H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 86
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Treatment of an epithelium with the protease trypsin destroys the tight junctions, supporting the proposal that proteins are essentialstructural components of these junctions.207The long C-terminal cytosolic segment of occludin bindsto PDZ domains in certain large cytosolic adapter proteins.These domains are found in various cytosolic proteins andmediate binding to the C-termini of particular plasmamembrane proteins. PDZ-containing adapter proteins associated with occludin are bound, in turn, to other cytoskeletal and signaling proteins and to actin fibers.
Theseinteractions appear to stabilize the linkage between occludinand claudin molecules that is essential for maintaining the integrity of tight junctions.A simple experiment demonstrates the impermeability ofcertain tight junctions to many water-soluble substances. Inthis experiment, lanthanum hydroxide (an electron-densecolloid of high molecular weight) is injected into the pancreatic blood vessel of an experimental animal; a few minuteslater, the pancreatic acinar cells, which are specialized epithelial cells, are fixed and prepared for microscopy. Asshown in Figure 6-10, the lanthanum hydroxide diffusesfrom the blood into the space that separates the lateral surfaces of adjacent acinar cells, but cannot penetrate past thetight junction.The importance of Ca2 to the formation and integrity oftight junctions has been demonstrated in studies with MDCKcells in the experimental system described previously (seeFigure 6-7).
If the growth medium in the chamber containsvery low concentrations of Ca2, MDCK cells form a monolayer in which the cells are not connected by tight junctions.As a result, fluids and salts flow freely across the cell layer.When sufficient Ca2 is added to the medium, tight junctionsform within an hour, and the cell layer becomes impermeableApical surfaceof left cellApical surfaceof right cellTight junctionLateralsurfaceof left cellLateralsurfaceof right cellLanthanum hydroxide(between cells)▲ EXPERIMENTAL FIGURE 6-10 Tight junctions preventpassage of large molecules through extracellular spacebetween epithelial cells. This experiment, described in the text,demonstrates the impermeability of tight junctions in thepancreas to the large water-soluble colloid lanthanum hydroxide.[Courtesy of D.
Friend.]208CHAPTER 6 • Integrating Cells into Tissuesto fluids and salts. Thus Ca2 is required for the formationof tight junctions as well as for cell–cell adhesion mediatedby cadherins.Plasma-membrane proteins cannot diffuse in the plane ofthe membrane past tight junctions. These junctions also restrict the lateral movement of lipids in the exoplasmic leafletof the plasma membrane in the apical and basolateral regionsof epithelial cells. Indeed, the lipid compositions of the exoplasmic leaflet in these two regions are distinct.
Essentiallyall glycolipids are present in the exoplasmic face of the apicalmembrane, as are all proteins linked to the membrane by aglycosylphosphatidylinositol (GPI) anchor (see Figure 5-15).In contrast, lipids in the cytosolic leaflet in the apical and basolateral regions of epithelial cells have the same composition and can apparently diffuse laterally from one region ofthe membrane to the other.Differences in Permeability of Tight JunctionsCan Control Passage of Small MoleculesAcross EpitheliaThe barrier to diffusion provided by tight junctions is not absolute.
Owing at least in part to the varying properties of thedifferent isoforms of claudin located in different tight junctions, their permeability to ions, small molecules, and watervaries enormously among different epithelial tissues. In epithelia with “leaky” tight junctions, small molecules canmove from one side of the cell layer to the other through theparacellular pathway in addition to the transcellular pathway (Figure 6-11).The leakiness of tight junctions can be altered by intracellular signaling pathways, especially G protein–coupledpathways entailing cyclic AMP and protein kinase C (Chapter 13). The regulation of tight junction permeability is oftenTightjunctionParacellular TranscellularpathwaypathwayApicalmembraneBasolateralmembrane▲ FIGURE 6-11 Transcellular and paracellular pathways oftransepithelial transport.
Transcellular transport requires thecellular uptake of molecules on one side and subsequent releaseon the opposite side by mechanisms discussed in Chapters 7and 17. In paracellular transport, molecules move extracellularlythrough parts of tight junctions, whose permeability to smallmolecules and ions depends on the composition of the junctionalcomponents and the physiologic state of the epithelial cells.[Adapted from S.
Tsukita et al., 2001, Nature Rev. Mol. Cell Biol. 2:285.]studied by measuring ion flux (electrical resistance) or themovement of radioactive or fluorescent molecules acrossmonolayers of MDCK cells.The importance of paracellular transport is illustrated in several human diseases. In hereditary hypomagnesemia, defects in the claudin16 geneprevent the normal paracellular flow of magnesium throughtight junctions in the kidney. This results in an abnormallylow blood level of magnesium, which can lead to convulsions.
Furthermore, a mutation in the claudin14 gene causeshereditary deafness, apparently by altering transport aroundhair cells in the cochlea of the inner ear.Toxins produced by Vibrio cholerae, which causescholera, and several other enteric (gastrointestinal tract)bacteria alter the permeability barrier of the intestinal epithelium by altering the composition or activity of tight junctions.
Other bacterial toxins can affect the ion-pumpingactivity of membrane transport proteins in intestinal epithelial cells. Toxin-induced changes in tight junction permeability (increased paracellular transport) and in protein-mediatedion-pumping proteins (increased transcellular transport) canresult in massive loss of internal body ions and water into thegastrointestinal tract, which in turn leads to diarrhea and potentially lethal dehydration.❚Many Cell–Matrix and Some Cell–CellInteractions Are Mediated by IntegrinsThe integrin family comprises heterodimeric integral membrane proteins that function as adhesion receptors, mediating many cell–matrix interactions (see Figure 6-2).
Invertebrates, at least 24 integrin heterodimers, composed of18 types of subunits and 8 types of subunits in variouscombinations, are known. A single chain can interact withany one of multiple chains, forming integrins that bind different ligands. This phenomenon of combinatorial diversity,which is found throughout the biological world, allows a relatively small number of components to serve a large number of distinct functions.In epithelial cells, integrin 64 is concentrated inhemidesmosomes and plays a major role in adhering cells tomatrix in the underlying basal lamina, as discussed in detailin Section 6.3. Some integrins, particularly those expressedby certain blood cells, participate in heterophilic cell–cellinteractions.
The members of this large family play important roles in adhesion and signaling in both epithelial andnonepithelial tissues.Integrins typically exhibit low affinities for their ligandswith dissociation constants KD between 106 and 108 mol/L.However, the multiple weak interactions generated by thebinding of hundreds or thousands of integrin molecules totheir ligands on cells or in the extracellular matrix allow a cellto remain firmly anchored to its ligand-expressing target.Moreover, the weakness of individual integrin-mediated interactions facilitates cell migration.6.3 • The Extracellular Matrix of Epithelial SheetsParts of both the and the subunits of an integrinmolecule contribute to the primary extracellular ligandbinding site (see Figure 6-2).
Ligand binding to integrinsalso requires the simultaneous binding of divalent cations(positively charged ions). Like other cell-surface adhesivemolecules, the cytosolic region of integrins interacts withadapter proteins that in turn bind to the cytoskeleton andintracellular signaling molecules. Although most integrinsare linked to the actin cytoskeleton, the cytosolic domainof the 4 chain in the 64 integrin in hemidesmosomes,which is much longer than those of other integrins,binds to specialized adapter proteins (e.g., plectin) that inturn interact with keratin-based intermediate filaments.In addition to their adhesion function, integrins can mediate outside-in and inside-out transfer of information (signaling). In outside-in signaling, the engagement of integrinswith their extracellular ligands can, through adapter proteinsbound to the integrin cytosolic region, influence the cytoskeleton and intracellular signaling pathways.
Conversely,in inside-out signaling, intracellular signaling pathways canalter, from the cytoplasm, the structure of integrins and consequently their abilities to adhere to their extracellular ligands and mediate cell–cell and cell–matrix interactions.Integrin-mediated signaling pathways influence processes asdiverse as cell survival, cell proliferation, and programmedcell death (Chapter 22). Many cells express several differentintegrins that bind the same ligand. By selectively regulatingthe activity of each type of integrin, these cells can fine-tunetheir cell–cell and cell–matrix interactions and the associatedsignaling processes.We will consider various integrins and the regulation oftheir activity in detail in Section 6.5.KEY CONCEPTS OF SECTION 6.2Sheetlike Epithelial Tissues: Junctionsand Adhesion MoleculesPolarized epithelial cells have distinct apical, basal, andlateral surfaces.
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