Key points
- Prototypical member of the type-1 classical cadherins
- A key component of adherens junctions (AJs) (cell-cell adhesions)
- a2+-dependent adhesion molecule
- Single-pass transmembrane glycoprotein
- Connect cells through homophilic interaction
- Mostly expressed in epithelial cells
Description
- E-cadherin (epithelial cadherin) is a calcium-dependent adhesion molecule that plays a fundamental role in epithelial tissue organization, morphogenesis, and maintenance of tissue integrity. As a key member of the classical cadherin family, E-cadherin mediates homophilic cell-cell adhesion and is essential for the formation and maintenance of adherens junctions.
- The structure of E-cadherin consists of three main domains: an extracellular domain containing five cadherin repeats that mediate calcium-dependent adhesion, a single-pass transmembrane domain, and a cytoplasmic domain that interacts with various intracellular proteins. The cytoplasmic domain forms a complex with catenins (α-, β-, and p120-catenin), which link E-cadherin to the actin cytoskeleton and participate in signaling pathways.
- E-cadherin’s function extends beyond simple mechanical adhesion. It serves as a crucial regulator of epithelial cell behavior, including cell polarity, differentiation, and migration. Through its interactions with the cytoskeleton and various signaling molecules, E-cadherin influences cell shape, tissue organization, and cellular responses to environmental cues. The dynamic regulation of E-cadherin expression and function is essential for normal development and tissue homeostasis.
- In embryonic development, E-cadherin plays a vital role in early morphogenetic events, including compaction of the early embryo and formation of the trophectoderm. Its expression patterns are tightly regulated during development, and changes in E-cadherin levels or function can significantly impact tissue organization and differentiation. This regulation is particularly important during epithelial-mesenchymal transition (EMT), a process crucial for both development and disease progression.
- The loss or dysfunction of E-cadherin is strongly associated with cancer progression and metastasis. E-cadherin is considered a tumor suppressor, and its downregulation is a hallmark of EMT in cancer cells. The loss of E-cadherin expression or function promotes cell detachment, increased motility, and invasive behavior. This process is particularly important in carcinomas, where the loss of E-cadherin correlates with increased tumor aggressiveness and poor prognosis.
- Regulation of E-cadherin occurs at multiple levels, including transcriptional control, post-translational modifications, and protein trafficking. Transcriptional repressors such as Snail, Slug, and ZEB1/2 directly suppress E-cadherin expression during EMT. Post-translational modifications, including phosphorylation and glycosylation, can affect E-cadherin stability, localization, and function. Additionally, endocytic trafficking of E-cadherin provides another layer of regulation for adherens junction dynamics.
- In normal epithelial tissues, E-cadherin-mediated adhesion is essential for maintaining the barrier function and structural integrity of epithelia. It helps establish and maintain cell polarity, regulate cell proliferation, and coordinate tissue-wide responses to mechanical stress. The proper functioning of E-cadherin is crucial for wound healing, tissue repair, and the maintenance of epithelial homeostasis.
- Mutations in the E-cadherin gene (CDH1) are associated with various diseases, including hereditary diffuse gastric cancer and lobular breast cancer. These mutations can affect protein expression, stability, or function, leading to compromised cell-cell adhesion and increased cancer susceptibility. Understanding these mutations has important implications for cancer screening and prevention strategies.
- The role of E-cadherin in disease extends beyond cancer. Altered E-cadherin function is implicated in inflammatory conditions, fibrosis, and developmental disorders. In inflammatory diseases, disruption of E-cadherin-mediated adhesion can compromise epithelial barrier function, contributing to tissue damage and chronic inflammation. In fibrosis, EMT-associated loss of E-cadherin contributes to the accumulation of fibroblasts and excessive matrix deposition.
- Research continues to reveal new aspects of E-cadherin biology and its therapeutic potential. Current areas of investigation include understanding the mechanistic details of E-cadherin-mediated mechanotransduction, developing strategies to target E-cadherin trafficking in disease, and exploring the potential of E-cadherin as a therapeutic target in cancer and other diseases.
- Therapeutic approaches targeting E-cadherin or its regulatory pathways are being developed for various conditions. In cancer, strategies aim to restore E-cadherin expression or function to suppress tumor progression and metastasis. These approaches include targeting transcriptional repressors, modulating signaling pathways that regulate E-cadherin, and developing drugs that stabilize adherens junctions.
- Understanding E-cadherin biology has important implications for tissue engineering and regenerative medicine. The ability to control E-cadherin-mediated adhesion and signaling could help in developing better methods for tissue reconstruction and organ regeneration. Additionally, E-cadherin’s role in stem cell maintenance and differentiation makes it relevant for stem cell-based therapies.
- The study of E-cadherin continues to provide insights into fundamental biological processes and disease mechanisms. As our understanding grows, new therapeutic opportunities are likely to emerge, potentially leading to improved treatments for cancer and other diseases where E-cadherin dysfunction plays a role. The continued investigation of this crucial adhesion molecule remains important for both basic research and clinical applications.
