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Some integrins, for example,mediate cell-cell rather than cell-matrix attachment. Moreover, there are othertypes of cell adhesion molecules that can provide attachments more flimsy thananchoring junctions, but sufficient to stick cells together in special circumstances.Cell-cell adhesions based on cadherins. however, seem to be the mostfundamentally important class,and we begin our account of cell-cell adhesionwith them.
<CGAA>CadherinsMediateCa2*-DependentCell-CellAdhesionin AllAn i m a l sCadherins are present in all multicellular animals whose genomes have beenanalyzed, and in one other knor,rrngroup, the choanoflagellates.These creaturescan exist either as free-living unicellular organisms or as multicellular coloniesand are thought to be representativesof the group of protists from which all animals evolved.
Other eucaryotes,including fungi and plants, Iack cadherins, andthey are absent from bacteria and archaea also. Cadherins therefore seem to bepart of the essenceof what it is to be an animal.The cadherins take their name from their dependence on Ca2*ions: removing Ca2* from the extracellular medium causes adhesions mediated by cadherins to come adrift. Sometimes, especially for embryonic tissues, this isenough to let the cells be easily separated. In other cases,a more severetreatment is required, combining Ca2*removal with exposure to a protease such astrypsin.
The protease loosens additional connections mediated by extracellularmatrix and by other cell-cell adhesion molecules that do not depend on Ca2*.Ineither case, when the dissociated cells are put back into a normal culturemedium, they will generally stick together again by reconstructing their adhesions.This tlpe of cell-cell associationprovided one of the first assaysthat allowedcell-cell adhesion molecules to be identified. In these experiments, monoclonalantibodies were raised against the cells of interest, and each antibodywas testedfor its ability to prevent the cells from sticking together again after they had beendissociated. Rare antibodies that bound to the cell-cell adhesion moleculesshowed this blocking effect. These antibodies then were used to isolate theadhesion molecule that they recognized.Virtually all cells in vertebrates, and probably in other animals too, seem toexpressone or more proteins of the cadherin family, according to the cell type.c[-catenin,B-catenin,plakoglobin (lcatenin;,p 12 0 - c a t e n i nv,i n c u l i n ,c[-actininplakoglobin (y-catenin),plakophilin,desmoplakin1136Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrix'1.5days3 .
5d a y s2 cells32 cellsSeverallines of evidence indicate that they are the main adhesion molecules holding cells together in early embryonic tissues. For example, embryonic tissues inculture disintegrate when treated with anti-cadherin antibodies, and if cadherinmediated adhesion is Ieft intact, antibodies against other adhesion moleculeshave little effect. Studies of the early mouse embryo illustrate the role of cadherinsin development. Up to the eight-cell stage, the mouse embryo cells are only veryloosely held togetheS remaining individually more or less spherical; then, rathersuddenly, in a process called compaction, they become tightly packed togetherand joined by cell-cell junctions, so that the outer surface of the embryo becomessmoother (Figure l$-5).
Antibodies against a specific cadherin, caTledE-cadherin,block compaction, whereas antibodies that react with various other cell-surfacemolecules on these cells do not. Mutations that inactivate E-cadherin cause theembryos to fall apart and die early in development.1oPmFigure19-5 Compactionof an earlymouseembryo.Thecellsof the earlyembryoat firststicktogetheronlyweakly.At about the eight-cellstage,they beginto expressE-cadherinand asa resultbecomestronglyand closelyadherentto one another.(Scanningelectronmicrographscourtesyof PatriciaCalarco;16-32-cellstageisfromP.Calarcoand C.J.Epstein,Dev.Biol.32:208-213,1973.With permissionfromAcademicPress.)TheCadherinSuperfamilyin VertebratesIncludesHundredsofDifferentProteins,IncludingManywith SignalingFunctionsThe first three cadherins that were discovered were named according to themain tissues in which they were found: E-cadherin is present on many types ofepithelial cells; N-cadherin on nerve, muscle, and lens cells; and p-cadherin oncells in the placenta and epidermis.
All are also found in various other tissues;Ncadherin, for example, is expressedin fibroblasts, and E-cadherin is expressedinparts ofthe brain (Figure 19-6). These and other classical cadherins are closelyrelated in sequence throughout their extracellular and intracellular domains.vtrhile all of them have well-defined adhesive functions, they are also importantin signaling.
Through their intracellular domains, as we shall see later, they relayinformation into the cell interior, enabling the cell to adapt its behavior according to whether it is attached or detached from other cells.There are also a large number of nonclassical cadherins more distantlyrelated in sequence,with more than 50 expressedin the brain alone. The nonclassical cadherins include proteins with known adhesive function, such as thediverse protocadherlrzsfound in the brain, and the desmocollinsand, desmogleinsthat form desmosome junctions.
They also include proteins that appear to beprimarily involved in signaling, such as T-cadherin, which lacks a transmembrane domain and is attached to the plasma membrane of nerve and muscleE-cadherinR-cadherincadherin-6Figure19-6 Cadherindiversityin thecentral nervoussystem,The diagramshowsthe expressionpatternsofthreedifferentclassicalcadherinsin theembryonicmousebrain.Morethan70 othercadherins,both classicalandnonclassical,arealsoexpressedin thebrain,in complexpatternsthat arethoughtto reflecttheir rolesin guidingand maintainingthe organizationof thisintricateoroan.satrs 01 purq suor +zBO'(96-6I ernBIC)e8uq e ,r(qururuop ulraqpss ueu eqt olpaurof 'lpn p€rr ssalJo eJoruE sruJoJuletuop uIJaqpEJqJeg '0t ueqt eJou eleqsurJaqpef,IporssplJuouetuos lnq'g Jo t eJBeJeql suqloJoruseppue sutalSorusapur pue 'sleadar eseql Jo g eJe eJaql saleJqauel Jo sulJeqpec IucIssPIJeql uI'urDtuop uuaqpul eql pelleJJlloru e;o satdoc pralas Jo Supslsuoc uoprod repl-laJeJtxa ue eleq 'uop1ugep ,(q flruregradns eq] Jo sraqruelu eql 11V'selnJeloruuuaqppr Suqedrcured eqt Jo ernlcnrls eql uo spuadap pue paugap dlasrc-ard sr uorlcunf Surroqcue uu le seueJqruau IIeo eql ueem]aq Surceds aq1'(V6-6I arn81g)Jeqlo aqlJo 1a1codeq] ur euo qJee Jo qoDI eql Jo uoluasul,iq pulq seuuJqrueu lac alrsoddo ruo4 Sutpnrlord salnoeloru ulJeqpeJ eqlpue 'lalcod rtqreau e pue qoDI IeuIIuJa] € sruJoJeJeq uleqJ utalord eqJ 'auuJq-tueu eql tuoq tsequrg aITteq] spue eql-selnf,alou ulreqpeJ aql;o sdp pu-ruJal-N aqt tE sJnJJoSurpurq aql 'laporu lueJJnJ e o1Sutproccy's1ac luacefpeuo addlqns palelar flasolc Jo arues eI{}Jo sapceloru ulJeqpeJ ol pulq IIaJ auo uoadfiqns cgrcadse Jo se1ncalou urreqpef, :(g-51 arnS1g'a4u-o1-a4l) cg;qdouoq,{leraua8 sr surJaqpeJueemlaq Surpurq eql 'IJEJuI 'osle apls Jeqlo aql uo IIeJeqt ul ul]oe ol aq IIIM lr 'uorlcunf aq]Jo apISauo uo IIao eq] ur 'aldruexaroJ 'uI]Jeo1 sr a8e1u11eql JI :lecrJleururrts,{ypnsn eJE slleJ uee \laq suotpunf Sutroqcuyuorseqpv)!l!qdouoHalerpewsulreqpe)atuaql Jo,{ueru os eJeq} eJedq,,r,tpue 'suor}JunJ Jreql ol e}eleJ sula}ord asaql So seJnlonJlsaql op ^loH 'suprunq ur sreqrxeur 0BI ueql eroru qlyv\ '(s-6I aIqBI puB 2-6Iarn81g) flgrrugradns ulJaqpuJ eql e]n]psuoc sura]ord urJeqpeJ IpJISselJuou pue'l.lantpadsar 'a1e1n8ar'raqta3ol .{lgeyodIIeJ pue qlr'tor8 pllaqrrdaIucrsselJ aql'sutetordler4laptldosot6' ur saua8go slcnpord aql se palJlluepl ]sJIJaJa^ qolqmoBulwa1g pue rul aql pue 'roqrue (IdC) Iolrsoullrtppuqdsoqdflsocd13 e t(q s11acuv'rn'r'r3)vulx3u\fln1'll)vurNluuaqpe)-l6 qprd)suuaqpe)oloJo(€zqpl)€z uuoqpe)(urllo)otusep)uuaqpe) leuJosoursap(lau)s u u a q p e )e s e u r lu r a l o .
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