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This suggeststhatnormal epithelial polarity depends on tvvo interlocking mechanisms: one thatendows individual cells with a tendency to become polarized cellautonomously, and another that orients their polarity axis in relation to theirneighbors and the basal lamina. The latter mechanism would be peculiar toepithelia; the former could be much more general, operating also in other polarized cell types.The molecules knor,rryrto be needed for epithelial polarity can be classified inrelation to these two mechanisms.
Central to the polarity of individual animalcells in general is a set of three membrane-associatedproteins: Par3, Par6, andatypical protein kinase C (aPKC). Par3 and Par6 are both scaffold proteins containing PDZ domains, and they bind to one another and to aPKC.The complex ofthese three components also has binding sites for various other molecules,including the small GTPasesRac and Cdc42.Theselatter molecules play a crucialpart. Thus, for example,when Rac function is blocked in a cluster of MDCK cells,the cells develop with inverted polarity (see Figure 19-298). Rac and Cdc42 arekey regulators of actin assembly, as explained in Chapter 16; through them, itseems,assemblyof a Par3-Par6-aPKCcomplex in a specific region of the cell cortex is associated with polarization of the cltoskeleton towards that region.
Theassembly process is evidently cooperative and involves some positive feedbackand spatial signaling, so that a small initial cluster of these components is able torecruit more of them and to inhibit the development of clusters of the same t],peelsewherein the cell. One source of positive feedback may lie in the behavior ofCdc42 and Rac: a high activity of these molecules at a particular site, by organizing the cytoskeleton, may direct intracellular transport so as to bring still moreCdc42 or Rac,or more of their activators,to the same site.This is suspectedto bean essentialpart of the polarization mechanism in budding yeast cells,and it maybe the way in which cells such as migrating fibroblasts establish the differencebetween their leading edge and the rest of their periphery. It could be the core ofthe eucaryotic cell polarization machinery at least in evolutionary terms.The Par3-Par6-aPKCcomplex, combined with Cdc42 or Rac, seems to control the organization of other protein complexes associated with the internalface of the cell membrane.
In particular, in epithelial cells, it causes the Crumbscomplex,held together by the PDZ-domain scaffold proteins Discs-lost and Stardust, to become localized toward the apex of the cell, while a third such complex, called lhe Scribblecomplex,held together by the scaffold proteins Scribbleand Discs-large (the same protein that we encountered previously) is localizedmore basally (Figure 19-3f ). These various protein assembliesinteract with oneanother and with other cell components in ways that are only beginning to beunderstood.But how is this whole elaborate system oriented correctly in relation toneighboring cells?In an epithelium, the Par3-Par6-aPKCcomplex assemblesatFigure 19-30 Developmentof polarityin singleisolatedepithelialcells.Cellsofa linederivedfrom intestinaleoitheliumwere transfectedwith DNAconstructscodingfor regulatorycomponentsthroughwhichthe activityof the LKBIprotein could be switchedon or off by achangein the compositionof the culturemedium.WhenLKBlactivityis low,thecellsappearunpolarized;when it is high,polarized.they becomeindividuallyTheirpolarityis manifestin the distributionoftight-junctionproteins(ZO1) andproteins(p120adherens-junctionwhichaccumulatecatenin),on one sideof the cell,arounda cap of actin-filledmicrovilli,eventhough the cellsareisolatedfrom one anotherand makenoThiscell-autonomouscell-celljunctions.oolarizationoccursevenwhen the cellsareculturedin suspension,withoutcontactwith any substratumthat couldtell them whichway wasup.
(FromA.F.Baaset al.,Cell 116:457-466, 2004.With permissionfrom Elsevier.)TIGHTJUNCTIONSANDTHEORGANIZATIONOF EPITHELIA1157Figure19-31The coordinatedarrangementof three membraneassociatedprotein complexesthought tobe criticalfor epithelialpolarity.A Drosophilaepithelialcellis shownschematicallyon the left,and a vertebrateepithelialcellon the right.All threecomplex,complexes-thePa13-Pa16-aPkcthe Crumbscomplex,and the Scribblecomplex-are organizedaroundscaffoldproteinscontainingPDZdomains.Thedetaileddistributionof the complexesvariessomewhataccordingto celltype./ C r u m b sc o m p l e xa d h e r e n sj u n c t i o ntight junctionPar3-Par6-aPKCcomprex_\\ Cdc42lRacseptatejunctionS c r i b b l ec o m p l e xG o l g i a p p a r a t u s/_D r o s o p h i l ae p i t h e l i a lc e l lb a s a l a m i n a_v e r t e b r a t ee p i t h e l i a cl e l lcell-cell junctions-tight junctions in vertebrates, adherens junctions inDrosophila-because the scaffold proteins in the complex bind to the tails ofcertain of the junctional transmembrane adhesion proteins.
Meanwhile, thecltoskeleton, under the influence of Rac or its relatives, directs the delivery ofbasal lamina components to the opposite end of the cell. These extracellularmatrix molecules then act back on the cell to give that region a basal character(seeFigure 19-29C).In this way, the polarity of the cell is coupled to its orientation in the epithelial sheet and its relation to the basal lamina.Figure19-32 Planarcell polarity.(A)Winghairson the wing of a fly.Eachcellin thewing epitheliumformsone of theselittleor"hairs"atits apex,andspikyprotrusionsall the hairspointthe samewa, towardthe tip of the wing.Thisreflectsa planarpolarityin the structureof eachcell.(B)Sensoryhaircellsin the innerearof aplanarmousesimilarlyhavea well-definedpolarity,manifestin the orientedpattern(actin-filledprotrusions)onof stereociliatheir surface.Thedetectionof sounddeoendson the correct,coordinatedorientationof the haircells.(C)A mutationin the geneFlamingoin the fly,codingforcadherin,disruptsthea non-classicalpatternof planarcellpolarityin the wing.(D)A mutationin a homologousFlomingogenein the mouserandomizestheorientationof the planarcellpolarityvectorof the haircellsin the ear.Themutantmicearedeaf.(A and C,fromJ.
Chaeet al.,Development126:5421-5429,from TheCompany1999.With permissionCurtinetB and D,from .J.A.of Biologists;Withal.,Curr.Biol.13:1129-1133,2003.from Elsevier.)oermissionA SeparateSignalingSystemControlsPlanarCellPolarityApico-basal polarity is a universal feature of epithelia, but the cells of someepithelia show an additional polarity at right anglesto this axis:it is as if they hadan arrow written on them, pointing in a specific direction in the plane of theepithelium. This tlpe of polarity is called planar cell polarity (Figure l9-32Aand B).
In the wing of a fly, for example, each epithelial cell has a tiny asymmetrical projection, called a wing-hair, on its surface, and the hairs all point towardthe tip of the wing. Similarly, in the inner ear of a vertebrate, each mechanosensory hair cell has an asymmetric bundle of stereocilia (actin-filled rod-like protrusions) sticking up from its apical surface: tilting the bundle in one directioncausesion channels to open, stimulating the cell electrically; tilting in the opposite direction has the contrary effect. For the ear to function correctly, the haircells must be correctly oriented.
Planar cell polarity is important also in the respiratory tract, for example, where every ciliated cell must orient its beating so asto sweep mucus up out of the lungs, and not down into them (seeChapter 23).Screensfor mutants with disorderly wing hairs in Drosophilahave identifieda set of genes that are critical for planar cell polarity in the fly. Some of these,e p i d e r m acl e l l si n f l y w i n gs e n s o r yh a i r c e l l si n m o u s ee a rIe p i d e r m a cl e l l si n f l y w i n gs e n s o r yh a i r c e l l si n m o u s ee a rr(B)5pmW I L DT Y P E10 pLmFlamingoMUTANT1 158Chapter19:Cell Junctions,Cell Adhesion,and the ExtracellularMatrixsuch as Frizzled, for example, and Disheuelled, code for proteins that have sincebeen shown to be components of the Wnt signaling pathway (discussed inChapter 15).
Two others, Flamingo (seeFigure l9-32C) and Dachsous,code formembers of the cadherin superfamily. Still others are less easily classified functionally, but it is clear that planar cell polarity is organized by machinery formedfrom these components and assembled at cell-cell junctions in such a way thata polarizing influence can propagate from cell to cell. Essentiallythe same system of proteins controls planar cell polarity in vertebrates.Mice with mutationsin a Flamingo homolog, for example, have incorrectly oriented hair cells in theirears (among other defects) and thus are deaf (seeFigure l9-32D).Su m m a r yOccluding junctions-tight junctions in uertebrates,septatejunctions in insectsandmolluscs-seal the gaps betweencellsin epithelia, creating a barrier to the diffusion ofmoleculesacrossthe cell sheet.Theyalsoform a bar to the diffusion of proteins in theplane of the membrane,and so help to maintain a dffirence betweenthe populationsof proteins in the apical and basolateralmembrane domains of the epithelial cell.
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