- Cadherins are a superfamily of calcium-dependent cell adhesion molecules that mediate homophilic interactions between adjacent cells. As key components of adherens junctions, cadherins are essential for maintaining tissue architecture, polarity, and morphogenesis in multicellular organisms. They are one of the four major groups of cell adhesion molecules—alongside integrins, selectins, and members of the immunoglobulin superfamily—and play pivotal roles in embryonic development, tissue integrity, and disease progression.
- Cadherins are type I transmembrane glycoproteins with three primary domains: a large extracellular domain, a single-pass transmembrane region, and a cytoplasmic tail. The extracellular domain typically consists of five cadherin repeat motifs (EC1–EC5), which mediate calcium-dependent homophilic binding between cadherins on neighboring cells. Calcium ions are crucial for maintaining the rigidity and adhesive function of the extracellular region. The EC1 domain at the N-terminus is primarily responsible for the adhesive interaction through a mechanism often involving the insertion of a tryptophan residue into a hydrophobic pocket of the opposing cadherin.
- The cytoplasmic domain of classical cadherins, such as E-cadherin (epithelial), N-cadherin (neural), and VE-cadherin (vascular endothelial), binds to catenins—particularly β-catenin, p120-catenin, and α-catenin—which link cadherins to the actin cytoskeleton. This cadherin–catenin–actin complex not only provides mechanical strength to cell-cell adhesion but also participates in intracellular signaling pathways that influence cell behavior. For example, β-catenin, when released from cadherin complexes, can translocate to the nucleus and regulate Wnt signaling, linking cadherins to gene transcription and cellular fate decisions.
- Cadherins exhibit tissue-specific expression patterns, with E-cadherin being a hallmark of epithelial cells, N-cadherin expressed in neurons and mesenchymal tissues, and VE-cadherin restricted to vascular endothelial cells. During embryogenesis, a well-coordinated cadherin expression switch—known as the cadherin switch—is crucial for cell migration and tissue remodeling. For instance, during epithelial–mesenchymal transition (EMT), cells downregulate E-cadherin and upregulate N-cadherin to gain migratory and invasive capabilities, a process that also plays a key role in cancer metastasis.
- Dysfunction or loss of cadherin-mediated adhesion is associated with a wide range of pathologies, including carcinoma progression, developmental abnormalities, and inflammatory disorders. In many cancers, reduced E-cadherin expression correlates with poor prognosis and increased invasiveness. Genetic mutations in cadherin genes, such as CDH1 (encoding E-cadherin), are implicated in hereditary diffuse gastric cancer and lobular breast cancer. Moreover, cadherin–catenin interactions can be hijacked or disrupted by pathogens (e.g., Listeria monocytogenes and Helicobacter pylori) to breach epithelial barriers.
- Cadherins also function beyond structural adhesion. They are involved in contact inhibition, synaptic plasticity in neurons, angiogenesis, and the regulation of cell proliferation and apoptosis. Their adhesive strength is dynamically regulated through post-translational modifications, including phosphorylation, endocytosis, and proteolytic cleavage. This dynamic regulation allows cadherins to mediate transient or stable cell-cell contacts depending on the physiological context.
- In summary, cadherins are multifunctional adhesion molecules that integrate mechanical adhesion with signaling pathways to orchestrate tissue organization, cell communication, and developmental processes. Their precise regulation is essential for normal physiology, while their dysfunction contributes to a broad spectrum of diseases, including cancer, cardiovascular disorders, and developmental syndromes.
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