The assembly of cells into an epithelium is a reversible process. By switching on expression of adhesion molecules, dispersed unattached mesenchymal cells, such as fibroblasts, can come together to form an epithelium. Conversely, epithelial cells can change their character, disassemble, and migrate away from their parent epithelium as separate cells. Such epithelial–mesenchymal transitions play an important part in normal embryonic development; the origin of the neural crest is one example. These transitions depend in part on transcription regulatory proteins called Slug, Snail, and Twist. Increased expression of Twist, for example, converts epithelial cells to a mesenchymal character, and switching it off does the opposite. Twist exerts its effects, in part, by inhibiting expression of cadherins, including E-cadherin, that hold epithelial cells together.
Epithelial–mesenchymal transitions also occur as pathological events during adult life, in cancer. Most cancers originate in epithelia, but become dangerously prone to spread—that is, malignant—only when the cancer cells escape from the epithelium of origin and invade other tissues. Experiments with malignant breast cancer cells in culture show that blocking expression of Twist can convert the cells back toward a nonmalignant character. Conversely, by forcing Twist expression, one can make normal epithelial cells undergo an epithelial–mesenchymal transition and behave like malignant cells. Mutations that disrupt the production or function of E-cadherin are often found in cancer cells and are thought to help make them malignant.
Catenins Link Classical Cadherins to the actin Cytoskeleton
The extracellular domains of cadherins mediate homophilic binding at adherens junctions. The intracellular domains of typical cadherins, including all classical and some nonclassical ones, interact with filaments of the cytoskeleton: actin at adherens junctions and intermediate filaments at desmosomes (see Table 19–1). These cytoskeletal linkages are essential for efficient cell–cell adhesion, as cadherins that lack their cytoplasmic domains cannot stably hold cells together.
The linkage of cadherins to the cytoskeleton is indirect and depends on adaptor proteins that assemble on the cytoplasmic tail of the cadherin. At adherens junctions, the cadherin tail binds two such proteins: β-catenin and a distant relative called p120-catenin; a third protein called α-catenin interacts with β-catenin and recruits a variety of other proteins to provide a dynamic linkage to actin filaments (Figure 19–10). At desmosomes, cadherins are linked to intermediate filaments through other adaptor proteins, including a β-catenin-related protein called plakoglobin, as we discuss later.
In their mature form, adherens junctions are enormous protein complexes containing hundreds to thousands of cadherin molecules, packed into dense, regular arrays that are linked on the extracellular side by lateral interactions between cadherin domains, as we discussed earlier (see Figure 19–6C). On the cytoplasmic side, a complex network of catenins, actin regulators, and contractile actin bundles holds the cluster of cadherins together and links it to the actin cytoskeleton. Assembling a structure of this complexity is not a simple task, and it involves a complex sequence of events controlled by the actin-regulatory proteins discussed in Chapter 16. The general features of the assembly process are summarized in Figure 19–11.
adherens Junctions respond to Forces Generated by the actin Cytoskeleton
Most adherens junctions are linked to contractile bundles of actin filaments and non-muscle myosin II. These junctions are therefore subjected to pulling forces generated by the attached actin. The pulling forces are important for junction assembly and maintenance: disruption of myosin activity, for example, results in