While cells exist in the organism in various environments of extracellular matrix, both epithelial and mesenchymal cells interact directly with each other to form stable arrangements, as in epi- dermis and glandular and mucosal epithelium; they also undergo transient interactions involving lymphocytes in nodes and lymphoid organs, polymorphonuclear leukocytes, and macrophages. These cell-cell interactions form the basis for the architecture of tissues as well as their morpho- genesis (Gumbiner, 1996). Both stable and transient cellular adhesions are the result of the inter- action of ectoproteins of the plasma membrane interacting with each other on different or the same cell types as well as an interaction with the ECM. Diagrams of the structure of the four major molecular species of cell adhesion molecules are given in Figure 10.4. Each of these mo- lecular species consists of a single transmembrane polypeptide with the exception of the inte- grins, which are heterodimers, an α and a β chain. The α subunit provides the molecular basis for ligand binding, while the β subunit is the major link to the cytoskeleton and signal transduc- tion apparatus. At least 15 α subunits and 8 β subunits are known, giving rise to at least 19 different integrins (cf. Elangbam et al., 1997). Various members of the integrin family function in a variety of ways in different cell types, including embryogenesis, wound healing, and the immune response. These functions involve cell migration, cell-cell adhesion, and cell-ECM in- teraction, as well as signaling molecules, the latter primarily through the β integrins (LaFlamme and Aver, 1996). They are the most widely distributed adhesion molecules in mammalian organ- isms and possibly the most versatile (Faull, 1995). The extracellular heterodimeric portion of the molecule serves as a receptor for a variety of ligands, including collagen, laminin, fibronectin, fibrinogen, and several other cell adhesion proteins as well (Faull, 1995). The intracellular por- tion of these molecules, in turn, interacts with the cytoskeleton (Chapter 16) allowing for poten- tial signal transduction mechanisms (see below).
The immunoglobulin family of molecules involved in cell adhesion are products of the immunoglobulin gene superfamily, which is discussed further in Chapter 17. Members of this family are linked to the plasma membrane as shown in Figure 10.4 and are involved in protein recognition, a process essential in the immune response (Chapter 19) as well as in cell adhesion. A short list of members of the immunoglobulin gene superfamily that are involved in cell adhe- sion is seen in Table 10.3. These adhesion molecules are expressed extensively on lymphocytes and other members of the immune system as well as in vascular endothelial cells and cells of the nervous system (Turner, 1992). One member of the family, NCAM, is a primary cell adhesion
Figure 10.4 Diagrams of the molecular structure of families of cell adhesion molecules. See text for explanation. (Adapted from Garrod, 1993, with permission of the author and publisher.)
molecule that appears very early in development in all three germ layers and plays a very impor- tant role in the development of the central nervous system. Many other members of the family are involved in the relatively transient interaction of leukocytes, macrophages, and related cells in the vascular system during tissue injury, inflammation, and related processes. The selectins play a similar role in these processes in that they are expressed on the surface of endothelial cells, leukocytes, and platelets. These molecules influence the localization of circulating leuko- cytes on the endothelium at the site of inflammation. Members of this family are involved in a
Table 10.3 Adhesion Molecules of the Immunoglobulin Gene Superfamily
very early period of immune-inflammatory reactions as well as in the “homing” of lymphocytes to various places in the organism (Elangbam et al., 1997). The ligands for the selectins are car- bohydrate moieties on protein molecules, such as mucins and sialated polysaccharide antigens on cell surfaces (Faull, 1995). A major contribution to cell-cell adhesion is made by calcium- dependent cadherins. These are simple transmembrane glycoproteins involved in establishing and maintaining intercellular connections through homophilic binding—i.e., a cadherin mole- cule on one cell binds to another cadherin molecule of the same type on an adjacent cell. The cytoplasmic domain of cadherins is linked to cellular components through catenins, proteins that are necessary for cadherin function (cf. Garrod, 1993). Three subclasses of cadherins have been recognized: epithelial (E)-cadherin or uvomorulin, placental (P)-cadherin, and neural (N)- cadherin (Elangbam et al., 1997). Cadherins function in cell-cell adhesion by clustering on the plasma membrane to form adhesion junctions. Interactions between cells involve the N-terminal cadherin repeat domain, potentially generating a “cadherin zipper,” whose strength depends on the number of cadherin molecules involved in the adhesion junction (Klymkowsky and Parr, 1995). An excellent example of these adhesion junctions is seen in the skin, where a subgroup of cadherins termed the desmosomal cadherins localize to desmosomes in the skin and are linked to the keratin filament network, giving strength to the epidermal covering (Faull, 1995).
Several other adhesion molecules have been described, the most important of which is CD44, expressed on the surface of T lymphocytes (Chapter 19). This glycoprotein, which is a receptor for hyaluronic acid, regulates adhesion of these and other cells to endothelial cells and monocytes, a process that effects the recruitment of T lymphocytes to sites of inflammation (Elangbam et al., 1997). Since specific glycoproteins and mucins have now been shown to inter- act with individual selectins, one may also suggest that these proteins can act as adhesion mole- cules, at least with a transitory function (Menger and Vollmar, 1996).