By Levi Clancy for Student Reader on
Adhesion molecules are membrane proteins that form a link between the cytoskeleton inside a cell and the cell’s environment, which consists of other cells and the ECM. Far from being a simple “glue” that keeps cells together, adhesion molecules play an active role in virtually every aspect of animal development. Differential adhesive properties of cells play an important part in maintaining the boundaries between different cell populations. For example, we will see in an upcoming lecture that the segregration of the ectodermal germ layer into epidermis and neural tissue is controlled by changing the adhesive properties of cells. We will consider the role of two main classes of adhesion molecules, the cadherins and integrins.
Cell-Cell Adhesion: Cadherins
Cadherins are transmembrane proteins which adhere to identical cadherins on the surface of other cells. This is an example of homophilic interaction, an association between identical molecules. Cadherins thus provide adhesive specificity: only cells expressing the same types of cadherins can adhere to each other.
Cadherins are a large and diverse class of cell adhesion molecules.
In this way, cadherins provide adhesive specificity: only those cells expressing the same types of cadherins can adhere to each other. Some cadherins are preferentially expressed in certain cell types. For example, E-cadherin (from “epithelial” cadherin) is mainly expressed in the ectoderm of all animals, N-cadherin in the nervous system. However, this correlation is not absolute; most cadherins are expressed in a variety of different tissues, and a given cell often expresses more than one cadherin at a time. Intracellularly, cadherins have a highly conserved cytoplasmic domain that binds to a group of adapter proteins known as catenins. Cadherins and catenins together form an adhesion complex that links the membrane to the actin cytoskeleton.
Cadherins control many morphogenetic movements during embryonicdevelopment. By expressing E-cadherin, the ectoderm of many animals becomes established as a stable epithelial layer. Epithelial morphogenesis in every organ system in vertebrates and invertebrates depends on E-cadherin.
To function normally, the cadherin mediated adhesion must be up- and downregulated rapidly. Cells about to migrate must be able to “let go” of their neighbors. As a matter of fact, the migration of a cell is accompanied by cyclic disruption and reformation of adhesive cell contacts. Regulation of cadherin function can occur at different levels. First, the rate of transcription of a cadherin gene determines the amount of cadherin in the membrane and is thereby correlated with the adhesiveness of the corresponding cell population. There are numerous examples of cells that, in order to move out of a particular tissue and migrate, reduce adhesiveness by turning off the expression of cadherin.
The second, more rapid mechanism to control the level of adhesion mediated by cadherin is by modifying its coupling to the actin cytoskeleton. Several receptor tyrosine kinases and -phosphatases have been identified that affect this coupling.
Whereas some adhesion molecules are distributed in a diffuse manner over the entire cell membrane, other adhesion molecules, such as the cadherins or integrins, are concentrated in membrane specializations called cellular junctions. On the basis of their electron microscopic structure and biochemical composition, several different types of cellular junctions have been defined: the adherens junctions, tight junctions, desmosomes and gap junctions.
Cell-Substrate Adhesion: Integrins
In the previous sections we had encountered different classes of adhesion molecules that link cells to each other. In addition, cells are bound to the extracellular matrix (ECM) that surrounds them on all sides, as in mesenchymal cells, or forms a basement membrane, as in epithelial cells. There exist different types of membrane proteins that act as receptors for extracellular matrix proteins. Members of these cell-substrate adhesion molecules are the integrins.
Different isoforms of integrin bind to many different extracellular proteins, including laminin, fibronectin, and collagen. Intracellularly, integrins are linked to microfilaments via many different kinds of adapter proteins (talin, vinculin paxillin). In addition, signal transducing molecules such as focal adhesion kinase (FAK) are linked to the cytoplasmic domain of integrin and are activated when integrin binds to an extracellular ligand. Integrin coupled FAK feeds into signal transduction pathways, forming an important link between cell adhesion and cell fate determination.
Conformational changes of integrins, induced by signals inside the cell or changes in the ECM, lead to a reorganization of the actin cytoskeleton that causes dramatic changes in cell shape and motility. Similar to cadherins, integrins also control the membrane attachment of microfilaments. Finally, integrin binding to ligands presented by the basement membrane triggers the contraction of thick myosin containing microfilament bundles called stress fibers. Stress fiber contraction enhances the firm adhesion of cells to their substrate.