Cadherin SuperfamilyEdit
Cadherin superfamily
The cadherin superfamily is a broad and evolutionarily ancient group of calcium-dependent cell–cell adhesion proteins that orchestrate the organization of tissues across metazoans. Members mediate homophilic binding between neighboring cells, helping to establish and maintain compartment boundaries, coordinate morphogenesis during development, and preserve the integrity of epithelia and cardiac muscle. The family encompasses classical cadherins such as E-cadherin, N-cadherin, and P-cadherin, as well as desmosomal cadherins (desmogleins and desmocollins), and a large and diverse set of non-classical cadherins including protocadherins. The story of cadherins is tightly linked to the broader history of cell biology and the genetic underpinnings of tissue architecture, and it has become a foundation for understanding how form and function are built at the cellular level. The discovery and subsequent elaboration of cadherins have been driven by decades of work in both academic and clinical settings, illustrating how basic science can illuminate mechanisms relevant to human health and disease. For the historical origins and the core concept, see the work of Masatoshi Takeichi and the initial demonstrations of calcium-dependent adhesion.
Structure and mechanism
Cadherins characteristically possess multiple extracellular cadherin (EC) repeats that form a rigid, elongated ectodomain capable of engaging in homophilic interactions with cadherins on adjacent cells. The extracellular region is tuned by calcium ions that bind at the linker regions, stabilizing the cadherin architecture and enabling selective adhesion. The cytoplasmic tail of classical cadherins associates with a suite of cytoplasmic partners, most notably the catenins, to connect the adhesive complex to the actin cytoskeleton. In classical cadherins, the core complex involves β-catenin and α-catenin, with p120 catenin (p120ctn) regulating cadherin stability and turnover. This cadherin–catenin–actin linkage forms adherens junctions, which are critical for tissue integrity and dynamic remodeling during development. For a detailed look at the assembly and molecular interactions, see Adherens junction and β-catenin.
Desmosomal cadherins—desmogleins and desmocollins—provide a parallel adhesion system that anchors intermediate filaments rather than actin, contributing to the mechanical resilience of tissues such as skin and heart. These cadherins interact with plakophilins and desmoplakin to couple to the intracellular keratin network, helping tissues withstand mechanical stress. See Desmosome and Desmoglein for more on these specialized junctions.
Protocadherins and other non-classical cadherins add diversity and nuance to cell–cell recognition, particularly in the nervous system. Protocadherins often exist in large gene clusters and are believed to participate in combinatorial tagging of neurons, which may influence synaptic specificity and neural circuit formation. See Protocadherin for more on this subfamily. Other non-classical members, including FAT and CELSR cadherins, contribute to signaling and polarity in various tissues; their roles are an active area of research and review in the field. See FAT cadherin and CELSR for further details.
Classes within the superfamily
Classical cadherins: The best-studied subset includes E-cadherin (CDH1), N-cadherin (CDH2), and P-cadherin (CDH3). These proteins are central to epithelial integrity, neural development, and tissue remodeling. Their adhesive function is tightly regulated during processes such as epithelial-to-mesenchymal transition (EMT), a program that has implications for development and cancer progression. See E-cadherin and N-cadherin for in-depth coverage.
Desmosomal cadherins: Desmogleins (DSG1–DSG4) and desmocollins (DSC1–DSC3) form the adhesive core of desmosomes, structures that link to intermediate filaments and confer mechanical strength to tissues under strain. See Desmoglein and Desmocollin.
Protocadherins and non-classical cadherins: Protocadherins provide a rich repertoire of isoforms thought to support neuronal identity and specificity. Non-classical cadherins, including the FAT family and the CELSR (cadherin EGF LAG7) group, participate in signaling networks, cell polarity, and tissue patterning beyond simple adhesion. See Protocadherin, FAT cadherin, and CELSR.
Genomic organization and evolution
Cadherin genes show diverse organizational strategies. Classical cadherins are often encoded by single genes with defined expression patterns, while protocadherins can be organized in large clusters that enable combinatorial expression. The cadherin repeats themselves are a recognizable motif that has diversified through gene duplication and diversification across animal lineages. This evolutionary expansion correlates with the increasing complexity of tissue organization and neuronal circuitry in vertebrates. See evolution of cadherins for a broader evolutionary perspective.
Developmental roles and tissue organization
Cadherins are essential players in embryonic development, guiding tissue sorting, boundary formation, and collective cell movements. E-cadherin is especially important for maintaining epithelial sheets during gastrulation and organogenesis, while N-cadherin and other cadherins modulate neural tube closure, neural crest migration, and synapse formation. Desmosomal cadherins fortify tissues that experience mechanical load, such as skin and heart, while protocadherins contribute to the wiring of neural circuits. See gastrulation, neurulation, and neural development for related processes.
Signaling crosstalk and molecular consequences
Beyond physical adhesion, cadherins influence signaling pathways through their interactions with β-catenin and other signaling mediators. The sequestration of β-catenin at the membrane by cadherins can modulate Wnt signaling and downstream transcriptional programs, linking cell contact to gene expression. The p120 catenin arm of the complex modulates cadherin stability and also impacts cytoskeletal dynamics via Rho family GTPases, influencing cell shape and motility. See Wnt signaling and β-catenin for related signaling concepts.
Clinical relevance, disease, and therapeutics
Deregulation of cadherin-mediated adhesion has clear implications for human disease. Loss of E-cadherin function, often through germline or somatic mutations in CDH1, is a hallmark of invasive cancers and is linked to diffuse gastric cancer and lobular breast cancer. In some hereditary cancer syndromes, germline CDH1 mutations confer elevated cancer risk, highlighting the role of cell–cell adhesion in suppressing malignant progression. Desmosomal cadherin mutations contribute to cardiomyopathies and skin disorders, illustrating how tissue-specific adhesion networks underpin organ function. These connections have driven interest in targeting adhesion molecules in cancer therapy and in diagnostic and prognostic applications. See Hereditary diffuse gastric cancer, Breast cancer, and arrhythmogenic right ventricular cardiomyopathy for concrete disease contexts.
Controversies and debates
As in many fields at the intersection of biology and medicine, there are active debates about the precise roles of cadherins in development and disease, and about how best to translate basic insights into therapies. Some scientists argue that protocadherin diversity constitutes a combinatorial code underlying neural connectivity, while others emphasize redundancy and non-synaptic roles in cell recognition and barrier function. The interpretation of cadherin alterations in cancer is likewise nuanced: while loss of E-cadherin is a clear marker of disrupted epithelial integrity and potential metastatic capability, additional pathways and context-dependent factors shape tumor behavior. In policy terms, supporters of robust basic science funding point to historical gains in medical advances that followed fundamental discoveries about adhesion molecules, while proponents of targeted translational programs emphasize expeditious paths to therapies. The ongoing dialogue reflects a broader, iterative relationship between curiosity-driven inquiry and practical applications.
See also