Cellmatrix Adhesions

▲ FIGURE 6-1 Schematic overview of major adhesive interactions that bind cells to each other and to the extracellular matrix. Schematic cutaway drawing of a typical epithelial tissue, such as the intestines. The apical (upper) surface of these cells is packed with fingerlike microvilli 1 that project into the intestinal lumen, and the basal (bottom) surface & rests on extracellular matrix (ECM). The ECM associated with epithelial cells is usually organized into various interconnected layers (e.g., the basal lamina, connecting fibers, connective tissue), in which large, interdigitating ECM macromolecules bind to one another and to the cells 3. Cell-adhesion molecules (CAMs) bind to CAMs on other cells, mediating cell-cell adhesions 4|, and adhesion receptors bind to various components of the ECM, mediating cell-matrix adhesions 5. Both types of cell-surface adhesion molecules are usually integral membrane proteins whose cytosolic domains often bind to multiple intracellular adapter proteins. These adapters, directly or indirectly, link the CAM to the cytoskeleton (actin or intermediate filaments) and to intracellular signaling pathways. As a consequence, information can be transferred by CAMs and the macromolecules to which they bind from the cell exterior into the intracellular environment, and vice versa. In some cases, a complex aggregate of CAMs, adapters, and associated proteins is assembled. Specific localized aggregates of CAMs or adhesion receptors form various types of cell junctions that play important roles in holding tissues together and facilitating communication between cells and their environment. Tight junctions 6, lying just under the microvilli, prevent the diffusion of many substances through the extracellular spaces between the cells. Gap junctions 7| allow the movement through connexon channels of small molecules and ions between the cytosols of adjacent cells. The remaining three types of junctions, adherens junctions 8, spot desmosomes 9, and hemidesmosomes 10, link the cytoskeleton of a cell to other cells or the ECM. [See V. Vasioukhin and E. Fuchs, 2001, Curr. Opin. Cell Biol. 13:76.]

adhesion) through the binding of adhesion receptors in the plasma membrane to components of the surrounding extracellular matrix (ECM), a complex interdigitating meshwork of proteins and polysaccharides secreted by cells into the spaces between them. These two basic types of interactions not only allow cells to aggregate into distinct tissues but also provide a means for the bidirectional transfer of information between the exterior and the interior of cells.

In this chapter, we examine the various types of adhesive molecules and how they interact. The evolution of plants and animals is thought to have diverged before multicellular organisms arose. Thus multicellularity and the molecular means for assembling tissues and organs must have arisen independently in animal and plant lineages. Not surprisingly, then, animals and plants exhibit many differences in the organization and development of tissues. For this reason, we first consider the organization of epithelial and nonepithe-lial tissues in animals and then deal separately with plant tissues. Although most cells in living organisms exist within tissues, our understanding about cells depends greatly on the study 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*l| Cell-Cell and Cell-Matrix Adhesion: An Overview

We begin with a brief orientation to the various types of adhesive molecules, their major functions in organisms, and their evolutionary origin. In subsequent sections, we examine in detail the unique structures and properties of the various participants in cell-cell and cell-matrix interactions in animals.

Cell-Adhesion Molecules Bind to One Another and to Intracellular Proteins

A large number of CAMs fall into four major families: the cadherins, immunoglobulin (Ig) superfamily, integrins, and selectins. As the schematic structures in Figure 6-2 illustrate, many CAMs are mosaics of multiple distinct domains, many

Homophilic interactions

Cadherins lg-superfamily

(E-cadherin) CAMs (NCAM)

-Calcium-binding sites

Heterophil^ interactions

Integrins (avß3)

Integrins (avß3)

-'' Fibronectin

-'' Fibronectin

Selectins (P-selectin)


Cadherin domain

Ig domain

Type III () fibronectin repeat o

Lectin domain


-Calcium-binding sites

▲ FIGURE 6-2 Major families of cell-adhesion molecules (CAMs) and adhesion receptors. Dimeric E-cadherins most commonly form homophilic (self) cross-bridges with E-cadherins on adjacent cells. Members of the immunoglobulin (Ig) superfamily of CAMs can form both homophilic linkages (shown here) and heterophilic (nonself) linkages. Selectins, shown as dimers, contain a carbohydrate-binding lectin domain that recognizes specialized sugar structures on glycoproteins (shown here) and glycolipids on adjacent cells. Heterodimeric integrins (for example, av and p3 chains) function as CAMs or as adhesion receptors (shown here) that bind to very large, multiadhesive matrix proteins such as fibronectin, only a small part of which is shown here (see also Figure 6-25). Note that CAMs often form higher-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. The cytoplasmic domains of these proteins are often associated with adapter proteins that link them to the cytoskeleton or to signaling pathways. [See R. O. Hynes, 1999, Trends Cell Biol. 9(12):M33, and R. O. Hynes, 2002, Cell 110:673-687.]

of which can be found in more than one kind of CAM. They are called "repeats" when they exist multiple times in the same molecule. Some of these domains confer the binding specificity that characterizes a particular protein. Some other membrane proteins, whose structures do not belong to any of 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 (homotypic adhesion) or between cells of different types (heterotypic adhesion). A CAM on one cell can directly bind to the same kind of CAM on an adjacent cell (homophilic binding) or to a different class of CAM (heterophilic binding). CAMs can be broadly distributed along the regions of plasma membranes that contact other cells or clustered in discrete patches or spots called celljunctions. Cell-cell adhesions can be tight and 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 and pass 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 adapters act as linkers that directly or indirectly connect CAMs to elements of the cytoskeleton (Chapter 5); they can also recruit intracellular molecules that function in signaling pathways to control protein activity and gene expression (Chapters 13 and 14). In some cases, a complex aggregate of CAMs, adapter proteins, and other associated proteins is assembled at the inner surface of the plasma membrane. Because cell-cell adhesions are intrinsically associated with the cy-toskeleton and signaling pathways, a cell's surroundings influence its shape and functional properties ("outside-in"

▲ FIGURE 6-3 Schematic model for the generation of cell-cell adhesions. Lateral Interactions between cell-adhesion molecules (CAMs) within the plasma membrane of a cell form dimers and larger oligomers. The parts of the molecules that participate in these cis interactions vary among the different effects); likewise, cellular shape and function influence a cell's surroundings ("inside-out" effects). Thus connectivity and communication are intimately related properties of cells in tissues.

The formation of many cell-cell adhesions entails two types of molecular interactions (Figure 6-3). First, CAMs on one cell associate laterally through their extracellular domains or cytosolic domains or both into homodimers or higher-order oligomers in the plane of the cell's plasma membrane; these interactions are called intracellular, lateral, or cis interactions. Second, CAM oligomers on one cell bind to the same or different CAMs on an adjacent cell; these interactions are called intercellular or trans interactions. Trans interactions sometimes induce additional cis interactions and, as a consequence, yet even more trans interactions.

Adhesive interactions between cells vary considerably, depending on the particular CAMs participating and the tissue. Just like Velcro, very tight adhesion can be generated when many weak interactions are combined together in a small, well-defined area. Furthermore, the association of in-tracellular molecules with the cytosolic domains of CAMs can dramatically influence the intermolecular interactions of CAMs by promoting their cis association (clustering) or by altering their conformation. Among the many variables that determine the nature of adhesion between two cells are the binding affinity of the interacting molecules (thermodynamic properties); the overall "on" and "off" rates of association and dissociation for each interacting molecule (kinetic properties); the spatial distribution (clustering, high or low density) of adhesion molecules (geometric properties); the active versus 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).

CAMs. Subsequent trans interactions between distal domains of CAMs on adjacent cells generate a zipperlike strong adhesion between the cells. [Adapted from M. S. Steinberg and P M. McNutt, 1999, Curr. Opin. Cell Biol. 11:554.]

The Extracellular Matrix Participates in Adhesion and Other Functions

Certain cell-surface receptors, including some integrins, can bind components of the extracellular matrix (ECM), thereby indirectly adhering cells to each other through their interactions with the matrix. Three abundant ECM components are proteoglycans, a unique type of glycoprotein; collagens, proteins that often form fibers; and soluble multiadhesive matrix proteins (e.g., fibronectin). The relative volumes of cells versus matrix vary greatly among different animal tissues and organs. Some connective tissue, for instance, is mostly matrix, whereas many organs are composed of very densely packed cells with relatively little matrix.

Although the extracellular matrix generally provides mechanical support to tissues, it serves several other functions as well. Different combinations of ECM components tailor the extracellular matrix for specific purposes: strength in a tendon, tooth, or bone; cushioning in cartilage; and adhesion in 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 and what it should do (environmental cues). Changes in ECM components, which are constantly being remodeled, degraded, and resynthesized locally, can modulate the interactions of a cell with its environment. The matrix also serves as a reservoir for many extracellular signaling molecules that control 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. Morpho-genesis—the later stage of embryonic development in which tissues, organs, and body parts are formed by cell movements and rearrangements—also is critically dependent on cellmatrix adhesion as well as cell-cell adhesion.

Diversity of Animal Tissues Depends on Evolution of Adhesion Molecules with Various Properties

Cell-cell adhesions and cell-matrix adhesions are responsible for the formation, composition, architecture, and function of animal tissues. Not surprisingly, adhesion molecules of animals are evolutionarily ancient and are some of the most highly conserved proteins among multicellular (metazoan) organisms. Sponges, the most primitive metazoans, express certain CAMs and multiadhesive ECM molecules whose structures are strikingly similar to those of the corresponding human proteins. The evolution of organisms with complex tissues and organs has depended on the evolution of diverse CAMs, adhesion receptors, and ECM molecules with novel properties and functions, whose levels of expression differ in different types of cells.

The diversity of adhesive molecules arises in large part from two phenomena that can generate numerous closely related proteins, called isoforms, that constitute a protein fam ily. In some cases, the different members of a protein family are encoded by multiple genes that arose from a common ancestor by gene duplication and divergent evolution (Chapter 9). Analyses of gene and cDNA sequences can provide evidence for the existence of such a set of related genes, or gene family. In other cases, a single gene produces an RNA transcript that can undergo alternative splicing to yield multiple mRNAs, each encoding a distinct isoform (Chapter 4). Alternative splicing thus increases the number of proteins that can be expressed from one gene. Both of these phenomena contribute to the diversity of some protein families such as the cadherins. Particular isoforms of an adhesive protein are often expressed in some cell types but not others, accounting for their differential distribution in various tissues.

Was this article helpful?

0 0
Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook

Post a comment