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Cell Division: Cell Adhesion Inhibitors | | | Cell adhesion is crucial in the formation and maintenance of coherent multi-cellular structures. Two major types of cell adhesion processes are seen in multi-cellular organisms: cell-cell adhesion where physical bonds are formed between adjacent cells, and cell-matrix adhesion where cells bind to adhesive proteins in the extracellular matrix (ECM). A wide variety of adhesion molecules have been identified that fall into four major families: cadherins, immunoglobulin (Ig)-like adhesion molecules, integrins, and selectins.
Cadherins are the main mediators of Ca2+-dependent cell-cell adhesion. Cadherin-mediated cell-cell adhesion is accomplished by homophilic protein-protein interactions between two cadherin molecules on cell surface. This interaction is mediated by interactions between the His-Ala-Val domains and between Trp residues and hydrophobic pockets in amino-terminal cadherin domains. Cadherins are critical in segregating embryonic cells into tissues.
The Ig superfamily of cell adhesion molecules (CAM) is expressed in a wide variety of cell types, including neurons, leukocytes, epithelial, and endothelial cells. Collectively, they function by both homophilic and heterophilic binding. Their heterogeneous expression pattern implicates them in diverse biological processes, such as brain development, immune responses, tissue sorting, morphogenesis, and development of the vascular network. They are characterized by the presence of one or more Ig-like domains in their extracellular region. In addition, the ectodomain of Ig-CAMs may contain various numbers of fibronectin type III (FNIII) repeats, which possess the Arg-Gly-Asp (RGD) cell attachment site. Neural cell adhesion molecules (N-CAMs) and the intercellular cell adhesion molecules (ICAMs) are the best-studied members of this family.
Integrins belong to a superfamily of non-covalently bound heterodimeric membrane receptor glycoproteins. They are composed of a variable a-subunit of 150-170 kDa and a conserved 95-kDa b-subunit. Although both subunits are required for adhesion, the binding specificity primarily depends on the extracellular portion of the a-subunit. While generally classified as adhesion molecules, integrins also play an important role in signal transduction. Signal transduction through integrins occurs in two directions - moving from the extracellular microenvironment into the cell (outside-in signaling) and from the cytoplasm to the extracellular domain of the receptor (inside-out signaling). Among the signaling molecules involved in integrin-mediated cell survival is focal adhesion kinase, which is activated following integrin ligation. It activates downstream survival pathways, such as PI 3-kinase, Akt, and MAPK/ERK. In response to specific stimuli, integrins that are generally diffused over the cell surface cluster in focal contacts. Their combined affinities create a region with sufficient adhesive capacity to adhere to the ECM. This allows cells to bind to a large numbers of matrix molecules simultaneously while still maintaining their ability to explore their environment.
Selectins are expressed primarily on leukocytes and endothelial cells. They play an important role in host defense mechanisms. In contrast to other CAMs, selectins bind to carbohydrate ligands. Hence, the resulting binding forces are relatively weak. This allows selectinmediated interactions between leukocytes and endothelial cells and promotes rolling of the leukocytes along the endothelium. L-selectins are expressed on most leukocytes, E-selectins are inducible on vascular endothelium upon stimulation with cytokines, and P-selectins are found on activated platelets and vascular endothelium.
Dysregulation of several CAMs, particularly the Ig-CAMs, has been linked to tumor progression and metastasis making them a suitable target for therapeutic intervention. Also, increased expression of CAMs on the vascular endothelium is postulated to play an important role in atherogenesis. CAMs also play critical roles in the recruitment and migration of cells to sites of inflammation. Hence, these molecules have become targets for the development of drugs for treatment of cancer, inflammation, and autoimmune diseases.
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| | | Related Resource  Cell Adhesion, Invasion, and Migration Research Tools | | | | | |
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