Module 23: Cell Adhesion Molecules (PDF)

MODULE 23 Definitions and Significance cell adhesion: the cell’s attachment to a surface (substrate), or another cell the interactions are mediated by cell adhesion molecules (CAMs) the interactions are required for the maintenance of multicellular structures and signal transduction Extrac...

MODULE 23 Definitions and Significance cell adhesion: the cell’s attachment to a surface (substrate), or another cell the interactions are mediated by cell adhesion molecules (CAMs) the interactions are required for the maintenance of multicellular structures and signal transduction Extracellular Matrix (ECM) the major ECM components are proteins, with the most abundant protein being collagen collagen fibers are interwoven with proteoglycans ECM holds the cells together to form tissues ECM allows the cells within the tissue to communicate with each other Cell Junction Molecules (Cell Adhesion Molecules, CAMs) cadherins (cell-cell): cadherin dimers predominantly form homophilic interactions with cadherin dimers on adjacent cells integrins (mostly cell-ECM): heterodimers, function as both CAMs and receptors immunoglobulin superfamily (cell-cell): form both homophilic and heterophilic linkages selectins (cell-cell): dimers, contain a carbohydrate-binding domain that recognizes glycoproteins and glycolipids on adjacent cells Cadherins (cell-cell) single-pass transmembrane glycoproteins, often dimers; mostly homophilic, Ca+-dependent the cytoplasmic domain binds catenins that bind the actin cytoskeleton; however, some (nonclassical) cadherins (e.g., desmoglein, desmocollin) bind intermediate filaments role in morphogenesis: the construction of tissues and organs in embryos Integrins (mostly cell-ECM) α− and β−chains form heterodimers; Ca+-independent; with low-, intermediate-, and high-ligand affinity states cell-ECM attachment/signaling, except for integrins with β2-chains binding IgSF proteins for cell-cell adhesion MODULE 23 the binding of cytoskeletal proteins triggers the recruitment of extracellular ligands (inside-out signaling); the binding of extracellular ligands triggers the recruitment of cytoskeletal proteins (outside-in signaling); the combination of inside-out and outside-in signaling leads to a high-affinity conformation most known integrins are linked to actin filaments Inside-out and Outside-in Signaling Inside-out signaling: An intracellular activator binds to the β-subunit, induces a conformational change, and increases its affinity for extracellular ligands. This process regulates cell adhesion, migration, and invasion. Outside-in signaling: An extracellular matrix (ECM) ligand binds to integrin and induces (due to multivalency) integrin clustering. This leads to intracellular signals regulating cell polarity, survival, changes in the cytoskeleton, and gene expression. Integrins (mostly cell-ECM) Multivalent extracellular ligand binding that leads to clustering of the integrins activates intracellular tyrosine kinases FAK and SRC. FAK and SRC initiate phosphorylation of other proteins, some of which regulate gene expression. Proliferation, motility, survival, cytoskeleton organization and cell spreading Selectins (cell-cell) The name is derived from the word lectins, a term for proteins that bind carbohydrate groups. Membrane glycoproteins that bind to oligosaccharides on neighboring cells. Ca²⁺-dependent binding. E-selectins are on endothelial cells, P-selectins are on platelets and endothelial cells, and L- selectins are on leukocytes. Mediate transient interactions between leukocytes and vessel walls at sites of inflammation and clotting. MODULE 23 The Immunoglobulin Superfamily (IgSF) (cell-cell) mediate Ca2+-independent cell-cell adhesion; hemophilic or heterophilic (bind the same or other IgSF proteins, as well as integrins with a β2 chain) some mediate interactions of lymphocytes with other cells in immune response (e.g., macrophages, other lymphocytes, target cells) some mediate adhesions between non-immune cells (e.g., VCAM, NCAM, L1) functions: neurite outgrowth, myelination, firm adhesion of leukocytes (at inflammation sites) Putting It Together cadherin dimers mediate cell-to-cell binding integrins primarily mediate cell-ECM interactions; thus, the integrin α-β heterodimers bind extracellular matrix proteins (e.g., fibronectin, laminin, collagen); changes in the integrin cytoplasmic domain send an inside-out signal to modify the binding to extracellular ligands; integrin binding to extracellular ligands induces outside-in signaling to change intracellular activities selectins bind to carbohydrate groups on the surface of other cells; allow for transient interactions between leukocytes and blood vessel walls at sites of inflammation or blood clot formation IgSF proteins mediate cell-cell interactions, interact with integrins or other/same IgSF proteins selectins and cadherins require Ca2+ for their adhesive function; IgSF proteins and integrins do not