H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 82
Текст из файла (страница 82)
Although most cells in living organisms exist withintissues, our understanding about cells depends greatly on thestudy of isolated cells. Hence, we present some general fea-tures of working with populations of cells removed from tissues and organisms in the last section of this chapter.6.1 Cell–Cell and Cell–MatrixAdhesion: An OverviewWe begin with a brief orientation to the various types of adhesive molecules, their major functions in organisms, andtheir evolutionary origin.
In subsequent sections, we examinein detail the unique structures and properties of the various participants in cell–cell and cell–matrix interactions inanimals.Cell-Adhesion Molecules Bind to One Anotherand to Intracellular ProteinsA large number of CAMs fall into four major families: thecadherins, immunoglobulin (Ig) superfamily, integrins, andselectins. As the schematic structures in Figure 6-2 illustrate,many CAMs are mosaics of multiple distinct domains, manyHomophilic interactionsCadherins(E-cadherin)199Heterophilic interactionslg-superfamilyCAMs (NCAM)Selectins(P-selectin)Integrins(αvβ3)CalciumbindingsitesFibronectinSugarsCadherindomainIg domainType IIIfibronectinrepeat▲ FIGURE 6-2 Major families of cell-adhesion molecules(CAMs) and adhesion receptors.
Dimeric E-cadherins mostcommonly form homophilic (self) cross-bridges with E-cadherinson adjacent cells. Members of the immunoglobulin (Ig)superfamily of CAMs can form both homophilic linkages (shownhere) and heterophilic (nonself) linkages. Selectins, shown asdimers, contain a carbohydrate-binding lectin domain thatrecognizes specialized sugar structures on glycoproteins (shownhere) and glycolipids on adjacent cells. Heterodimeric integrins(for example, v and 3 chains) function as CAMs or as adhesionGlycoproteinLectindomainreceptors (shown here) that bind to very large, multiadhesivematrix proteins such as fibronectin, only a small part of which isshown here (see also Figure 6-25).
Note that CAMs often formhigher-order oligomers within the plane of the plasma membrane.Many adhesive molecules contain multiple distinct domains,some of which are found in more than one kind of CAM. Thecytoplasmic domains of these proteins are often associated withadapter proteins that link them to the cytoskeleton or to signalingpathways. [See R. O. Hynes, 1999, Trends Cell Biol. 9(12):M33, andR. O. Hynes, 2002, Cell 110:673–687.]200CHAPTER 6 • Integrating Cells into Tissuesof which can be found in more than one kind of CAM. Theyare called “repeats” when they exist multiple times in thesame molecule.
Some of these domains confer the bindingspecificity that characterizes a particular protein. Some othermembrane proteins, whose structures do not belong to anyof the major classes of CAMs, also participate in cell–cell adhesion in various tissues.CAMs mediate, through their extracellular domains, adhesive interactions between cells of the same type (homotypicadhesion) or between cells of different types (heterotypicadhesion).
A CAM on one cell can directly bind to the samekind of CAM on an adjacent cell (homophilic binding) or toa different class of CAM (heterophilic binding). CAMs canbe broadly distributed along the regions of plasma membranes that contact other cells or clustered in discrete patchesor spots called cell junctions. Cell–cell adhesions can be tightand long lasting or relatively weak and transient. The associations between nerve cells in the spinal cord or the metabolic cells in the liver exhibit tight adhesion. In contrast,immune-system cells in the blood can exhibit only weak,short-lasting interactions, allowing them to roll along andpass through a blood vessel wall on their way to fight an infection within a tissue.The cytosol-facing domains of CAMs recruit sets of multifunctional adapter proteins (see Figure 6-1).
These adaptersact as linkers that directly or indirectly connect CAMs to elements of the cytoskeleton (Chapter 5); they can also recruitintracellular molecules that function in signaling pathways tocontrol protein activity and gene expression (Chapters 13and 14). In some cases, a complex aggregate of CAMs,adapter proteins, and other associated proteins is assembledat the inner surface of the plasma membrane.
Becausecell–cell adhesions are intrinsically associated with the cytoskeleton and signaling pathways, a cell’s surroundingsinfluence its shape and functional properties (“outside-in”effects); likewise, cellular shape and function influence acell’s surroundings (“inside-out” effects). Thus connectivityand communication are intimately related properties of cellsin tissues.The formation of many cell–cell adhesions entails twotypes of molecular interactions (Figure 6-3). First, CAMson one cell associate laterally through their extracellulardomains or cytosolic domains or both into homodimersor higher-order oligomers in the plane of the cell’s plasmamembrane; these interactions are called intracellular, lateral, or cis interactions.
Second, CAM oligomers on onecell bind to the same or different CAMs on an adjacentcell; these interactions are called intercellular or trans interactions. Trans interactions sometimes induce additionalcis interactions and, as a consequence, yet even more transinteractions.Adhesive interactions between cells vary considerably,depending on the particular CAMs participating and the tissue. Just like Velcro, very tight adhesion can be generatedwhen many weak interactions are combined together in asmall, well-defined area. Furthermore, the association of intracellular molecules with the cytosolic domains of CAMscan dramatically influence the intermolecular interactions ofCAMs by promoting their cis association (clustering) or byaltering their conformation.
Among the many variables thatdetermine the nature of adhesion between two cells are thebinding affinity of the interacting molecules (thermodynamicproperties); the overall “on” and “off” rates of associationand dissociation for each interacting molecule (kinetic properties); the spatial distribution (clustering, high or low density) of adhesion molecules (geometric properties); the activeversus inactive states of CAMs with respect to adhesion (biochemical properties); and external forces such as the laminar and turbulent flow of cells in the circulatory system(mechanical properties).CELL 1Cis + trans+Cis(lateral)Trans+Cis(lateral)TransCis + transCELL 2▲ FIGURE 6-3 Schematic model for the generation ofcell–cell adhesions.
Lateral interactions between cell-adhesionmolecules (CAMs) within the plasma membrane of a cell formdimers and larger oligomers. The parts of the molecules thatparticipate in these cis interactions vary among the differentCAMs. Subsequent trans interactions between distal domains ofCAMs on adjacent cells generate a zipperlike strong adhesionbetween the cells.
[Adapted from M. S. Steinberg and P. M. McNutt,1999, Curr. Opin. Cell Biol. 11:554.]6.2 • Sheetlike Epithelial Tissues: Junctions and Adhesion MoleculesThe Extracellular Matrix Participatesin Adhesion and Other FunctionsCertain cell-surface receptors, including some integrins, canbind components of the extracellular matrix (ECM), therebyindirectly adhering cells to each other through their interactions with the matrix. Three abundant ECM components areproteoglycans, a unique type of glycoprotein; collagens, proteins that often form fibers; and soluble multiadhesive matrixproteins (e.g., fibronectin). The relative volumes of cells versus matrix vary greatly among different animal tissues andorgans. Some connective tissue, for instance, is mostly matrix, whereas many organs are composed of very denselypacked cells with relatively little matrix.Although the extracellular matrix generally provides mechanical support to tissues, it serves several other functionsas well.
Different combinations of ECM components tailorthe extracellular matrix for specific purposes: strength in atendon, tooth, or bone; cushioning in cartilage; and adhesionin most tissues. In addition, the composition of the matrix,which can vary, depending on the anatomical site and physiological status of a tissue, can let a cell know where it is andwhat it should do (environmental cues).
Changes in ECMcomponents, which are constantly being remodeled, degraded, and resynthesized locally, can modulate the interactions of a cell with its environment. The matrix also serves asa reservoir for many extracellular signaling molecules thatcontrol cell growth and differentiation. In addition, the matrix provides a lattice through or on which cells can move,particularly in the early stages of tissue assembly. Morphogenesis—the later stage of embryonic development in whichtissues, organs, and body parts are formed by cell movementsand rearrangements—also is critically dependent on cell–matrix adhesion as well as cell–cell adhesion.Diversity of Animal Tissues Dependson Evolution of Adhesion Moleculeswith Various PropertiesCell–cell adhesions and cell–matrix adhesions are responsiblefor the formation, composition, architecture, and function ofanimal tissues. Not surprisingly, adhesion molecules of animals are evolutionarily ancient and are some of the mosthighly conserved proteins among multicellular (metazoan)organisms.
Sponges, the most primitive metazoans, expresscertain CAMs and multiadhesive ECM molecules whosestructures are strikingly similar to those of the correspondinghuman proteins. The evolution of organisms with complextissues and organs has depended on the evolution of diverseCAMs, adhesion receptors, and ECM molecules with novelproperties and functions, whose levels of expression differin different types of cells.The diversity of adhesive molecules arises in large partfrom two phenomena that can generate numerous closely related proteins, called isoforms, that constitute a protein fam-201ily.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
