H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 85
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Interestingly, -catenin notonly mediates cytoskeletal attachment but can also translocateto 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 tissuedistribution. In the course of differentiation, the amount ornature of the cell-surface cadherins changes, affecting many205aspects of cell–cell adhesion and cell migration. For instance,the reorganization of tissues during morphogenesis is oftenaccompanied by the conversion of nonmotile epithelial cellsinto motile precursor cells for other tissues (mesenchymalcells). Such epithelial-to-mesenchymal transitions are associated with a reduction in the expression of E-cadherin.
Theconversion of epithelial cells into cancerous melanoma cellsalso is marked by a loss of E-cadherin activity. The resultingdecrease 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(a)PlasmamembraneIntercellularspaceIntermediatefilamentsDesmoglein anddesmocollin(cadherins)(b)Intermediate filamentsCytoplasmic plaque(plakoglobin‚desmoplakins)Cytoplasmic plaquesPlasma membranes0.2 µm▲ FIGURE 6-8 Desmosomes. (a) Schematic model showingcomponents of a desmosome between epithelial cells andattachments to the sides of keratin intermediate filaments, whichcrisscross the interior of cells.
The transmembrane CAMs,desmoglein and desmocollin, belong to the cadherin family.(b) Electron micrograph of a thin section of a desmosomeconnecting two cultured differentiated human keratinocytes.Bundles of intermediate filaments radiate from the two darklystaining cytoplasmic plaques that line the inner surface of theadjacent 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.]CHAPTER 6 • Integrating Cells into TissuesThe cadherin desmoglein was first identified by anunusual, but revealing, skin disease called pemphigus vulgaris, an autoimmune disease. Patients withautoimmune disorders synthesize antibodies that bind to anormal body protein. In this case, the autoantibodies disruptadhesion between epithelial cells, causing blisters of the skinand mucous membranes.
The predominant autoantibodywas shown to be specific for desmoglein; indeed, the additionof such antibodies to normal skin induces the formation ofblisters and disruption of cell adhesion.❚(a)Microvillidesmocollin, whose cytosolic domains are distinct fromthose in the classical cadherins. The cytosolic domains ofdesmosomal cadherins interact with plakoglobin (similar instructure to -catenin) and the plakophilins. These adapterproteins, which form the thick cytoplasmic plaques characteristic of desmosomes, in turn interact with intermediate filaments.
Thus desmosomes and adherens junctions are linkedto different cytoskeletal fibers.Tight junction206(b)MicrovilliTight Junctions Seal Off Body Cavitiesand Restrict Diffusion of Membrane ComponentsFor polarized epithelial cells to carry out their functions asbarriers and mediators of selective transport, extracellularfluids surrounding their apical and basolateral membranesmust be kept separate. The tight junctions between adjacentepithelial cells are usually located just below the apical surface and help establish and maintain cell polarity (see Figures6-1 and 6-5).
These specialized regions of the plasma membrane form a barrier that seals off body cavities such asthe intestine, the stomach lumen, the blood (e.g., theblood–brain barrier), and the bile duct in the liver.TightjunctionIntercellularspaceLinkage of proteinparticles in adjacentcells FIGURE 6-9 Tight junctions. (a) Freeze-fracture preparationof tight junction zone between two intestinal epithelial cells. Thefracture plane passes through the plasma membrane of one ofthe two adjacent cells.
A honeycomb-like network of ridges andgrooves below the microvilli constitutes the tight junction zone.(b) Schematic drawing shows how a tight junction might beformed by the linkage of rows of protein particles in adjacentcells. In the inset micrograph of an ultrathin sectional view of atight junction, the adjacent cells can be seen in close contactwhere the rows of proteins interact. (c) As shown in theseschematic 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 singletransmembrane domain and a large extracellular region. See textfor 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. Photographin 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, NatureRev. Mol. Cell Biol. 2:285.]Rows ofproteinparticles50 nmNJAM(c)OccludinClaudin-1NCNCC6.2 • Sheetlike Epithelial Tissues: Junctions and Adhesion MoleculesTight junctions prevent the diffusion of macromoleculesand to varying degrees impede the diffusion of small watersoluble molecules and ions across an epithelial sheet in thespaces between cells. They also maintain the polarity of epithelial cells by preventing the diffusion of membrane proteins and glycolipids (lipids with covalently attached sugars)between the apical and the basolateral regions of the plasmamembrane, ensuring that these regions contain differentmembrane components. As a consequence, movement ofmany nutrients across the intestinal epithelium is in largepart through the transcellular pathway. In this pathway, specific transport proteins in the apical membrane import smallmolecules from the intestinal lumen into cells; other transport proteins located in the basolateral membrane then export these molecules into the extracellular space.
Suchtranscellular transport is covered in detail in Chapter 7.Tight junctions are composed of thin bands of plasmamembrane proteins that completely encircle a polarized celland are in contact with similar thin bands on adjacent cells.When thin sections of cells are viewed in an electron microscope, the lateral surfaces of adjacent cells appear to toucheach other at intervals and even to fuse in the zone just belowthe apical surface (see Figure 6-5b).
In freeze-fracture preparations, tight junctions appear as an interlocking network ofridges in the plasma membrane (Figure 6-9a). More specifically, there appear to be ridges on the cytosolic face of theplasma membrane of each of the two contacting cells. Corresponding grooves are found on the exoplasmic face.Very high magnification reveals that rows of protein particles 3–4 nm in diameter form the ridges seen in freezefracture micrographs of tight junctions.
In the model shownin Figure 6-9b, the tight junction is formed by a double rowof these particles, one row donated by each cell. The twoprincipal integral-membrane proteins found in tight junctions are occludin and claudin. Initially, investigatorsthought that occludin was the only essential protein component of tight junctions. However, when investigators engineered mice with mutations inactivating the occludin gene,the mice still had morphologically distinct tight junctions.(This technique, called gene knockout, is described in Chapter 9.) Further analysis led to the discovery of claudin. Eachof these proteins has four membrane-spanning helices (Figure 6-9c).
The claudin multigene family encodes numeroushomologous proteins (isoforms) that exhibit distinct tissuespecific patterns of expression. Recently, a group of junctionadhesion molecules (JAMs) have been found to contributeto homophilic adhesion and other functions of tight junctions. These molecules, which contain a single transmembrane helix, belong to the Ig superfamily of CAMs. Theextracellular domains of rows of occludin, claudin, and JAMproteins in the plasma membrane of one cell apparently formextremely tight links with similar rows of the same proteinsin an adjacent cell, creating a tight seal.
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