E-cadherin is a fundamental protein responsible for holding cells together, acting as a molecular glue within the body’s tissues. This protein is a transmembrane glycoprotein that spans the cell membrane. Its function is to form and maintain the integrity of epithelial tissues, which are sheets of cells that line the surfaces of organs and body cavities, such as the skin and the lining of the digestive tract.
E-cadherin: The Epithelial Gatekeeper
E-cadherin’s primary role is to maintain the physical integrity and polarity of epithelial cells, acting as a gatekeeper against unwanted movement or leakage. This protein is situated on the surface of epithelial cells, where it mediates calcium-dependent cell-to-cell adhesion. The mechanism it uses is called homophilic binding, where an E-cadherin molecule on one cell links directly to another E-cadherin molecule on an adjacent cell. This interaction creates a strong, physical connection that spans the gap between neighboring cells, forming the adherens junction. The result is a continuous, robust barrier that prevents substances from passing between cells, a function called paracellular sealing.
Building the Cell Adhesion Complex
While E-cadherin provides the external adhesion between cells, it is only one part of the larger, multi-protein Adherens Junction. To provide mechanical strength, the external E-cadherin molecule must be anchored to the cell’s internal structural framework, the actin cytoskeleton. This internal connection requires specialized intracellular partner proteins, collectively referred to as catenins.
The cytoplasmic tail of E-cadherin first binds directly to proteins like \(\beta\)-catenin and p120-catenin. \(\beta\)-catenin then acts as a bridge, linking the E-cadherin complex to \(\alpha\)-catenin. \(\alpha\)-catenin interacts with the actin cytoskeleton to create a stable anchor. This linkage is a dynamic connection that allows the cells to sense and respond to physical forces, transmitting mechanical tension between the cells and the internal cytoskeleton.
E-cadherin Loss and Disease
The loss or functional impairment of E-cadherin is central to the progression of many diseases, particularly cancer, due to its role as a tumor suppressor protein. When E-cadherin is downregulated or inactivated, the strong cell-to-cell adhesion is weakened, allowing epithelial cells to detach from their neighbors. This loss of adhesion is often the first step in Epithelial-Mesenchymal Transition (EMT).
EMT is a process where stationary epithelial cells lose their characteristic shape and polarity, acquiring the mobile, invasive characteristics of mesenchymal cells. During EMT, cells actively lose E-cadherin and gain new proteins associated with motility and migration, such as N-cadherin and vimentin. This transformation enables cancer cells to escape the primary tumor mass and move into the bloodstream or lymphatic system, a process known as metastasis.
The inactivation of E-cadherin is achieved through various mechanisms, including gene mutations, epigenetic silencing, or transcriptional repression by factors like Snail and Twist. Germline mutations in the gene that codes for E-cadherin, \(CDH1\), are directly associated with an extremely high lifetime risk of hereditary diffuse gastric cancer (HDGC). In HDGC, the loss of this protein allows cancer cells to spread early and aggressively through the stomach wall without forming a solid, detectable tumor mass.