Adherens junctions (AJs) are specialized protein structures that mediate strong physical connections between neighboring cells, often forming a continuous belt around the cell. These junctions are fundamental to the organization of multicellular life, serving as the primary anchor points that hold cells together in tissues like the skin, intestines, and blood vessels. AJs create integrated layers of cells, such as epithelial and endothelial sheets, which line and protect the body’s internal and external surfaces. Their presence establishes a foundational structure that ensures cells remain associated and coordinate their activities.
The Molecular Architecture
The adherens junction structure begins with the transmembrane protein classical cadherin, which serves as the molecular “glue” spanning the cellular membrane. These proteins are calcium-dependent, requiring calcium ions to fold correctly and mediate adhesion. The extracellular domain of a cadherin molecule on one cell physically engages with an identical cadherin molecule on the adjacent cell via homophilic binding.
Inside the cell, the cytoplasmic tail of the cadherin molecule associates with a complex of adaptor proteins known as catenins. This complex includes p120-catenin and beta-catenin, which bind directly to the cadherin tail. Beta-catenin then links to alpha-catenin, which is the final bridge in the assembly.
Alpha-catenin connects the entire cadherin-catenin complex to the cell’s internal structural framework, specifically the actin cytoskeleton. This linkage provides the junction with mechanical strength, allowing the tissue to resist physical forces and tension. This molecular scaffolding ensures that forces applied to one cell are effectively distributed across the entire tissue sheet.
Essential Roles in Tissue Integrity
The primary function of adherens junctions is providing mechanical strength to tissues, integrating individual cells into a collective structural unit. By linking the actin cytoskeletons of adjacent cells, AJs create a syncytium that can withstand stretching and compression during normal physiological processes. Inhibition of these junctions impedes the emergence of tissue-level tension, highlighting their role in maintaining structural stability.
AJs also play a role in establishing and maintaining epithelial cell polarity, which is the distinction between the cell’s apical (top) and basolateral (bottom) surfaces. The adherens junction ring acts as a moveable diffusion barrier, or “molecular fence,” that helps segregate membrane proteins and lipids. While not required for initial polarity formation, this fence function is necessary for the control and maintenance of the apical and basolateral domains.
Adherens junctions cooperate closely with tight junctions, which are often located immediately apical to AJs in epithelial sheets. While tight junctions form the primary seal against fluid leakage, the adherens junction is required to initiate the formation and maturation of the tight junction complex. This collaboration ensures that the epithelial layer is both strong and sealed, regulating the passage of substances between cells.
Dynamic Regulation and Cellular Signaling
Adherens junctions are highly dynamic structures that can be rapidly assembled or disassembled in response to cellular needs and external signals. This dynamic control is necessary for processes that require cells to change shape or move, such as embryonic development, wound healing, and tissue remodeling. The primary mechanism regulating adhesion strength involves phosphorylation, where small chemical groups are added to or removed from junctional proteins.
Kinases, enzymes that add phosphate groups, target the catenin adaptor proteins, particularly beta-catenin. Phosphorylation of catenins acts as a switch, altering their ability to bind to cadherins or the actin cytoskeleton. For instance, increased tyrosine phosphorylation often leads to the loosening or disassembly of the junction, reducing adhesive strength.
This rapid regulation allows cells to quickly modify their connections, which is necessary for processes like leukocyte transmigration across the endothelial barrier during inflammation. The ability to rapidly loosen or tighten junctions enables cell migration and tissue morphogenesis by providing the necessary plasticity for cells to change position.
Adherens Junctions and Human Health
Dysregulation of adherens junctions is implicated in human diseases, particularly the progression of cancer. The breakdown of these junctions is a defining event in Epithelial-Mesenchymal Transition (EMT), a process where epithelial cells shed adhesive properties and become migratory. During EMT, cancer cells actively dismantle their AJs, typically by downregulating E-cadherin expression.
The loss of E-cadherin allows tumor cells to de-adhere from the primary mass and acquire the ability to invade surrounding tissue and metastasize. Signaling pathways reactivated in cancer, such as Wnt and Transforming Growth Factor-beta (TGF-β), are known inducers of EMT that target AJ components. The failure of cell-to-cell adhesion is a prerequisite for cancer cells to become invasive.
Malfunctions in AJ components are linked to developmental defects and structural disorders. For example, the regulation of cadherin expression is necessary for the migration of neural crest cells during embryonic development. Furthermore, some pathogens, including viruses, exploit AJ proteins as entry points to gain access to host cells.