CadherinEdit

Cadherins are a family of calcium-dependent adhesion proteins that orchestrate the orderly arrangement of cells in tissues. They mediate homophilic interactions—cells expressing the same cadherin molecule stick to one another—helping to establish and preserve the architecture of epithelia, endothelia, and other organized tissues. The cadherin system is central to development, wound healing, barrier function, and the maintenance of organ structure. Misregulation of cadherins is a hallmark of disease in many contexts, from cancer metastasis to autoimmune conditions and genetic syndromes such as hereditary diffuse gastric cancer. The cadherin superfamily includes classical cadherins and a broader set of cadherin-related proteins, each contributing to tissue cohesion in distinct ways. cadherin E-cadherin N-cadherin P-cadherin desmosomes protocadherins

Structure and function

Cadherins are transmembrane proteins with extracellular domains designed for calcium-dependent binding and intracellular domains that connect to the cell’s cytoskeleton. The classic cadherins consist of an extracellular region built from five cadherin repeats, each contributing to a robust, calcium-stabilized interface that promotes adherens junctions between neighboring cells. The cytoplasmic tail binds a set of linker proteins that translate adhesion into mechanical and signaling outcomes.

  • Extracellular interactions: The five cadherin repeats form zipper-like adhesions between adjacent cells, and the presence of calcium ions between repeats rigidifies the extracellular portion, enabling strong cell-cell contacts. For examples, see E-cadherin, N-cadherin, and other classical cadherins.
  • Cytoplasmic linkage: The cytoplasmic tail binds to catenins, including β-catenin and α-catenin, as well as p120-catenin. This complex anchors cadherins to the actin cytoskeleton and can modulate signaling pathways, notably the Wnt pathway when β-catenin is released from the junctional pool.
  • A dynamic system: Cadherin adhesion is regulated by endocytosis and recycling, post-translational modifications, and mechanical forces. The balance between membrane stability and turnover determines tissue remodeling during processes such as embryogenesis, wound repair, and epithelial maintenance. See also actin and cell junction.

In addition to the classical cadherins, the cadherin superfamily includes desmosomal cadherins (like desmoglein and desmocollin) that partner with intermediate filaments to strengthen desmosomes, and non-classical cadherins such as VE-cadherin in blood vessels. Protocadherins, a large subgroup, contribute to neural cell adhesion and synaptic organization. See desmosome and protocadherin for broader context.

Types and distribution

  • Classical cadherins: The best characterized group, including E-cadherin, N-cadherin, and P-cadherin. E-cadherin is a hallmark of epithelial tissues and helps define apical-basal polarity and barrier integrity. Loss or reduction of E-cadherin is associated with disruption of epithelial layers and increased invasiveness in malignancies.
  • Desmosomal cadherins: Desmogleins and desmocollins form desmosomes that attach to intermediate filaments, providing resilience to mechanical stress in tissues such as skin and heart.
  • Other cadherins: VE-cadherin is important for endothelial junctions; cadherins such as cadherin-6, cadherin-7, and many protocadherins contribute to tissue-specific adhesion programs, notably in the nervous system. See VE-cadherin and desmoglein for further detail.

Roles in development and tissue organization

Cadherins are essential for the orderly assembly of tissues during development and for preserving tissue integrity throughout life. They contribute to:

  • Morphogenesis: By controlling where cells stick together, cadherins influence tissue compaction, boundary formation between developing structures, and organogenesis. See embryogenesis and tissue morphogenesis.
  • Epithelial barrier function: E-cadherin–mediated adherens junctions help maintain selective barriers in organs such as the gut and the skin. Disruption can lead to leakage or inflammatory responses. See epithelial barrier.
  • Neural and vascular development: Protocadherins and VE-cadherin participate in neural circuit formation and blood vessel integrity, respectively. See neural development and vascular development.
  • Tissue homeostasis: In adult tissues, cadherins participate in turnover, wound healing, and response to injury by modulating adhesion and signaling that influence cell proliferation and differentiation. See tissue homeostasis.

Cadherins in health and disease

  • Cancer and metastasis: The best-known disease connection is the loss or misregulation of E-cadherin in carcinomas, which correlates with loss of epithelial traits and increased metastatic potential. The redistribution of β-catenin from the membrane to the nucleus can enhance transcription of genes that promote invasion and survival. The concept of a “cadherin switch”—loss of epithelial E-cadherin with upregulation of mesenchymal N-cadherin—has been a focus of research and therapeutic interest. See epithelial-mesenchymal transition and CDH1 for specific gene details.
  • Genetic syndromes: Mutations in cadherin genes can cause inherited disorders marked by tissue fragility or cancer predisposition. The CDH1 gene, which encodes E-cadherin, is associated with hereditary diffuse gastric cancer and related cancer risks. See hereditary diffuse gastric cancer.
  • Autoimmune and autoimmune-like diseases: Autoantibodies against desmogleins lead to pemphigus, a disease of the skin and mucous membranes, illustrating how cadherin function is crucial for tissue integrity and how its disruption can cause pathology. See pemphigus and pemphigus vulgaris.
  • Other pathologies: Endothelial barrier defects, inflammatory diseases, and some neurodevelopmental disorders are areas where cadherin dysregulation is implicated or studied, highlighting the broad role of adhesion in health.

Controversies and debates

Biology is full of debates where the implications for treatment and policy matter as much as the science itself. A few key debates around cadherins, approached from a pragmatic, outcome-focused perspective, include:

  • The role of EMT in metastasis: Traditional models emphasized epithelial-mesenchymal transition (EMT) as a driver of metastatic spread via loss of epithelial adhesion. More recent work emphasizes that metastasis can occur via alternative routes and that partial EMT or hybrid adhesion states may be sufficient or advantageous in certain contexts. This nuanced view encourages researchers and clinicians to rely on robust, pathway-specific evidence rather than one-size-fits-all targets. See epithelial-mesenchymal transition.
  • Targeting cadherin signaling in cancer: Therapies aimed at adhesion molecules face challenges such as redundancy among cadherin family members and compensatory mechanisms. While channels of cadherin-catenin signaling offer attractive targets, clinical success requires precise patient stratification and combination strategies. Proponents argue for steady, evidence-based progress that builds on solid understanding of structure-function relationships, rather than speculative “miracle” therapies. See cancer therapy.
  • EMT, adhesion, and translation to practice: Critics of pollyannaish translational hype caution that clear, reproducible biomarkers and endpoints are essential before adopting cadherin-targeted strategies in the clinic. Supporters contend that disciplined investment in translational research yields improvements in diagnosis and therapy while respecting patient access and affordability. This debate touches on broader policy questions about research funding, regulatory pathways, and the role of private versus public support in driving medical innovation.
  • Woke criticisms versus scientific rigor: In broader science discourse, some critics argue that social-identity-focused critiques should not steer research priorities or interpretation of data. Advocates of a pragmatic, evidence-first approach maintain that progress comes from rigorous experimentation, reproducible results, and transparent reporting, rather than ideology. In the cadherin field, this translates into a preference for cautious interpretation of signaling roles and a focus on clinically meaningful outcomes such as metastasis patterns, treatment response, and survival. See scientific method and research funding.

History and evolution

The cadherin concept emerged from work showing that cell adhesion depended on calcium and specific cell-surface proteins. Early genetic and biochemical studies laid the groundwork for understanding how cadherins form adhesive junctions, connect to the cytoskeleton, and participate in signaling. The cadherin-catenin complex was shown to link junctional adhesions to actin, establishing a foundational view of how cells maintain tissue integrity while remaining capable of remodeling during development and disease. The field has expanded to consider non-classical cadherins, desmosomal cadherins, and protocadherins, revealing a versatile toolkit that organisms use to sculpt tissues and respond to physiological demands. The discovery and ongoing study of cadherins are closely associated with the work of researchers such as those who characterized adherens junctions and the cadherin-catenin complex. See historical overview of cadherins.

See also