Cell-cell adhesion is mediated through membrane proteins called cell-adhesion molecules (CAMs). Many CAMs fall into one of four major families: the cadherins, the immunoglobulin (Ig) superfamily, the integrins, and the selectins. As the schematic structures in Figure 20-2 illustrate, CAMs are often mosaics of multiple distinct domains, many of which can be found in more than one kind of protein. The functions of these domains vary. Some confer the ability to bind specifically to their partner CAMs on neighboring cells, or even to CAMs on the same cell. Some of these domains are present in multiple copies and contribute to the length of the CAMs, and thus help define the distance between the plasma membranes of cells bound together by the CAMs. Other membrane proteins, whose structures do not belong to any of the major classes of CAMs in Figure 20-2, are also CAMs and participate in cell-cell adhesion in various tissues. As we will see later, integrins can function both as CAMs and, as depicted in Figure 20-2, adhesion receptors that bind to ECM components. Some Ig-superfamily CAMs can play this dual role as well.

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 cell junctions. Cell-cell adhesions can be tight and long lasting or relatively weak and transient. For example, the associations between neurons in the spinal cord or the metabolic cells in the liver exhibit tight adhesion. In contrast, immune-system cells in the blood often exhibit only brief, weak interactions, which allow them to roll along and pass through a blood vessel wall on their way to fight an infection within a tissue.

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The cytosolic domains of CAMs recruit sets of multifunctional adapter proteins (see Figure 20-1). These adapters act as linkers that directly or indirectly connect CAMs to elements of the cytoskeleton (see Chapters 17 and 18); they can also recruit intracellular molecules that function in signaling pathways (see Chapters 15 and 16) to modify cellular behavior, including gene expression and the activities of a variety of intracellular proteins, including the CAMs themselves. In many cases, a complex aggregate of CAMs, adapter proteins, and other associated proteins is assembled at the inner surface of the plasma membrane. These complexes facilitate two-way, “outside-in” and “inside-out,” communication between cells and their surroundings.

The formation of many cell-cell adhesions entails two types of molecular interactions, called trans and cis binding interactions (Figure 20-3). Trans interactions are also called intercellular or adhesive interactions, and cis interactions are also called intracellular or lateral interactions. In trans interactions, CAMs on one cell bind to the CAMs on an adjacent cell. In cis interactions, monomeric CAMs on one cell bind to one or more CAMs in the same cell’s plasma membrane. The lateral interactions in one cell may increase the probability of monomer-to-monomer or oligomer-to-oligomer trans interactions with clustered CAMs on an adjacent cell. In addition, formation of monomer-to-monomer trans interactions can induce cis interactions that can then strengthen trans adhesive interactions. It appears that trans and cis interactions are mutually reinforcing

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Adhesive interactions between cells vary considerably, depending on the tissue and the particular CAMs participating. Just like Velcro, CAMs can generate very tight adhesion when many weak interactions are combined, and this is especially the case when CAMs are concentrated in small, well-defined areas such as cell junctions. Some CAMs require calcium ions to form effective adhesions. Furthermore, the association of intracellular molecules with the cytosolic domains of CAMs can dramatically influence the intermolecular interactions of CAMs by promoting their clustering together and cis association or by altering their conformation in a way that increases the affinity of trans interactions. 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 or density of adhesion molecules (ensemble properties), the active versus inactive states of CAMs with respect to adhesion (biochemical properties), and external forces such as stretching and pulling, such as that in muscle, or the laminar and turbulent flow of cells and surrounding fluids in the circulatory system (mechanical properties).