CadherinsEdit
Cadherins are a large family of calcium-dependent cell-surface proteins that mediate the selective adhesion between neighboring cells. Their adhesive contacts build and maintain tissue architecture, regulate cell movement during development, and contribute to barrier function in epithelia and endothelia. The cadherin family includes classical cadherins such as E-cadherin (E-cadherin; gene CDH1), N-cadherin (N-cadherin; CDH2), P-cadherin (P-cadherin; CDH3), and VE-cadherin (VE-cadherin; CDH5), as well as desmosomal cadherins such as desmogleins (desmoglein) and desmocollins (desmocollin), and a large set of protocadherins. These proteins engage in homophilic binding—cadherins of the same type on adjacent cells bind to one another—to create specialized cell-cell junctions that coordinate tissue organization.
Cadherins do more than simply glue cells together. They anchor to the actin or intermediate filament cytoskeleton through intracellular binding partners, most notably catenins, and thereby connect adhesion to the cell’s mechanical and signaling machinery. The extracellular domain of classical cadherins contains multiple cadherin repeats that coordinate calcium binding; this calcium dependence rigidifies the extracellular region and enables strong, specific adhesion. In the cytoplasm, cadherins recruit beta-catenin (beta-catenin) and other catenins such as p120-catenin (p120-catenin), which in turn link to actin filaments or participate in signaling pathways. Through these connections, cadherins influence cell shape, polarity, migration, and gene expression.
Structure and function
Architecture and binding
- Classical cadherins are single-pass transmembrane proteins with an extracellular region formed by multiple cadherin repeats (EC1–EC5) that engage in trans interactions with cadherins on neighboring cells. Calcium ions bound between these repeats stabilize the adhesive interface, enabling a robust homophilic bond. The intracellular tail binds adaptor proteins that connect to the cytoskeleton and modulate signaling.
- Desmosomal cadherins, including desmogleins (desmoglein) and desmocollins (desmocollin), assemble into desmosomes, which link to intermediate filaments and provide mechanical resilience in tissues subjected to stress, such as skin and heart.
- Protocadherins (protocadherin) comprise a diverse family implicated in neural connectivity and circuit assembly, expanding the cadherin repertoire beyond adhesion into complex tissue patterning.
Membrane organization and junctions
- At adherens junctions, classical cadherins cluster and recruit actin-associated proteins, forming a dynamic meshwork that balances adhesion with cellular remodeling. VE-cadherin at endothelial junctions is essential for vascular barrier function, while epithelial cadherins maintain tight epithelial integrity in mucosal and glandular tissues.
- Cadherins function in both cis (on the same cell surface) and trans (between adjacent cells) interactions, and their adhesive strength can be modulated by mechanical tension, clustering, and post-translational modifications.
Signaling and developmental roles
- Intracellular cadherin-catenin complexes regulate signaling pathways that influence proliferation, differentiation, and polarity. Free beta-catenin released from cadherin complexes can enter the nucleus and participate in transcriptional programs associated with the Wnt pathway, linking cell adhesion to gene expression. p120-catenin can regulate cadherin stability at the membrane and modulate small GTPases that control the cytoskeleton.
- Cadherin expression patterns contribute to a “cadherin code” that helps establish tissue boundaries during development; for example, distinct cadherin profiles in epithelia, endothelia, and neural tissue guide morphogenetic movements and cell sorting.
Regulation and turnover
- Cadherin levels and adhesive strength are tightly regulated at the transcriptional, post-transcriptional, and post-translational levels. Transcription factors such as Snail and ZEB families can repress E-cadherin transcription during developmental processes and in diseases, while promoter methylation or microRNAs can silence cadherin genes in other contexts. This regulation enables cells to modulate adhesion as tissues grow, remodel, or respond to injury.
Cadherins in development and tissue organization
Cadherins contribute to key developmental events, including tissue separation, organ formation, and neural wiring. The combinatorial expression of different cadherins in adjacent tissues helps delineate boundaries and allows coordinated cell movements during morphogenesis. In the nervous system, protocadherins and other cadherins participate in neuronal sorting, axon guidance, and synaptic organization, ensuring precise circuitry. In vascular development, VE-cadherin supports endothelial cell cohesion and barrier properties that are vital for proper blood vessel formation and function.
The cadherin code concept describes how cells interpret and respond to adhesive cues by selecting specific cadherin types, thereby controlling tissue architecture. This code interacts with the cytoskeleton and signaling pathways to govern processes such as epithelial polarization, tubulogenesis, and wound healing.
Cadherins in disease and cancer
Cancer and epithelial-mesenchymal dynamics
- A central theme in cancer biology is the alteration of cadherin-mediated adhesion, most famously the loss of E-cadherin (E-cadherin; CDH1) from epithelial tissues. E-cadherin loss reduces cell-cell cohesion and can promote epithelial-mesenchymal transition (EMT; epithelial-mesenchymal transition), a process associated with increased migratory capacity and invasiveness. However, the relationship is nuanced: not all metastases require complete EMT, and some tumors exhibit partial EMT or cadherin switching (for example, upregulation of N-cadherin) that supports different phases of metastasis.
- Genetic mutations in CDH1 underlie hereditary diffuse gastric cancer and other epithelial malignancies, illustrating a direct tumor-suppressive role for certain cadherins. In other cancers, promoter methylation, transcriptional repression, or post-translational regulation can reduce cadherin function without overt mutations.
- The signaling consequences of cadherin disruption extend beyond adhesion. Loss of membrane-associated cadherins can liberate catenins, potentially activating pro-tumorigenic transcriptional programs and altering cell survival, differentiation, and immune interactions. Therapeutic strategies that aim to restore cadherin function or to target cadherin-associated pathways face challenges due to the essential roles cadherins play in normal tissues and development.
Non-neoplastic disease and autoimmunity
- Desmosomal cadherins are targets in certain autoimmune blistering diseases. Pemphigus vulgaris, for example, involves autoantibodies against desmogleins that destabilize desmosomes and compromise epidermal integrity, producing painful and potentially life-threatening skin lesions. These conditions highlight the critical balance cadherins maintain between adhesion and tissue integrity in adult organisms.
- VE-cadherin and other endothelial cadherins influence vascular permeability and inflammatory responses. Disruption of endothelial adhesion can contribute to edema, hemorrhage, or exaggerated inflammatory damage in various diseases, underlining the replicable significance of cadherin-mediated adhesion beyond cancer.
Therapeutic considerations and challenges
- Because cadherins are indispensable for normal tissue function, therapies aimed at modulating cadherin adhesion must balance anti-tumor or anti-inflammatory aims with potential harms to healthy tissues. Some approaches explore restoring epithelial adhesion to restrain invasion, while others seek to inhibit cadherin switching or downstream signaling that accompanies disease progression. The complexity of cadherin networks and their integration with signaling pathways means that effective interventions require a nuanced understanding of context, tissue type, and disease stage.
Research and techniques
Researchers study cadherins using a range of methods, from genetic models to structural biology and cell biology. Conditional knockout mice illuminate tissue-specific roles for individual cadherins, while CRISPR-based approaches allow precise manipulation of cadherin genes in cell culture and animal models. Biochemical studies dissect cadherin-catenin interactions, and imaging techniques reveal how adherens junctions and desmosomes respond to mechanical forces. Structural analyses of the extracellular domains have illuminated how calcium-dependent binding and strand-swapping contribute to the adhesive interface, while live-cell assays like calcium-switch experiments shed light on how adhesion is assembled and disassembled during tissue remodeling. The study of cadherins intersects with broader themes in cell adhesion, tissue morphogenesis, and signaling.