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Conversely, by forcingTwist expression, one can make normal epithelial cells undergo an epithelial-mesenchymal transition and behave like malignant cells. TWist exerts itseffects, in part at least, by inhibiting expression of the cadherins that holdepithelial cells together. E-cadherin, in particular, is a target.
Mutations that disrupt the production or function of E-cadherin are in fact often found in cancercells and are thought to help make them malignant, as we shall discussin Chapter 2O.Figure19-1 2 Changingpatternsof cadherinexpressionduringofconstructionof the nervoussystem.The figure showscross-sectionsthe earlychickembryo,asthe neuraltube detachesfrom the ectodermand then as neuralcrestcellsdetachfrom the neuraltube.(A,B)lmmunofluorescenceshowingthe developingneuralmicrographsand (B)N-cadherin.tube labeledwith antibodiesagainst(A)E-cadherin(C)As the patternsof geneexpressionchange,the differentgroupsof cellsthey express.segregatefrom one anotheraccordingto the cadherins(Micrographscourtesyof KoheiHattaand MasatoshiTakeichi.)rem:-(c)c e l l se x p r e s s i n Eg -cadherinc e l l se x p r e s s i n cga d h e r i n6 8c e l l se x p r e s s i n Ng -cadherinc e l l se x p r e s s i ncga d h e r i n7n e u r a lt u b e1 0 0p m'1142Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixCateninsLinkClassicalCadherinsto the ActinCytoskeletonThe extracellular domains of cadherins mediate homophilic binding.
The intracellular domains of typical cadherins, including all classicaland some nonclassical ones, provide anchorage for filaments of the cytoskeleton: anchorage toactin at adherens junctions, and to intermediate filaments at desmosome junctions, as mentioned earlier (seeFigure 19-3). The linkage to the c],toskeleton isindirect and depends on a cluster of accessoryintracellular anchor proteins thatassembleon the tail of the cadherin.
This linkage, connecting the cadherin family member to actin or intermediate filaments, includes several different components (Figure f9-f4). These components vary somewhat according to thetype of anchorage-but in general a central part is played by B-cateninandlor itsclose relative y-catenin (plakoglobin).At adherens junctions, a remote relative of this pair of proteins, p120catenin, is also present and helps to regulate assembly of the whole complex.\Arhen pl2O-catenin is artificially depleted, cadherin proteins are rapidlydegraded,and cell-cell adhesion is lost.
An artificial increasein the level of p120catenin has an opposite effect. It is possible that cells use changes in the level ofpl20-catenin or in its phosphorylation state as one way to regulate theirstrength of adhesion. In any case,it seems that the linkage to actin is essentialfor efficient cell-cell adhesion, as classicalcadherins that lack their cvtoolasmicdomain cannot hold cells strongly together.AdherensJunctionsCoordinatethe Actin-BasedMotilityofAdjacentCellsAdherens junctions are an essential part of the machinery for modeling theshapes of multicellular structures in the animal body. By indirectly linking theactin filaments in one cell to those in its neighbors, they enable the cells in thetissue to use their actin cltoskeletons in a coordinated way.Adherens junctions occur in various forms.
In many nonepithelial tissues,they appear as small punctate or streaklike attachments that indirectly connectthe cortical actin filaments beneath the plasma membranes of two interactingcells. In heart muscle (discussedin chapter 23), they anchor the actin bundlesof the contractile apparatus and act in parallel with desmosomejunctions to linkthe contractile cells end-to-end. (The cell-cell interfaces in the muscle wherethese adhesions occur are so substantial that they show up clearly in stainedlight-microscope sections as so-called intercalated discs.)But the prototypicalexamples of adherensjunctions occur in epithelia, where they often form a continuous adhesion belt (or zonula adherens)close beneath the apical face of theepithelium, encircling each of the interacting cells in the sheet (Figure r9-r5).within each cell, a contractile bundle of actin filaments lies adjacent to theadhesion belt, oriented parallel to the plasma membrane and tethered to it bythe cadherins and their associatedintracellular anchor proteins.
The actin bundles are thus linked, via the cadherins and anchor proteins, into an extensivetranscellular network. This network can contract with the help of myosin motorproteins (discussedin chapter l6), providing the motile force for a fundamentalprocess in animal morphogenesis-the folding of epithelial cell sheets intotubes, vesicles,and other related structures (Figure fg-f6).Figure19-14 The linkageof classicalcadherinsto actinfilaments.Thecadherinsarecoupledindirectlyto actinfilamentsvia B-cateninand otheranchorproteins.s-Catenin,vinculin,and plakoglobin(a relativeofalsocalledlcatenin) areprobablyalsopresentin the linkageorB-catenin,involvedin controlof its assembly,but the detailsof the anchoragearenotwell understood.Anotherintracellularprotein,calledp120-catenin,alsobindsto the cadherincytoplasmictail and regulatescadherinfunction.hasa second,and very important,functionin intracellularB-Cateninsignaling,aswe discussin Chapter15 (seeFigure15-77).c e lI e x p r e s s i n gc e l le x p r e s s i n gh i g h l e v e lo f E - c a d h e r i nl e v e lo f E - c a d h e r i n(B)F i g u r e 19 - 1 3 C a d h e r i n - d e p e n d e n t c e l ls o r t i n g .
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