I p120-catenin


Plasma membrane

Cell 2

in experiments with cultured cells called Madin-Darby canine kidney (MDCK) cells. When grown in specialized containers, these cells form a continuous one-cell-thick sheet (monolayer) of polarized kidneylike epithelial cells (Figure 6-6). In this experimental system, the addition of an antibody that binds to E-cadherin, preventing its homophilic interactions, blocks the Ca2 +-dependent attachment of suspended MDCK cells to a substrate and the subsequent formation of intercellular adherens junctions.

Each classical cadherin contains a single transmembrane domain, a relatively short C-terminal cytosolic domain, and five extracellular "cadherin" domains (see Figure 6-2). The extracellular domains are necessary for Ca2+ binding and cadherin-mediated cell-cell adhesion. Cadherin-mediated adhesion entails both lateral (intracellular) and trans (intercellular) molecular interactions as described previously (see Figure 6-3). The Ca2+-binding sites, located between the cadherin repeats, serve to rigidify the cadherin oligomers. The cadherin oligomers subsequently form intercellular complexes to generate cell-cell adhesion and then additional lateral contacts, resulting in a "zippering up" of cadherins into clusters. In this way, multiple low-affinity interactions sum to produce a very tight intercellular adhesion.

The results of domain swap experiments, in which an extracellular domain of one kind of cadherin is replaced with the corresponding domain of a different cadherin, have indicated that the specificity of binding resides, at least in part, in the most distal extracellular domain, the N-terminal domain. In the past, cadherin-mediated adhesion was commonly thought to require only head-to-head interactions between the N-terminal domains of cadherin oligomers on adjacent cells, as depicted in Figure 6-3. However, the results of some experiments suggest that under some experimental conditions at least three cadherin domains from each molecule, not just the N-terminal domains, participate by inter-digitation in trans associations.

The C-terminal cytosolic domain of classical cadherins is linked to the actin cytoskeleton by a number of cytosolic adapter proteins (Figure 6-7). These linkages are essential for strong adhesion, apparently owing primarily to their contributing to increased lateral associations. For example, disruption of the interactions between classical cadherins and a- or P-catenin—two common adapter proteins that link these cadherins to actin filaments—dramatically reduces cadherin-mediated cell-cell adhesion. This disruption occurs spontaneously in tumor cells, which sometimes fail to express a-catenin, and can be induced experimentally by depleting the cytosolic pool of accessible p-catenin. The cytosolic domains of cadherins also interact with intracellular signaling molecules such as p-catenin and p120-catenin. Interestingly, p-catenin not only mediates cytoskeletal attachment but can also translocate to the nucleus and alter gene transcription (see Figure 15-32).

Although E-cadherins exhibit primarily homophilic binding, some cadherins mediate heterophilic interactions. Importantly, each classical cadherin has a characteristic tissue distribution. In the course of differentiation, the amount or nature of the cell-surface cadherins changes, affecting many aspects of cell-cell adhesion and cell migration. For instance, the reorganization of tissues during morphogenesis is often accompanied by the conversion of nonmotile epithelial cells into motile precursor cells for other tissues (mesenchymal cells). Such epithelial-to-mesenchymal transitions are associated with a reduction in the expression of E-cadherin. The conversion of epithelial cells into cancerous melanoma cells also is marked by a loss of E-cadherin activity. The resulting decrease in cell-cell adhesion permits melanoma cells to invade the underlying tissue and spread throughout the body.

Desmosomal Cadherins Desmosomes (Figure 6-8) contain two specialized cadherin proteins, desmoglein and

▲ FIGURE 6-8 Desmosomes. (a) Schematic model showing components of a desmosome between epithelial cells and attachments to the sides of keratin intermediate filaments, which crisscross the interior of cells. The transmembrane CAMs, desmoglein and desmocollin, belong to the cadherin family. (b) Electron micrograph of a thin section of a desmosome connecting two cultured differentiated human keratinocytes. Bundles of intermediate filaments radiate from the two darkly staining cytoplasmic plaques that line the inner surface of the adjacent plasma membranes. [Part (a) see B. M. Gumbiner, 1993, Neuron 11:551, and D. R. Garrod, 1993, Curr. Opin. Cell Biol. 5:30. Part (b) courtesy of R. van Buskirk.]

desmocollin, whose cytosolic domains are distinct from those in the classical cadherins. The cytosolic domains of desmosomal cadherins interact with plakoglobin (similar in structure to ^-catenin) and the plakophilins. These adapter proteins, which form the thick cytoplasmic plaques characteristic of desmosomes, in turn interact with intermediate filaments. Thus desmosomes and adherens junctions are linked to different cytoskeletal fibers.

The cadherin desmoglein was first identified by an unusual, but revealing, skin disease called pemphigus vulgaris, an autoimmune disease. Patients with autoimmune disorders synthesize antibodies that bind to a normal body protein. In this case, the autoantibodies disrupt adhesion between epithelial cells, causing blisters of the skin and mucous membranes. The predominant autoantibody was shown to be specific for desmoglein; indeed, the addition of such antibodies to normal skin induces the formation of blisters and disruption of cell adhesion.I

Tight Junctions Seal Off Body Cavities and Restrict Diffusion of Membrane Components

For polarized epithelial cells to carry out their functions as barriers and mediators of selective transport, extracellular fluids surrounding their apical and basolateral membranes must be kept separate. The tight junctions between adjacent epithelial cells are usually located just below the apical surface and help establish and maintain cell polarity (see Figures 6-1 and 6-5). These specialized regions of the plasma membrane form a barrier that seals off body cavities such as the intestine, the stomach lumen, the blood (e.g., the blood-brain barrier), and the bile duct in the liver.

► FIGURE 6-9 Tight junctions. (a) Freeze-fracture preparation of tight junction zone between two intestinal epithelial cells. The fracture plane passes through the plasma membrane of one of the two adjacent cells. A honeycomb-like network of ridges and grooves below the microvilli constitutes the tight junction zone. (b) Schematic drawing shows how a tight junction might be formed by the linkage of rows of protein particles in adjacent cells. In the inset micrograph of an ultrathin sectional view of a tight junction, the adjacent cells can be seen in close contact where the rows of proteins interact. (c) As shown in these schematic drawings of the major proteins in tight junctions, both occludin and claudin-1 contain four transmembrane helices, whereas the junction adhesion molecule (JAM) has a single transmembrane domain and a large extracellular region. See text for discussion. [Part (a) courtesy of L. A. Staehelin. Drawing in part (b) adapted from L. A. Staehelin and B. E. Hull, 1978, Sci. Am. 238(5):140, and D. Goodenough, 1999, Proc. Nat'l. Acad. Sci. USA 96:319. Photograph in part (b) courtesy of S. Tsukita et al., 2001, Nature Rev. Mol. Cell Biol. 2:285. Drawing in part (c) adapted from S. Tsukita et al., 2001, Nature Rev. Mol. Cell Biol. 2:285.]

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