KO mice, RNA-seq, ChIP, co-IP, EMSA, luciferase reporter, CDH5 overexpression rescue

    PMID:41867034

    Open questions at the time
    • Whether KAT14/SRF axis operates in adult endothelium or is trophoblast-specific not determined
    • Interplay between Erg and KAT14/SRF at the CDH5 promoter unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of the VE-cadherin mechanosensory complex (VE-cadherin–VEGFR2–VEGFR3) and the precise mechanisms coupling VE-cadherin to force-dependent transcriptional programs remain undefined.
  • No high-resolution structure of the VE-cadherin transmembrane signaling complex
  • Mechanotransduction pathway downstream of VE-cadherin tension (gene expression changes) not mapped
  • Integration of proteolytic (ADAM10), phosphorylation, and endocytic regulatory inputs in a unified quantitative model is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 5 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005856 cytoskeleton 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1500931 Cell-Cell communication 8 R-HSA-162582 Signal Transduction 7 R-HSA-109582 Hemostasis 3 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3
Partners
ADAM10ARRB2CTNNB1CTNND1FLT4JUPKDRPTPRB
Complex memberships
VE-cadherin/catenin adherens junction complexVE-cadherin–VE-PTP complexVE-cadherin–VEGFR2–VEGFR3 mechanosensory complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 CDH5/VE-cadherin was identified as an endothelial-specific integral membrane glycoprotein (~140 kD) localized exclusively at intercellular junctions of endothelial cells; antibody blockade increased permeability across monolayers, establishing its role in controlling endothelial junction integrity. Monoclonal antibody generation, immunofluorescence, immunoprecipitation, NH2-terminal sequencing, permeability assay The Journal of cell biology High 1522121
1991 CDH5 (cadherin-5) was identified as a new member of the cadherin family based on deduced amino acid sequence similarity, establishing its classification within the classical cadherin superfamily. PCR-based cDNA cloning from brain/retina libraries, sequence analysis, Northern blot Cell regulation High 2059658
1995 VE-cadherin mediates homophilic, calcium-dependent cell aggregation and cell-to-cell adhesion; transfection into CHO cells demonstrated it concentrates at intercellular junctions, co-distributes with α-catenin, decreases permeability to high-molecular-weight molecules, and reduces cell migration. cDNA cloning, transfection into CHO cells, cell aggregation assay, permeability assay, wound-healing migration assay, immunofluorescence Arteriosclerosis, thrombosis, and vascular biology High 7627717
1996 The mouse Cdh5 gene spans ~36 kb, is composed of 12 exons with a single major transcriptional start site 75 bp upstream of the ATL codon, lacks consensus TATA/CAAT boxes, and maps to mouse chromosome 8 in a cluster with Cdh1, Cdh3, and Cdh14. Genomic library screening, exon-intron mapping, S1 nuclease/primer extension, chromosomal mapping Genomics High 8786117
1997 Tyrosine phosphorylation of VE-cadherin, β-catenin, and p120 occurs in loosely confluent endothelial cells and is reduced in tightly confluent monolayers; p120 and β-catenin associate with VE-cadherin in immature junctions whereas plakoglobin replaces them in mature junctions, and p120 binds a distinct cytoplasmic region of VE-cadherin from β-catenin. Immunofluorescence with phosphotyrosine antibodies, co-immunoprecipitation, transfection in CHO cells, phosphatase inhibitor treatment Journal of cell science High 9378757
1999 Targeted inactivation or cytosolic truncation of VE-cadherin (removing the β-catenin-binding domain) in mice causes embryonic lethality at E9.5 due to endothelial apoptosis; VE-cadherin's cytoplasmic tail is required for VEGF-A-mediated endothelial survival signaling through complex formation with VEGFR-2, β-catenin, and PI3-kinase leading to Akt/Bcl2 activation. Gene targeting/knockout, cytoplasmic truncation knock-in mice, survival signaling assays (Akt phosphorylation, Bcl2 expression), co-immunoprecipitation with VEGFR-2/β-catenin/PI3K Cell High 10428027
1999 VE-cadherin (but not PECAM-1/CD31) is required for vacuole fusion leading to intercellular lumen formation during endothelial tube assembly in 3D collagen gels; anti-VE-cadherin antibodies impair vacuolization or vacuole fusion. 3D collagen gel tube formation assay, blocking monoclonal antibodies against VE-cadherin and CD31, morphological analysis The American journal of pathology Medium 10487846
1999 VE-cadherin expression in ECV304 cells (which lack endogenous VE-cadherin) targets β-catenin to junctional regions, reorganizes F-actin into parallel cortical bundles, enables tube formation in 3D gels, and enforces contact inhibition of growth at confluence, mimicking in vivo endothelial behavior. Stable transfection of VE-cadherin cDNA into VE-cadherin-null ECV304 cells, immunofluorescence for β-catenin and F-actin, 3D gel tube formation, proliferation tracking International archives of allergy and immunology Medium 10592470
2001 VE-cadherin junctions transiently open during leukocyte transmigration: neutrophils and monocytes traverse paracellularly, pushing aside VE-cadherin in the junction plane; gaps form and reseal within ~5 min post-transmigration, visualized in real time. Real-time live-cell imaging of VE-cadherin/GFP fusion protein during leukocyte transmigration under flow Journal of immunology High 11490021
2002 VE-cadherin expression activates Rac (while decreasing active Rho), upregulates Tiam-1 (a Rac-specific GEF) at protein and mRNA levels, and recruits Tiam-1, Rac, PAK, and phospho-PAK to the membrane/cytoskeletal fraction, driving actin rearrangement and formation of vinculin-positive adhesion plaques. VE-cadherin transfection into VEC-null endothelial cells, Rac/Rho pull-down activation assays, Tiam-1 qRT-PCR/immunoblot, subcellular fractionation, dominant-negative Rac microinjection Molecular biology of the cell High 11950930
2002 VE-PTP (vascular endothelial protein tyrosine phosphatase) associates with VE-cadherin through their most membrane-proximal extracellular domains (ectodomain interaction); VE-PTP expression reduces VEGFR-2-induced tyrosine phosphorylation of VE-cadherin and decreases endothelial monolayer permeability, even with a catalytically inactive VE-PTP mutant. Co-immunoprecipitation from COS-7 and endothelial cell lysates, deletion/domain-mapping constructs, inducible promoter system in CHO cells, permeability assay The EMBO journal High 12234928
2005 Tyrosine phosphorylation of VE-cadherin at Tyr-658 prevents p120-catenin binding, and at Tyr-731 prevents β-catenin binding; phosphomimetic single mutations (Y658E or Y731E) are each sufficient to disrupt barrier function and restore endothelial cell migration, maintaining cells in a mesenchymal state. Site-directed mutagenesis (Y658E, Y731E), co-immunoprecipitation, barrier function assay, cell migration assay The Journal of biological chemistry High 16027153
2005 cAMP elevation via prostacyclin or forskolin enhances VE-cadherin-mediated cell adhesion and decreases endothelial permeability through the Epac-Rap1 pathway (PKA-independent); activated Rap1 promotes cortical actin rearrangement and requires VE-cadherin, as the effect is absent in VE-cadherin knockout cells and restored upon VE-cadherin re-expression. Epac-specific cAMP analogue (007), constitutively active/dominant-negative Rap1, siRNA, VE-cadherin KO/rescue cells, permeability assay, actin imaging Molecular and cellular biology High 15601837
2005 Epac1 controls VE-cadherin-mediated endothelial junction integrity; Epac1 siRNA blocks the barrier-tightening and cortical actin effects of cAMP, and in VE-cadherin knockout cells Epac1 activation fails to reduce permeability, establishing VE-cadherin as the essential downstream effector of Epac1 in endothelial barrier regulation. siRNA knockdown of Epac1, VE-cadherin KO cells, Epac-specific cAMP analogue, permeability assay, actin staining FEBS letters High 16115630
2006 VEGF promotes endothelial permeability by inducing PAK-mediated serine phosphorylation of VE-cadherin's intracellular tail, recruiting β-arrestin2, and driving clathrin-mediated endocytosis of VE-cadherin; the pathway involves VEGFR-2 → Src → Vav2 → Rac → PAK. Biochemical pathway dissection, site-directed mutagenesis of VE-cadherin serine residues, co-immunoprecipitation with β-arrestin2, clathrin inhibition, dominant-negative constructs, permeability assay Nature cell biology High 17060906
2006 VE-cadherin at junctions retains VEGFR-2 at the plasma membrane, preventing its clathrin-dependent internalization into endosomal signaling compartments; loss or non-engagement of VE-cadherin accelerates VEGFR-2 internalization, prolonging ERK/PLC-γ signaling and promoting cell proliferation; DEP-1/CD148 phosphatase mediates VE-cadherin-dependent retention. Endocytosis assays, VE-cadherin KO/re-expression, VEGFR-2 internalization tracking, DEP-1 siRNA, MAPK/PLC-γ phosphorylation assays The Journal of cell biology High 16893970
2008 ADAM10 metalloprotease specifically cleaves VE-cadherin ectodomain releasing a soluble fragment; the remaining membrane stub is subsequently cleaved by γ-secretase. ADAM10-mediated proteolysis is induced by Ca2+ influx or staurosporine, increases endothelial permeability, contributes to thrombin-induced junction disassembly, and is required (in both ECs and T cells) for T-cell transendothelial migration. Gain-of-function expression, metalloprotease inhibitors, RNA interference of ADAM10 in HUVECs and T cells, shedding assays, permeability assay, transmigration assay Circulation research High 18420943
2008 The ETS transcription factor Erg transcriptionally activates CDH5 by binding its promoter (shown by ChIP), and Erg-dependent endothelial survival and tube formation are partially rescued by VE-cadherin overexpression, placing Erg upstream of CDH5 in a pathway regulating endothelial apoptosis and angiogenesis. Antisense/siRNA knockdown of Erg, chromatin immunoprecipitation, luciferase reporter assay, VE-cadherin rescue overexpression, Matrigel plug angiogenesis model Blood High 18195090
2011 Fusobacterium nucleatum adhesin FadA directly binds VE-cadherin on endothelial cells (co-localization, required for bacterial binding), causing VE-cadherin relocalization away from junctions, increased endothelial permeability, and enabling bacterial transcellular/paracellular crossing. Co-localization by immunofluorescence, binding assays, VE-cadherin knockdown, permeability assay, transwell bacterial transmigration assay Molecular microbiology High 22040113
2012 VE-cadherin-based focal adherens junctions (FAJs) are defined by attachment to radial F-actin bundles and recruitment of Vinculin; Vinculin is recruited to FAJs in response to VEGF, TNFα, and thrombin via Rho-Rock-actomyosin contractility, and Vinculin protects VE-cadherin junctions from opening during force-dependent remodeling. Live-cell imaging, FRET-based tension sensors, α-catenin Vinculin-binding mutant expression, ROCK inhibition, Rho activation assays, endothelial monolayer remodeling assays The Journal of cell biology High 22391038
2012 S1PR1 signaling stabilizes VE-cadherin at endothelial junctions and inhibits VEGF-A-induced signaling, restricting angiogenic sprouting; loss of S1PR1 increases sprouting and ectopic branching, while S1PR1 activation inhibits sprouting and enhances cell-cell adhesion via VE-cadherin stabilization. S1PR1 loss-of-function in zebrafish and mice, live imaging, VE-cadherin localization analysis, VEGF signaling assays Developmental cell High 22975327
2013 VE-cadherin functions as an active guardian of vascular integrity by reshaping the endothelial cytoskeleton and modulating gene transcription; it controls vascular permeability and inhibits unrestrained vascular growth during embryogenesis and in the adult, acting through multiple pathways including catenin signaling. Review synthesizing genetic mouse models, signaling studies, and structural data (mechanistic review) Developmental cell High 24044891
2014 Cdh5/VE-cadherin promotes endothelial cell elongation during sprouting angiogenesis in zebrafish by organizing junctional and cortical actin cytoskeletons; cdh5 null mutations impair junctional remodeling and cell elongation associated with actin disorganization; a truncated Cdh5 lacking the cytoplasmic domain cannot rescue these defects; pharmacological inhibition of actin polymerization (but not actin-myosin contractility) phenocopies cdh5 loss. Zebrafish cdh5 null mutant generation (TALEN/CRISPR), rescue with truncated Cdh5 construct, live imaging, pharmacological inhibition of actin polymerization (latrunculin) vs myosin (blebbistatin) Cell reports High 25373898
2014 Tyr685 of VE-cadherin specifically controls vascular permeability in vivo (Y685F knock-in mice show impaired permeability induction), while Tyr731 specifically regulates neutrophil extravasation (Y731F knock-in mice show decreased extravasation); inflammatory mediators phosphorylate Tyr685 in vivo, while Tyr731 has high baseline phosphorylation; leukocytes trigger SHP-2-mediated Tyr731 dephosphorylation, allowing AP-2 binding and VE-cadherin endocytosis. Knock-in mice (Y685F, Y731F), intravital microscopy, permeability assays, phospho-specific antibodies, SHP-2 interaction studies, AP-2 co-immunoprecipitation Nature immunology High 24487320
2014 IL-2 induces VLS (vascular leak syndrome) through CD144/VE-cadherin redistribution away from endothelial cell junctions, demonstrated in primary human pulmonary microvascular endothelial cells. Ex vivo primary EC culture, IL-2 treatment, VE-cadherin localization by immunofluorescence, patient serum studies Journal of translational medicine Medium 24885155
2015 ZO-1 regulates tension on VE-cadherin-based adherens junctions via spatial regulation of actomyosin: ZO-1 depletion redistributes active myosin II from junctions to stress fibers, reduces VE-cadherin tension (measured by FRET), causes loss of junctional mechanotransducers vinculin and PAK2, and impairs angiogenesis in vitro and in vivo; ZO-1 acts through JACOP-p114RhoGEF to regulate junctional Rho activity. siRNA depletion, FRET-based VE-cadherin tension sensor, myosin activity assays, in vitro and in vivo angiogenesis models, epistasis with claudin-5/JAM-A/JACOP/p114RhoGEF knockdowns The Journal of cell biology High 25753039
2015 The transmembrane domain of VE-cadherin mediates a direct adapter function by binding the transmembrane domains of both VEGFR2 and VEGFR3, assembling the endothelial mechanosensory complex that mediates flow-induced signaling; VEGFR2 and VEGFR3 signal redundantly downstream of VE-cadherin in this complex. Transmembrane domain mutant constructs, co-immunoprecipitation, shear stress signaling assays, endothelial-specific VEGFR3 analysis in aorta The Journal of cell biology High 25800053
2016 In zebrafish, c1qr/cd93 and c1qrl/clec14a redundantly control angiogenesis by maintaining Cdh5 expression in inter-segmental vessel endothelium; double mutation of c1qr and c1qrl abolishes Cdh5 at ISVs, and Cdh5 replenishment rescues impaired ISV angiogenesis. Zebrafish single/double mutant analysis, ISV morphology imaging, Cdh5 rescue by overexpression Biochemical and biophysical research communications Medium 28007601
2016 VE-cadherin forms polarized junctional protrusions ('cadherin fingers') that leading endothelial cells extend from their rear and follower cells engulf at their front during collective migration; engulfment requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization, and cadherin fingers act as polarity guidance cues directing collective cell migration. Live-cell imaging (TIRF, LLSM), VE-cadherin/GFP constructs, Arp2/3 and actin inhibitors, catenin-binding mutants, curvature sensor recruitment assays Nature cell biology High 27842057
2022 VEGF-C/VEGFR3 signaling and VE-cadherin form a reciprocal inhibitory axis controlling sinusoidal and lymphatic vessel growth: VE-cadherin prevents VEGFR3 endocytosis required for optimal signaling, while VEGF-C/VEGFR3 induces SRC-mediated VE-cadherin phosphorylation and endocytosis/loss-of-function; membrane-retained VE-cadherin causes lymphatic and sinusoidal defects similar to VEGFR3 loss; loss of VE-cadherin rescues VEGFR3-deficient but not VEGF-C-deficient sinusoidal/lymphatic defects. Conditional mouse knockouts, membrane-retained VE-cadherin knock-in mice, epistasis analysis, SRC inhibition, VE-cadherin endocytosis assays, phosphorylation studies Nature cardiovascular research High 36910472
2025 CDH1/E-cadherin reduces endothelial cell permeability under chronic intermittent hypoxia by promoting CDH5/VE-cadherin expression on the cell membrane; ox-LDL decreases CDH1 membrane expression, impairing this protective mechanism. CIH endothelial cell model, ox-LDL treatment, immunofluorescence, FITC-dextran permeability assay, CDH1 overexpression European journal of medical research Medium 41419959
2026 Histone acetyltransferase KAT14 epigenetically activates CDH5 expression by acetylating histones H3K9 and H3K18 at the CDH5 locus in cooperation with transcription factor SRF; trophoblast-specific KAT14 knockout reduces CDH5 expression and impairs spiral artery remodeling (phenocopying preeclampsia), while CDH5 overexpression rescues these defects; CDH5-Cre; KAT14 knockout displays defective spiral artery remodeling and high fetal mortality. Trophoblast-specific conditional KO mice, RNA sequencing, ChIP, co-immunoprecipitation, EMSA, luciferase reporter assay, CDH5 overexpression rescue Hypertension High 41867034

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews 1645 30280653
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1999 Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1015 10428027
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2006 VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nature cell biology 839 17060906
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2013 VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Developmental cell 682 24044891
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. The Journal of cell biology 585 7806582
1992 A novel endothelial-specific membrane protein is a marker of cell-cell contacts. The Journal of cell biology 547 1522121
2015 ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. The Journal of cell biology 452 25753039
2006 Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. The Journal of cell biology 437 16893970
2012 Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. The Journal of cell biology 390 22391038
1991 Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue. Cell regulation 360 2059658
2005 Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Molecular and cellular biology 357 15601837
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2005 Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. The Journal of biological chemistry 294 16027153
2014 Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nature immunology 287 24487320
2012 The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2. Developmental cell 270 22975327
2005 Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS letters 262 16115630
2002 VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. The EMBO journal 256 12234928
2008 ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. Circulation research 244 18420943
1995 Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arteriosclerosis, thrombosis, and vascular biology 243 7627717
2015 Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. The Journal of cell biology 240 25800053
1997 Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells. Journal of cell science 237 9378757
2011 Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Molecular microbiology 233 22040113
2016 Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nature cell biology 227 27842057
2008 Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood 225 18195090
2001 Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. Journal of immunology (Baltimore, Md. : 1950) 224 11490021
2002 VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Molecular biology of the cell 207 11950930
1999 Functional roles for PECAM-1 (CD31) and VE-cadherin (CD144) in tube assembly and lumen formation in three-dimensional collagen gels. The American journal of pathology 196 10487846
2014 Cdh5/VE-cadherin promotes endothelial cell interface elongation via cortical actin polymerization during angiogenic sprouting. Cell reports 130 25373898
2013 CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia. Neuro-oncology 129 23645533
2018 IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma. Oncogene 94 30368528
2005 CD144 (VE-cadherin) is transiently expressed by fetal liver hematopoietic stem cells. Blood 85 15831702
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2018 Whole-Transcriptome Analysis of CD133+CD144+ Cancer Stem Cells Derived from Human Laryngeal Squamous Cell Carcinoma Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 38 29949786
2023 Cdh5-mediated Fpn1 deletion exerts neuroprotective effects during the acute phase and inhibitory effects during the recovery phase of ischemic stroke. Cell death & disease 29 36841833
2016 Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury. Liver international : official journal of the International Association for the Study of the Liver 28 27224670
2008 High-reproducible flow cytometric endothelial progenitor cell determination in human peripheral blood as CD34+/CD144+/CD3- lymphocyte sub-population. Journal of immunological methods 24 18402976
2020 Utility of LysM-cre and Cdh5-cre Driver Mice in Retinal and Brain Research: An Imaging Study Using tdTomato Reporter Mouse. Investigative ophthalmology & visual science 20 32232350
2014 Interleukin-2 alters distribution of CD144 (VE-cadherin) in endothelial cells. Journal of translational medicine 20 24885155
1999 Vascular-endothelial cadherin (CD144)- but not PECAM-1 (CD31)-based cell-to-cell contacts convey the maintenance of a quiescent endothelial monolayer. International archives of allergy and immunology 20 10592470
2014 Sequence and functional analyses of the aldehyde dehydrogenase 7B4 gene promoter in Arabidopsis thaliana and selected Brassicaceae: regulation patterns in response to wounding and osmotic stress. Planta 19 24619504
2016 C1qr and C1qrl redundantly regulate angiogenesis in zebrafish through controlling endothelial Cdh5. Biochemical and biophysical research communications 17 28007601
2023 A comprehensive pan-cancer analysis of CDH5 in immunological response. Frontiers in immunology 16 37809080
2015 CD144, CD146 and VEGFR-2 properly identify circulating endothelial cell. Revista brasileira de hematologia e hemoterapia 16 25818819
2021 Calcium Signal Profiles in Vascular Endothelium from Cdh5-GCaMP8 and Cx40-GCaMP2 Mice. Journal of vascular research 14 33706307
2019 The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors. Scientific reports 12 31101877
2022 Sinusoidal and lymphatic vessel growth is controlled by reciprocal VEGF-C-CDH5 inhibition. Nature cardiovascular research 9 36910472
2021 Inverse correlation of miR-27a-3p and CDH5 expression serves as a diagnostic biomarker of proliferation and metastasis of clear cell renal carcinoma. Pathology, research and practice 9 33740544
2020 Fenretinide reduces angiogenesis by downregulating CDH5, FOXM1 and eNOS genes and suppressing microRNA-10b. Molecular biology reports 9 31925643
2019 The upregulation of miR-101 promotes vascular endothelial cell apoptosis and suppresses cell migration in acute coronary syndrome by targeting CDH5. International journal of clinical and experimental pathology 9 31934175
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2018 Inhibition of hsa-miR-6086 protects human umbilical vein endothelial cells against TNFα-induced proliferation inhibition and apoptosis via CDH5. Gene 5 29605606
2024 Notch1 signaling pathway promotes growth and metastasis of gastric cancer via modulating CDH5. Aging 4 39172098
2010 mRNA levels of CD31, CD144, CD146 and von Willebrand factor do not serve as surrogate markers for circulating endothelial cells. Thrombosis and haemostasis 4 20589320
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2022 ANGPTL4 functions as an oncogene through regulation of the ETV5/CDH5/AKT/MMP9 axis to promote angiogenesis in ovarian cancer. Journal of ovarian research 3 36517864
2012 Decreased pre-surgical CD34+/CD144+ cell number in patients undergoing coronary artery bypass grafting compared to coronary artery disease-free valvular patients. Journal of cardiothoracic surgery 3 22214418
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2024 Determination of blood biochemical indices and research of egg quality-related candidate gene CDH5 in Putian black duck. Gene 1 39643146
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2026 A Novel Anti-CDH5/VE-Cadherin Monoclonal Antibody (Ca5Mab-8) for Flow Cytometry, Western Blotting, and Immunohistochemistry. Monoclonal antibodies in immunodiagnosis and immunotherapy 0 41954588
2026 miR-142-3p regulates RDH13 to impair trophoblast function via regulating CDH5/LFA-1/L-SELECTIN axis: a novel mechanism and diagnostic/therapeutic for pre-eclampsia. Frontiers in medicine 0 41958596
2025 DMP1-mediated transformation of DPSCs to CD31+/CD144+ cells demonstrate endothelial phenotype both in vitro and in vivo. Frontiers in cell and developmental biology 0 40861275
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2023 Comparison the therapeutic effects of bone marrow CD144+ endothelial cells and CD146+ mesenchymal stem cells in POF rats. BioImpacts : BI 0 38022384
2022 Mutations in the Spliceosome Component prp-6 and Overexpression of cdh-5 Suppress Axon Guidance Defects of cdh-4 Mutants in Caenorhabditis elegans. Neuroscience insights 0 36090596