H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 84
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Adherens junctions, which connect the lateral membranes of adjacent epithelial cells, are usually located near the apical surface, justbelow the tight junctions (see Figures 6-1 and 6-5). A circumferential belt of actin and myosin filaments in a complexwith the adherens junction functions as a tension cable thatcan internally brace the cell and thereby control its shape.Epithelial and some other types of cells, such as smooth muscle, are also bound tightly together by desmosomes, buttonlike points of contact sometimes called spot desmosomes.Hemidesmosomes, found mainly on the basal surface of epithelial cells, anchor an epithelium to components of the underlying extracellular matrix, much like nails holding downa carpet.
Bundles of intermediate filaments, running parallelto the cell surface or through the cell, rather than actin filaments, interconnect spot desmosomes and hemidesmosomes,imparting shape and rigidity to the cell.Desmosomes and hemidesmosomes also transmit shearforces from one region of a cell layer to the epithelium as awhole, providing strength and rigidity to the entire epithelial cell layer. These junctions are especially important inmaintaining the integrity of skin epithelia.
For instance, mutations that interfere with hemidesmosomal anchoring in theskin can lead to blistering in which the epithelium becomesdetached from its matrix foundation and extracellular fluidaccumulates at the basolateral surface, forcing the skin toballoon outward.204CHAPTER 6 • Integrating Cells into TissuesCa2-Dependent Homophilic Cell–Cell Adhesionin Adherens Junctions and DesmosomesIs Mediated by CadherinsThe primary CAMs in adherens junctions and desmosomesbelong to the cadherin family.
In vertebrates and invertebrates, this protein family of more than 100 members canbe grouped into at least six subfamilies. The diversity of cadherins arises from the presence of multiple cadherin genesand alternative RNA splicing, which generates multiplemRNAs from one gene.Cadherins are key molecules in cell–cell adhesion and cellsignaling, and they play a critical role during tissue differentiation.
The “classical” E-, P-, and N-cadherins are the mostwidely expressed, particularly during early differentiation.Sheets of polarized epithelial cells, such as those that linethe small intestine or kidney tubules, contain abundantE-cadherin along their lateral surfaces. Although E-cadherinis concentrated in adherens junctions, it is present throughout the lateral surfaces where it is thought to link adjacentcell membranes. The brain expresses the largest number ofdifferent cadherins, presumably owing to the necessity offorming many very specific cell–cell contacts to help establishits complex wiring diagram.Classical Cadherins The results of experiments with L cells, aline of cultured mouse fibroblasts grown in the laboratory,demonstrated that E-cadherin and P-cadherin preferentiallymediate homophilic interactions.
L cells express no cadherinsand adhere poorly to themselves or to other types of culturedcells. When genes encoding either E-cadherin or P-cadherinwere introduced into L cells with the use of techniques described in Chapter 9, the resulting engineered L cells expressedthe encoded cadherin. These cadherin-expressing L cells werefound to adhere preferentially to cells expressing the same typeApical surfaceCulture dishApical mediumBasal mediumBasallaminaPorousfilter▲ EXPERIMENTAL FIGURE 6-6 Madin-Darby caninekidney (MDCK) cells grown in specialized containers providea useful experimental system for studying epithelial cells.MDCK cells form a polarized epithelium when grown on a porousmembrane filter coated on one side with collagen and othercomponents of the basal lamina.
With the use of the specialculture dish shown here, the medium on each side of the filter(apical and basal sides of the monolayer) can be experimentallymanipulated and the movement of molecules across the layermonitored. Anchoring junctions and tight junctions form only ifthe growth medium contains sufficient Ca2.of cadherin molecules; that is, they mediate homophilic interactions. The L cells expressing E-cadherin also exhibited thepolarized distribution of a membrane protein similar to that inepithelial cells, and they formed epithelial-like aggregates withone another and with epithelial cells isolated from lungs.The adhesiveness of cadherins depends on the presence ofextracellular Ca2, the property that gave rise to their name(calcium adhering).
For example, the adhesion of engineeredL cells expressing E-cadherin is prevented when the cells arebathed in a solution (growth medium) that is low in Ca2.The role of E-cadherin in adhesion can also be demonstratedVinculin-Catenin-CateninMonolayerof MDCK cellsVASPE-cadherinF-actin-ActininZO1p120-cateninCytosolCell 1PlasmamembraneExtracellularspace▲ FIGURE 6-7 Protein constitutents of typical adherensjunctions. The exoplasmic domains of E-cadherin dimersclustered at adherens junctions on adjacent cells (1 and 2) formCa2-dependent homophilic interactions.
The cytosolic domainsof the E-cadherins bind directly or indirectly to multiple adapterproteins that connect the junctions to actin filaments (F-actin) ofCytosolPlasmamembraneCell 2the cytoskeleton and participate in intracellular signalingpathways (e.g., -catenin). Somewhat different sets of adapterproteins are illustrated in the two cells shown to emphasizethat a variety of adapters can interact with adherens junctions,which can thereby participate in diverse activities.
[Adapted fromV. Vasioukhin and E. Fuchs, 2001, Curr. Opin. Cell Biol.13:76.]6.2 • Sheetlike Epithelial Tissues: Junctions and Adhesion Moleculesin 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 (Figure6-6).
In this experimental system, the addition of an antibodythat binds to E-cadherin, preventing its homophilic interactions, blocks the Ca2-dependent attachment of suspendedMDCK cells to a substrate and the subsequent formation ofintercellular adherens junctions.Each classical cadherin contains a single transmembranedomain, a relatively short C-terminal cytosolic domain, andfive extracellular “cadherin” domains (see Figure 6-2). Theextracellular domains are necessary for Ca2 binding andcadherin-mediated cell–cell adhesion. Cadherin-mediated adhesion entails both lateral (intracellular) and trans (intercellular) molecular interactions as described previously (seeFigure 6-3).
The Ca2-binding sites, located between thecadherin 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 intoclusters. In this way, multiple low-affinity interactions sum toproduce a very tight intercellular adhesion.The results of domain swap experiments, in which an extracellular domain of one kind of cadherin is replaced withthe 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 interactionsbetween the N-terminal domains of cadherin oligomers onadjacent cells, as depicted in Figure 6-3.
However, the resultsof some experiments suggest that under some experimentalconditions at least three cadherin domains from each molecule, not just the N-terminal domains, participate by interdigitation in trans associations.The C-terminal cytosolic domain of classical cadherins islinked to the actin cytoskeleton by a number of cytosolicadapter proteins (Figure 6-7).
These linkages are essential forstrong adhesion, apparently owing primarily to their contributing to increased lateral associations. For example, disruption of the interactions between classical cadherins and - or-catenin—two common adapter proteins that link these cadherins to actin filaments—dramatically reduces cadherinmediated cell–cell adhesion. This disruption occurs spontaneously in tumor cells, which sometimes fail to express catenin, and can be induced experimentally by depleting thecytosolic pool of accessible -catenin. The cytosolic domains ofcadherins also interact with intracellular signaling moleculessuch as -catenin and p120-catenin.
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