Cell adhesion molecules (CAMs) are a subset of cell surface proteins[1] that are involved in thebinding of cells with other cells or with theextracellular matrix (ECM), in a process calledcell adhesion.[2] In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally.[3] In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.[4]
CAMs are typically single-passtransmembrane receptors[5] and are composed of three conserved domains: an intracellular domain that interacts with thecytoskeleton, a transmembrane domain, and an extracellular domain. CAMs can interact in two different ways:[6]homophilic binding to the same type of CAM on another cell, andheterophilic binding to a different type of CAM.
There are four major superfamilies or groups of CAMs: theimmunoglobulin super family of cell adhesion molecules (IgCAMs),Cadherins,Integrins, and the Superfamily ofC-type of lectin-like domains proteins (CTLDs).Proteoglycans are also considered to be a class of CAMs.
One classification system involves the distinction between calcium-independent CAMs and calcium-dependent CAMs.[7] The Ig-superfamily CAMs do not depend on Ca2+ while integrins, cadherins and selectins depend on Ca2+. In addition, integrins participate in cell–matrix interactions, while other CAM families participate in cell–cell interactions.[8]
Immunoglobulin superfamily CAMs (IgSF 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 byFibronectin 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.[citation needed]
Integrins, one of the major classes of receptors within the ECM,[9] mediate cell–ECM interactions withcollagen,fibrinogen,fibronectin, andvitronectin.[10] Integrins provide essential links between theextracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such asapoptosis,differentiation,survival, andtranscription.[11]
Integrins areheterodimeric, as they consist of an alpha and beta subunit.[12] There are currently 18 alpha subunits and 8 beta subunits, which combine to make up 24 different integrin combinations.[10] Within each of the alpha and beta subunits there is a large extracellular domain, a transmembrane domain and a short cytoplasmic domain.[13] The extracellular domain is where theligand binds through the use of divalentcations. The integrins contain multiple divalent cation binding sites in the extracellular domain[14]). The integrin cation binding sites can be occupied by Ca2+ or by Mn2+ ions. Cations are necessary but not sufficient for integrins to convert from the inactive bent conformation into the active extended conformation. Both the presence of cations bound to the multiple cation binding sites is required, along with the direct physical association with ECM ligands for integrins to attain the extended structure and concomitant activation.[15] Thus, rise in extracellular Ca2+ ions may serve to prime the integrin heterodimer. The release of intracellular Ca2+ have been shown to be important for integrin inside-out activation.[16] However, extracellular Ca2+ binding may exert different effects depending on the type of integrin and the cation concentration.[17]Integrins regulate their activity within the body by changing conformation. Most exist at rest in a lowaffinity state, which can be altered to high affinity through an external agonist which causes a conformational change within the integrin, increasing their affinity.[11]
An example of this is the aggregation ofplatelets;[11] Agonists such asthrombin orcollagen trigger the integrin into its high affinity state, which causes increasedfibrinogen binding, causing platelet aggregation.
Thecadherins are homophilicCa2+
-dependentglycoproteins.[18] The classic cadherins (E-,N- andP-) are concentrated at theintermediate cell junctions, which link to theactin filament network through specific linking proteins calledcatenins.[18]
Cadherins are notable in embryonic development. For example, cadherins are crucial ingastrulation for the formation of themesoderm,endoderm, andectoderm. 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 ofsynaptic stabilization. Each cadherin exhibits a unique pattern of tissue distribution that is carefully controlled by calcium. The diverse family of cadherins include epithelial (E-cadherins), placental (P-cadherins), neural (N-cadherins), retinal (R-cadherins), brain (B-cadherins and T-cadherins), and muscle (M-cadherins).[18] Many cell types express combinations of cadherin types.
Theextracellular domain has major repeats called extracellular cadherin domains (ECD). Sequences involved inCa2+
binding between the ECDs are necessary forcell adhesion. The cytoplasmic domain has specific regions where catenin proteins bind.[19]
Theselectins are a family of heterophilic CAMs that are dependent onfucosylated carbohydrates, e.g.,mucins for binding. The three family members areE-selectin (endothelial),L-selectin (leukocyte), andP-selectin (platelet). The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-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.[20]
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 isaddressin.[21] 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.[22] 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.[23] 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.[24]
{{cite journal}}:Cite journal requires|journal= (help)