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In this and other ways, practically all the classesof cell-cell and cell-matrix adhesion molecules that we have mentioned, including integrins, are deployed to help guide axon outgrowth in the developing nervous system.Table l9-5 summarizes the categories of cell adhesion molecules that wehave considered in this chapter. In the next section, we turn from the adhesionmolecules in cell membranes to look in detail at the extracellularmatrix that surrounds cells in connective tissues.T a b l e1 9 - 5 C e l lA d h e s i o nM o l e c u l eF a m i l i e sORHOMOPHILICHETEROPHILIChomophilicactin filaments(viacatenins)intermediatefilaments(viadesmoplakin,p l a k o g l o b i na, n dplakophilin)junctions,adherenssynapsesoesmoS0mesN-CAM,ICAM nobothunKnownyesL-,E-,andP-selectinsheterophilicactin filamentsn e u r o n aal n dimmunologicalsynapses(no prominentjunctionalstructure)yesheterophilicactin filamentsmanyrypesyesheterophilica6B4yesheterophilicsyndecansnoheterophilicfocal adhesionsactin filaments(viat a l i n ,p a x i l l i nf,i l a m i n ,u - a c t i n i na, n d v i n c u l i n )hemidesmosomesintermediatefilaments(via plectin and dystonin)(no prominentjunctionalactin filamentsstructure)yeshomophilicdesmoglein, yesdesmocollinlg family membersSelectins(blood cellsa n d e n d o t h e l i acl e l l sonty)E,N,BVEI n t e g r i n so n b l o o d c e l l s gLB2(LFA1)immunologicalsynapsesCell-Matrix AdhesionIntegrinsTransmembraneproteoglycans1'178 Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixSumm a r yIntegrins are the principal receptorsused by animal cells to bind to the extracellularmatrix: theyfunction as transmembranelinkers betweenthe extracellular matrix andthe cytoskeletonconnecting usually to actin, but to intermediateftlaments for the specialized integrins at hemidesmosomes.Integrin moleculesare heterodimers,and thebinding of ligands is associatedwith dramatic changesof conformation.
This createsan allosteric coupling betweenbinding to matrix outside the cell and binding to thecytoskeletoninside it, allowing the integrin to conueysignals in both directions acrossthe plasma membrane-from inside to out and from outside to in. Binding of theintracellular anchor protein talin to the tail of an integrin molecule tends to driue theintegrin into an extendedconformation with increasedffinity for its extracellular ligand. Conuersely,binding to an extracellular ligand, by promoting the sameconformational change, leads to binding of talin and formation of a linkage to the actincytoskeleton.Complex assembliesof proteins becomeorganized around the intracellular tails of integrins, producing intracellular signals that can influence almost anyaspectof cell behauiorfrom proliferation and suruiual, as in the phenomenonofanchoragedependence,to cell polarity and guidance of migration.THEEXTRACELLULARMATRIXOFANIMALCONNECTIVETISSUESWe have already discussed the basal lamina as an archetypal example of extracellular matrix, common to practically all multicellular animals and an essentialfeature of epithelial tissues.We now turn to the much more varied and bulkyforms of extracellular matrix found in connective tissues (Figure 19-53).
Here,the extracellular matrix is generally more plentiful than the cells it surrounds,and it determines the tissue'sphysical properties.The classesof macromolecules constituting the extracellular matrix in animal tissues are broadly similar, whether we consider the basal lamina or theother forms that matrix can take, but variations in the relative amounts of thesedifferent classesof molecules and in the ways in which they are organized giverise to an amazing diversity of materials.
The matrix can become calcified toform the rock-hard structures of bone or teeth, or it can form the transparentsubstance ofthe cornea, or it can adopt the ropelike organization that gives tendons their enormous tensile strength. It forms the jelly in a jellyfish. covering thebody of a beetle or a lobster, it forms a rigid carapace.Moreover, the extracellular matrix is more than a passive scaffold to provide physical support. It has anactive and complex role in regulating the behavior of the cells that touch it,inhabit it, or crawl through its meshes, influencing their survival, development,migration, proliferation, shape, and function.In this section, we focus our discussion on the extracellular matrix of connective tissues in vertebrates, but bulky forms of extracellular matrix play anepitheliumf *basal aminaI I Cor* *c o l l a g e nf i b e r lmacrophagefcapillaryUe l a s t i cf i b e rfibroblastm a s tc e l lFUzzh y al u r o n an ,proteoglycans,andglycoproteinsl50pmFigure 19-53 The connectivetissueunderlyingan epithelium.Thistissuecontainsa varietyof cellsand extracellularmatrixcomponents.The predominantcelltype is the fibroblast,which secretesabundantextracellularmatrix.THEEXTRACELLULARMATRIXOFANIMALCONNECTIVETISSUES1179important part in virtually all multicellularorganisms;examplesinclude thecuticlesof worms and insects,the shellsof mollusks,the cellwallsof fungi,and,aswe discusslater,the cellwalls of plants.TheExtracellularMatrixls Madeand Orientedby the CellsWithinltThe macromolecules that constitute the extracellular matrix are mainly produced locally by cells in the matrix.
As we discuss later, these cells also help toorganize the matrix the orientation of the cltoskeleton inside the cell can control the orientation of the matrix produced outside. In most connective tissues,the matrix macromolecules are secreted largely by cells called fibroblasts (Figure 19-54). In certain specialized tlpes of connective tissues, such as cartilageand bone, however, they are secreted by cells of the fibroblast family that havemore specific names: chondroblasfs, for example, form cartilage, and,osteoblastsform bone.The matrix in connective tissue is constructed from the same two mainclassesof macromolecules as in basal laminae: (1) glycosaminoglycan polysaccharide chains, usually covalently linked to protein in the form of proteoglycans,and (2) fibrous proteins such as collagen.We shall see that the members of bothclassescome in a great variety of shapes and sizes.The proteoglycan molecules in connective tissue tlpically form a highlyhydrated, gel-like "ground substance" in which the fibrous proteins are embedded.
The polysaccharide gel resists compressive forces on the matrix while permitting the rapid diffusion of nutrients, metabolites, and hormones between theblood and the tissue cells.The collagen fibers strengthen and help organize thematrix, while other fibrous proteins, such as the rubberlike elastin, give itresilience. Finally, many matrix proteins help cells migrate, settle, and differentiate in the appropriate locations.10lt.in connectiveFigure19-54 Fibroblaststissue.Thisscanningelectronmicrographshowstissuefrom the corneaof a rat.The extracellularmatrixis herethe fibroblastssurroundingcomposedlargelyof collagenfibrils.Theglycoproteins,andhyaluronan,proteoglycans,whichnormallyform aof thehydratedgel fillingthe intersticesfibrousnetwork,havebeen removedbyenzymeand acidtreatment.(FromT.
Nishidaet al.,lnvest.Ophtholmol.Vis.Sci.29:1887-'l 890,1988.With permissionfrom Associationfor Researchin Visionand Opthalmology.)(GAG)ChainsOccupyLargeAmountsofGlycosaminoglycanSpaceand FormHydratedGelsGlycosaminoglycans (GAGs) are unbranched polysaccharide chains composedof repeating disaccharide units. They are called GAGs because one of the twosugars in the repeating disaccharide is always an amino sugar (-0y'-acetylglucosamine or l/-acetylgalactosamine), which in most casesis sulfated.
The second sugar is usually a uronic acid (glucuronic or iduronic). Becausethere aresulfate or carboryl groups on most of their sugars, GAGs are highly negativelycharged (Figure l9-55). Indeed, they are the most anionic molecules producedby animal cells. Four main groups of GAGsare distinguished by their sugars,theti,pe of linkage between the sugars, and the number and location of sulfategroups: (l) hyaluronan, (2) chondroitin sulfate and dermatan sulfate, (3) heparan sulfate, and (4) keratan su$ote.Polysaccharide chains are too stiff to fold up into the compact globularstructures that pollpeptide chains typically form. Moreover, they are stronglyhydrophilic. Thus, GAGs tend to adopt highly extended conformations thatoccupy a huge volume relative to their mass (Figure f 9-56), and they form gelscooccH2osocoocN - a c e t y l g l u c o s a m i n eg l u c u r o n i ca c i dr e p e a t i n gd i s a c c h a r i d ecH2osoFigureI 9-55 The repeatingdisaccharidesequenceof a heparansulfateglycosaminoglycan(GAG)chain.Thesechainscan consistof as manyas200units,but aretypicallylessdisaccharidethan halfthat size.Thereis a high densityof negativechargesalongthe chaindueto the presenceof both carboxylandsulfategroups.The proteoglycansof theandbasallamina-perlecan,dystroglycan,collagenXVlll-all carryheparansulfateThe moleculeis shownherewith itsGAGs.maximafnumber of sulfategroups.ln vivo,the proportionof sulfatedandgroupsis variable.Heparinnonsulfatedsulfation,whiletypicallyhas>70o/oheparansulfatehas <500/o.1'l80Chapter19:Cell Junctions,Cell Adhesion,and the ExtracellularMatrixeven at very low concentrations.
The weight of GAGsin connective tissue is usually less than l0% of the weight of the fibrous proteins. But, because they formporous hydrated gels, the GAG chains fill most of the extracellular space.Theirhigh density of negative charges attracts a cloud of cations, especially Na+,thatare osmotically active, causing large amounts of water to be sucked into thematrix.
This creates a swelling pressure, or turgor, that enables the matrix towithstand compressive forces (in contrast to collagen fibrils, which resiststretching forces).The cartilage matrix that lines the knee joint, for example, cansupport pressuresof hundreds of atmospheres in this way.Defects in the production of GAGs can affect many different body systems.In one rare human genetic disease,for example, there is a severe deficiency inthe synthesis of dermatan sulfate disaccharide.The affected individuals have ashort stature, prematurely aged appearance, and generalized defects in theirskin, joints, muscles, and bones.In invertebrates, plants, and fungi, other types of polysaccharides, ratherthan GAGs,often dominate the extracellular matrix.
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