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Laura Parker

CELL ADHESION AND THE ECM Principles of cell adhesion: 1. individual receptors have low affinity; many receptors have high AVIDITY 2. ADAPTER protein bridges necessary between cytoskeleton and receptor 3. Mix of adhesion receptors determines precise interaction 4. Adhesiveness is highly regulated 5. Signaling roles 6. Specific ligand binding activity and biological function ANCHORING JUNCTIONS Actin Filaments Intermediate Filaments CADHERIN receptor ADHERINS DESMOSOME INTEGRIN receptor FOCAL ADHESION HEMIDESMOSOME (ECM) (Basal Lamina) Receptors: Cadherins – homophilic junctional IgCAM – homophilic or heterophilic transient Selectins – heterophilic (blood and endothelial) sugar residues are ligand transient Integrins - heterophilic (only one that can bind ECM) junctional LEUKOCYTE EXTRAVASATION 1. infected endothelial cells present P/E SELECTINS 2. Leukocytes form transient adhesions with selectins 3. Leukocyte B2 INTEGRIN is activated 4. Integrins bind endothelial ICAM  firm adhesion 5. Leukocytes squeeze through layer into damaged tissue ADHESION MODULATION – 1. Selection expression of cell adhesion receptors transcriptional post-translational (stored in granules) 2. state of activation of receptor changes by CONFORMATIONAL change 3. Aggregation (at leading edge of moving cell for example) INTEGRIN BIDIRECTIONAL SIGNAL TRANSDUCTION – Inside-Out: activating signal (extracellular) activates INTRAcellular cascade  integrin is activated in the end and binds appropriate ligand Outside-In: integrin binds extracellular ligand  cytoplasmic tail conf. changes  activates protein kinases ex/ FAK autophosphorylates when integrins bind ECM ligands FAK activates GRB2 (MAPK pathway) “anchorage dependence” – cell cycle activated by GF’s AND integrin ECM binding dependence is lost in cancerous cells Integrins bind RGD (Arg-Gly-Asp) sequences in ECM proteins each integrin has a specific ligand and biological function ECM MACROMOLECULES – 5 classes to produce a great variety of ECM 1. ADHESIVE GLYCOPROTEINS – mediators between cells and ECM (adaptors) domains: ECM binding sites surface receptor (integrin) binding sites FIBRONECTIN (FN) – homodimer connected at C term (tweezer shaped) RGD motif for integrin binding also binds collagen, heparin
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