Cellular Adhesion Molecules (CAMs) are proteins located on the cell surface that physically link cells to one another or to the surrounding extracellular matrix (ECM). These molecules are fundamental to organizing individual cells into structured, functional tissues and organs. CAMs are complex transmembrane receptors, composed of an extracellular binding domain, a transmembrane domain, and an intracellular domain that links to the cell’s internal cytoskeleton. This structure allows CAMs to function as sophisticated signaling devices, transmitting information about the external environment directly into the cell’s interior.
Classification of Cellular Adhesion Molecules
Cellular adhesion proteins fall into four major families, each with distinct structures and binding preferences. Binding can be homophilic (binding to an identical molecule on an adjacent cell) or heterophilic (binding to a different type of molecule). The specific CAMs expressed dictate a cell’s ability to interact with its surroundings and participate in specialized tissue functions.
Cadherins
Cadherins are glycoproteins that strictly depend on calcium ions for their adhesive function. They primarily mediate homophilic, cell-to-cell binding, such as an E-Cadherin binding specifically to an E-Cadherin on a neighboring cell. Inside the cell, Cadherins connect to the actin cytoskeleton through adapter proteins called Catenins, forming the structural basis for many epithelial junctions. E-Cadherin is mainly found in epithelial tissues.
Integrins
Integrins are heterodimeric proteins composed of alpha (\(\alpha\)) and beta (\(\beta\)) subunits. They typically mediate heterophilic binding, linking cells to Extracellular Matrix proteins like collagen or fibronectin. Integrins function as two-way signaling molecules. They transmit information from the ECM into the cell (“outside-in” signaling) and activate their ligand-binding affinity from within the cell (“inside-out” signaling).
Selectins
Selectins are proteins specialized for binding to specific carbohydrate structures on other cells. These molecules require calcium for binding and are involved in temporary, low-affinity interactions. Selectins are primarily expressed on blood cells and activated endothelial cells lining blood vessels. Their ability to bind carbohydrates is crucial for the initial tethering of circulating cells.
The Immunoglobulin Superfamily (IgSF)
The Immunoglobulin Superfamily (IgSF) is a large group characterized by extracellular domains resembling antibody structures. This family includes molecules like Intercellular Adhesion Molecules (ICAMs) and Vascular Cell Adhesion Molecules (VCAMs). IgSF CAMs can engage in both homophilic binding with identical molecules and heterophilic binding, often interacting with Integrins on opposing cells.
CAMs in Maintaining Tissue Structure
The coordinated action of CAMs provides tissues with physical strength, structural integrity, and the ability to act as selective barriers. In epithelial tissues, CAMs are organized into specialized cell junctions. These junctions provide mechanical support and prevent the passage of substances between cells, which is important in the digestive tract and blood vessels.
Adherens Junctions and Desmosomes
Cadherins are the primary components of Adherens Junctions, which hold adjacent epithelial cells together. These junctions connect the cell-cell adhesion complex directly to the actin cytoskeleton, creating a continuous belt-like structure that provides tensile strength. Cadherins are also found in Desmosomes. Desmosomes are spot-weld-like junctions that provide mechanical resilience by linking cells via the intermediate filament network, rather than the actin filaments.
Hemidesmosomes
Integrins play a structural role in cell-matrix adhesion by forming Hemidesmosomes. These structures anchor the basal surface of epithelial cells to the underlying basement membrane. Specific Integrins link the intermediate filaments inside the cell to Extracellular Matrix proteins like laminin. Dysfunction in these structural CAMs can lead to inherited disorders that compromise tissue integrity.
The Dynamic Role of CAMs in Immune Response and Disease
CAMs participate in highly dynamic biological processes, including the immune response and the progression of diseases like cancer. During inflammation, the body relies on the rapid engagement of CAMs to guide immune cells to the correct location. This process, known as leukocyte trafficking, involves a multi-step adhesion cascade.
Leukocyte Trafficking
Selectins initiate the first step by mediating the loose, transient attachment of circulating leukocytes to the blood vessel endothelium. P-Selectin and E-Selectin, upregulated on activated endothelial cells, bind to carbohydrate ligands on the leukocytes. This binding causes the immune cells to slow down and “roll” along the vessel wall, allowing them to encounter chemical signals that activate their Integrins. The activated Integrins, such as \(\beta_2\)-integrins, switch to a high-affinity state and bind firmly to IgSF CAMs (e.g., ICAM-1) on the endothelium. This strong interaction causes the leukocyte to arrest its movement and adhere firmly to the vessel wall.
CAMs in Cancer Metastasis
The regulation of CAMs is frequently altered in disease, profoundly influencing cancer metastasis. Tumor progression is often associated with the loss of E-Cadherin function on epithelial cancer cells. This loss weakens the cell-to-cell adhesion holding the primary tumor together, allowing individual cells to detach and become motile.
As cancer cells lose E-Cadherin, they often upregulate specific Integrins, such as \(\alpha_5\)-Integrin. This upregulation promotes their adhesion to the Extracellular Matrix, allowing them to invade new tissues. This reciprocal regulation between Cadherins and Integrins governs the invasive potential of the tumor.
Selectins also influence metastasis by mediating the attachment of tumor cells to endothelial cells. This facilitates their exit from the circulation to colonize distant organs.