CDH5 Human

What is CDH5 and what are its basic structural characteristics?

CDH5 (Cadherin 5) is a classical cadherin belonging to the cadherin superfamily of proteins. The CDH5 gene encodes a preproprotein that undergoes proteolytic processing to generate a mature glycoprotein. Structurally, this calcium-dependent cell-cell adhesion molecule contains five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail . The protein functions primarily in endothelial cells where it mediates homophilic binding between adjacent cells, contributing to the formation and maintenance of adherens junctions . The human CDH5 gene is located on chromosome 16 in a gene cluster region associated with loss of heterozygosity events in breast and prostate cancer .

What are the primary cellular functions of CDH5 in endothelial biology?

CDH5 plays several crucial roles in endothelial cell biology:

• Intercellular junction formation: CDH5 is essential for the cohesion and organization of intercellular junctions in the vascular endothelium .

• Cytoskeletal anchoring: It associates with alpha-catenin to form a link to the cytoskeleton, providing structural integrity to the endothelial barrier .

• Cell polarity establishment: CDH5 acts in concert with proteins like KRIT1 and PALS1 to establish and maintain correct endothelial cell polarity and vascular lumen formation .

• Signaling pathway regulation: It is required for the activation of protein kinase C zeta (PRKCZ) and for localizing phosphorylated PRKCZ, PARD3, TIAM1, and RAP1B to cell junctions .

• Vascular integrity maintenance: Through these mechanisms, CDH5 contributes to the control of vascular permeability and the maintenance of vascular integrity .

How is CDH5 expression regulated in human tissues?

CDH5 expression is tightly regulated through multiple mechanisms:

• Transcriptional regulation: Several transcription factors control CDH5 expression in a tissue-specific manner, particularly in endothelial cells.

• Hormonal regulation: Evidence indicates that corticosteroids downregulate CDH5 expression, which may contribute to increased permeability of choroidal vasculature in conditions like central serous chorioretinopathy (CSC) .

• Epigenetic control: DNA methylation and histone modifications likely play roles in regulating CDH5 expression in different contexts.

• Post-translational modifications: Phosphorylation, internalization, and degradation mechanisms modulate CDH5 protein levels and activity at cell junctions.

• Genetic variants: Common intronic variants such as rs7499886:A>G and rs1073584:C>T have been associated with altered CDH5 function in male patients with CSC .

What are the key protein interactions of CDH5 in adherens junctions?

CDH5 forms a complex network of interactions within adherens junctions:

• Catenin binding: The cytoplasmic domain of CDH5 interacts with beta-catenin and p120-catenin, which in turn connect to alpha-catenin, forming a bridge to the actin cytoskeleton .

• Signaling complexes: CDH5 associates with various signaling molecules including protein phosphatases and kinases to regulate junctional stability .

• Polarity complex interactions: CDH5 interacts with the Par polarity complex and RAP1B to establish apical-basal polarity in endothelial cells .

• VE-PTP association: Vascular endothelial protein tyrosine phosphatase (VE-PTP) associates with CDH5 to regulate its phosphorylation state and stability at cell junctions.

• Proximity interactome: Recent proximity labeling studies using VE-cadherin-miniTurbo constructs have identified numerous proteins that interact with CDH5 in lymphatic endothelial cells, revealing mechanisms controlling adherens junction remodeling .

How does CDH5 influence tumor microenvironment and cancer progression?

CDH5's role in cancer biology is complex and context-dependent:

• Vascular integrity in tumors: CDH5 maintains endothelial barrier function, which can restrict tumor cell intravasation and metastasis, but alterations in its expression or function can disrupt this barrier.

• Immune cell infiltration: Pan-cancer analysis reveals significant correlations between CDH5 expression and immune cell infiltration scores across various tumor types .

• Prognostic significance: CDH5 expression correlates with survival outcomes in multiple cancer types. High CDH5 expression is associated with better disease-free survival (DFS) in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC), but worse DFS in cervical squamous cell carcinoma (CESC) .

• Risk stratification: Cox proportional hazards models demonstrate that CDH5 can serve as either a high-risk or low-risk factor depending on the specific cancer type. It functions as a high-risk gene in CESC and kidney renal papillary cell carcinoma (KIRP) but a low-risk gene in kidney renal clear cell carcinoma (KIRC) and UCEC .

• Immune checkpoint potential: Research suggests CDH5 may function as a novel immune checkpoint in various tumors, offering potential therapeutic targets .

What mechanisms regulate CDH5-mediated vascular permeability in pathological conditions?

Several molecular mechanisms control CDH5-mediated vascular permeability in disease states:

• Phosphorylation-dependent regulation: Tyrosine phosphorylation of CDH5 by kinases like Src disrupts adherens junctions, increasing vascular permeability.

• Internalization and trafficking: Endocytosis and recycling of CDH5 can rapidly alter junctional integrity in response to inflammatory signals or vascular stress.

• Proteolytic cleavage: Matrix metalloproteinases can cleave the extracellular domain of CDH5, producing soluble fragments that may serve as biomarkers of vascular damage.

• Hormone-mediated regulation: Corticosteroids downregulate CDH5 expression, which may contribute to increased permeability of choroidal vasculature in conditions like CSC .

• Genetic variation impact: Common SNPs in the CDH5 gene are significantly associated with altered vascular integrity in male CSC patients, suggesting genetic factors influence CDH5-dependent permeability .

What role does CDH5 play in lymphatic endothelial cell function and lymphangiogenesis?

CDH5 functions crucially in lymphatic endothelial cells (LECs):

• Adherens junction formation: Similar to blood vessels, CDH5 forms adherens junctions in LECs, though with distinct characteristics suited to lymphatic function.

• Proximity interactome: Recent studies using VE-cadherin-miniTurbo constructs have identified LEC-specific interaction partners that regulate adherens junction remodeling and secretion in lymphatic vessels .

• Button-like junctions: In initial lymphatics, CDH5 organizes into specialized button-like junctions that allow fluid entry while maintaining vessel integrity.

• Lymphangiogenic regulation: CDH5 participates in lymphatic vessel formation and remodeling through coordination with VEGFR-3 signaling pathways.

• Immune cell trafficking: CDH5-dependent junctions in lymphatics regulate immune cell trafficking and lymph node entry, influencing immune surveillance.

How do CDH5 genetic variants contribute to disease susceptibility and progression?

Genetic variation in CDH5 has significant implications for disease:

• Disease associations: Variants in CDH5 have been linked to several pathological conditions, including central serous chorioretinopathy, vascular malformations, and potentially certain cancers .

• Sex-specific effects: Research shows a significant association of four common CDH5 SNPs with CSC specifically in male patients, potentially explaining the higher prevalence of this condition in men .

• Functional consequences: Intronic variants such as rs7499886:A>G and rs1073584:C>T may influence gene expression or splicing, affecting protein levels or function .

• Interaction with environmental factors: CDH5 variants may interact with stress and corticosteroid pathways, as demonstrated in CSC studies where both genetic and hormonal factors play roles .

• Prognostic implications: In cancer, specific CDH5 genetic variants may influence tumor progression and patient outcomes through altered vascular function and immune cell infiltration .

What proximity labeling techniques are effective for studying CDH5 protein interactions?

Proximity labeling has proven valuable for studying CDH5 interactome:

• BioID and TurboID approaches: These techniques use promiscuous biotin ligases fused to CDH5 to biotinylate proteins within a 10-20nm radius, identifying proximal interactors.

• VE-cadherin-miniTurbo construct: A miniTurbo-based approach has been successfully employed to study the proximity interactome of lymphatic VE-cadherin, revealing mechanisms controlling adherens junction remodeling and secretion .

• Temporal control considerations: Research has shown that temporal control is essential for proper proximity labeling with CDH5. Studies indicate that VE-cadherin-mT (miniTurbo) constructs offer better temporal control compared to standard TurboID (VE-cadherin-T) constructs, which show more pronounced background biotinylation .

• Data filtering strategies: After proximity labeling and mass spectrometry, data curation is essential. Effective approaches include removing proteins with Gene Ontology terms associated with ribosomes, RNA, translation, mitochondria, nuclear localization, splicing, transcription, viral infection, DNA binding, and biotin carboxylases to eliminate non-specific interactions .

• Validation techniques: Confirmation of proximity labeling results can be achieved through co-immunoprecipitation, immunofluorescence co-localization, and functional assays to verify biological relevance.

What genomic and transcriptomic approaches best capture CDH5 regulation and variation?

Several genomic and transcriptomic methods are particularly useful for CDH5 research:

• eQTL analysis: Expression quantitative trait loci (eQTL) analysis can identify genetic variants that influence CDH5 expression levels in different tissues.

• ChIP-seq for transcription factor binding: Chromatin immunoprecipitation sequencing helps identify transcription factors regulating CDH5 expression in endothelial cells.

• RNA-seq in disease models: Transcriptome profiling in models of vascular dysfunction can capture CDH5 expression changes and associated pathway alterations.

• Single-cell sequencing: This approach can reveal cell-type specific expression patterns of CDH5 in heterogeneous tissues and during developmental processes.

• TCGA data mining: Analysis of The Cancer Genome Atlas data has proven valuable for understanding CDH5's role across multiple cancer types, as demonstrated in pan-cancer analyses associating CDH5 with immune responses and patient survival .

What animal models are most appropriate for studying CDH5 functions in vascular development and disease?

Various animal models offer unique advantages for CDH5 research:

• Zebrafish models: The zebrafish cdh5 gene (ZDB-GENE-040816-1) serves as an excellent model for studying vascular development due to embryo transparency and rapid development .

• Conditional knockout mice: Endothelial-specific Cdh5 deletion in mice allows investigation of its role in vascular development, maintenance, and pathological conditions without embryonic lethality.

• Inducible systems: Temporal control of Cdh5 disruption using tamoxifen-inducible Cre-loxP systems enables studies of its function at different developmental stages or disease progression phases.

• Humanized mouse models: Mice expressing human CDH5 variants can help validate the functional significance of disease-associated polymorphisms.

• Organ-specific models: Models targeting CDH5 function in specific vascular beds (brain, retina, tumor) offer insights into tissue-specific roles and therapeutic opportunities.

What imaging technologies best visualize CDH5 dynamics during vascular remodeling?

Advanced imaging approaches reveal CDH5 behavior in living systems:

• Super-resolution microscopy: Techniques like STORM and PALM overcome diffraction limits to visualize CDH5 nanoscale organization at adherens junctions.

• Live-cell imaging with CDH5-fluorescent protein fusions: These enable real-time visualization of adherens junction remodeling during angiogenesis or inflammation.

• FRET/FLIM analysis: Förster resonance energy transfer combined with fluorescence lifetime imaging microscopy can detect CDH5 conformational changes and protein interactions.

• Intravital microscopy: This approach enables visualization of CDH5 dynamics in vascular beds of living animals during physiological or pathological processes.

• Correlative light and electron microscopy (CLEM): CLEM combines fluorescence imaging of CDH5 with ultrastructural analysis of the same sample, linking molecular dynamics to cellular architecture.

How can CDH5 be targeted therapeutically in vascular disorders and cancer?

Several therapeutic strategies targeting CDH5 show promise:

• Junction-stabilizing peptides: Synthetic peptides that mimic CDH5 adhesive interfaces can strengthen endothelial junctions, reducing vascular leakage in inflammation.

• Antibody-based approaches: Function-blocking or junction-stabilizing antibodies targeting CDH5 extracellular domains can modulate vascular permeability.

• Small molecule inhibitors: Compounds targeting CDH5-associated kinases or phosphatases can stabilize junctions by preventing disruptive phosphorylation events.

• Gene therapy approaches: Correction of CDH5 expression in conditions where it is dysregulated may restore normal vascular function.

• Combination therapies: Targeting CDH5 in combination with immune checkpoint inhibitors may enhance cancer immunotherapy by modulating tumor vascular permeability and immune cell infiltration, as suggested by the correlation between CDH5 expression and immune responses in multiple cancers .

What is the diagnostic and prognostic value of CDH5 in human diseases?

CDH5 shows significant potential as a biomarker:

• Soluble CDH5 as a biomarker: Elevated levels of soluble CDH5 fragments in circulation correlate with vascular damage and may serve as biomarkers for conditions involving endothelial dysfunction.

• Cancer prognosis: CDH5 expression patterns correlate with survival outcomes across multiple cancer types. It functions as either a high-risk or low-risk factor depending on the specific cancer type, as demonstrated in comprehensive pan-cancer analyses .

• Genetic testing: Genotyping CDH5 variants like rs7499886:A>G and rs1073584:C>T may help identify individuals at risk for vascular conditions such as central serous chorioretinopathy, particularly in men .

• Tissue expression patterns: Immunohistochemical assessment of CDH5 distribution and integrity in tumor vasculature may predict treatment response or metastatic potential.

• Combination biomarker panels: CDH5 may be most valuable as part of multimarker panels that assess vascular function or cancer progression more comprehensively.

How does CDH5 contribute to blood-brain barrier integrity in neurological disorders?

CDH5 plays critical roles in blood-brain barrier (BBB) function:

• BBB junction formation: CDH5 forms the backbone of endothelial adherens junctions in brain microvessels, contributing to BBB integrity.

• Response to neuroinflammation: During neuroinflammatory conditions, CDH5 undergoes phosphorylation and internalization, leading to junction disruption and increased BBB permeability.

• Interaction with BBB-specific proteins: CDH5 interacts with other BBB components, including tight junction proteins and astrocyte-derived factors that regulate barrier function.

• Role in neurodegenerative diseases: Dysfunction of CDH5-dependent junctions contributes to BBB breakdown in conditions like Alzheimer's disease, multiple sclerosis, and stroke.

• Therapeutic target potential: Stabilizing CDH5 junctions represents a promising approach to preserve or restore BBB integrity in neurological disorders and limit neuroinflammation.

What is the relationship between CDH5 and corticosteroid-mediated vascular effects?

Corticosteroids significantly impact CDH5 function:

• Transcriptional regulation: Research has demonstrated that corticosteroids downregulate CDH5 expression, which may lead to altered endothelial barrier function .

• Relevance to central serous chorioretinopathy: This regulatory relationship helps explain why CSC, a condition characterized by fluid leakage from the choroid into the subretinal space, is associated with both endogenous and exogenous corticosteroid imbalance .

• Sex-specific effects: The interaction between corticosteroids and CDH5 may have sex-specific aspects, potentially contributing to the higher prevalence of CSC in men. Studies have identified significant associations between common CDH5 SNPs and CSC specifically in male patients .

• Stress response pathway integration: CDH5 functions within broader stress response and corticosteroid metabolism pathways, as indicated by studies of 44 genes from these pathways in CSC patients .

• Therapeutic implications: Understanding this relationship suggests potential for managing steroid-induced vascular effects through interventions that preserve CDH5 function or expression.