Cell adhesion molecule


Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in creating force and movement and consequently ensure that organs are able to execute their functions. In addition to serving as "molecular glue", cell adhesion is important in affecting cellular mechanisms of growth, contact inhibition, and apoptosis. Oftentimes aberrant expression of CAMs will result in pathologies ranging from frostbite to cancer.
Combined with cell junctions and ECM, CAMs help hold animal cells together.

Structure

CAMs are typically single-pass transmembrane receptors and are composed of three conserved domains: an intracellular domain that interacts with the cytoskeleton, a transmembrane domain, and an extracellular domain. These proteins can interact in several different ways. The first method is through homophilic binding, where CAMs bind with the same CAMs. They are also capable of heterophilic binding, meaning a CAM on one cell will bind with different CAMs on another cell. The final type of binding occurs between cells and substrate, where a mutual extracellular ligand that binds two different CAMs.

Families of CAMs

There are four major superfamilies or groups of CAMs: the immunoglobulin super family of cell adhesion molecules, Cadherins, Integrins, and the Superfamily of C-type of lectin-like domains proteins. Proteoglycans are also considered to be a class of CAMs.
One classification system involves the distinction between calcium-independent CAMs and calcium-dependent CAMs. Integrins and the Ig-superfamily CAMs do not depend on Ca2+ while cadherins and selectins depend on Ca2+. In addition, integrins participate in cell–matrix interactions, while other CAM families participate in cell–cell interactions.

Calcium-independent

Integrins

s, one of the major classes of receptors within the ECM, mediates cell–ECM interactions with collagen, fibrinogen, fibronectin, and vitronectin. Integrins provide essential links between the extracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such as apoptosis, differentiation, survival, and transcription.
Integrins are heterodimeric, as they consist of an alpha and beta subunit. There are currently 18 alpha subunits and 8 beta subunits, which combine to make up 24 different integrin combinations. Within each of the alpha and beta subunits there is a large extracellular domain, a transmembrane domain and a short cytoplasmic domain. The extracellular domain is where the ligand binds through the use of divalent cations. In general, increases affinity, promotes adhesion to cells, and decreases cell adhesion.
Integrins regulate their activity within the body by changing conformation. Most exist at rest in a low affinity state, which can be altered to high affinity through an external agonist which causes a conformational change within the integrin, increasing their affinity.
An example of this is the aggregation of platelets; Agonists such as thrombin or collagen trigger the integrin into its high affinity state, which causes increased fibrinogen binding, causing platelet aggregation.

IgSF CAMs

CAMs is regarded as the most diverse superfamily of CAMs. This family is characterized by their extracellular domains containing Ig-like domains. The Ig domains are then followed by Fibronectin type III domain repeats and IgSFs are anchored to the membrane by a GPI moiety. This family is involved in both homophilic or heterophilic binding and has the ability to bind integrins or different IgSF CAMs.

Calcium-dependent

Cadherins

The cadherins are homophilic -dependent glycoproteins. The classic cadherins are concentrated at the intermediate cell junctions, which link to the actin filament network through specific linking proteins called catenins.
Cadherins are notable in embryonic development. For example, cadherins are crucial in gastrulation for the formation of the mesoderm, endoderm, and ectoderm. Cadherins also contribute significantly to the development of the nervous system. The distinct temporal and spatial localization of cadherins implicates these molecules as major players in the process of synaptic stabilization. Each cadherin exhibits a unique pattern of tissue distribution that is carefully controlled by calcium. The diverse family of cadherins include epithelial, placental, neural, retinal, brain, and muscle. Many cell types express combinations of cadherin types.
The extracellular domain has major repeats called extracellular cadherin domains. Sequences involved in binding between the ECDs are necessary for cell adhesion. The cytoplasmic domain has specific regions where catenin proteins bind.

Selectins

The selectins are a family of heterophilic CAMs that are dependent on fucosylated carbohydrates, e.g., mucins for binding. The three family members are E-selectin, L-selectin, and P-selectin. The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1, which is a mucin-type glycoprotein expressed on all white blood cells. Selectins have been implicated in several roles but they are especially important in the immune system by helping white blood cell homing and trafficking.

Biological function of CAMs

The variety in CAMs leads to diverse functionality of these proteins in the biological setting. One of the CAMS that are particularly important in the lymphocyte homing is addressin. Lymphocyte homing is a key process occurring in a strong immune system. It controls the process of circulating lymphocytes adhering to particular regions and organs of the body. The process is highly regulated by cell adhesion molecules, particularly, the addressin also known as MADCAM1. This antigen is known for its role in tissue-specific adhesion of lymphocytes to high endothelium venules. Through these interactions they play a crucial role in orchestrating circulating lymphocytes.
CAM function in cancer metastasis, inflammation, and thrombosis makes it a viable therapeutic target that is currently being considered. For example, they block the metastatic cancer cells' ability to extravasate and home to secondary sites. This has been successfully demonstrated in metastatic melanoma that hones to the lungs. In mice, when antibodies directed against CAMs in the lung endothelium were used as treatment there was a significant reduction in the number of metastatic sites.