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Lecture 15

BIOC 212 Lecture 15.docx

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BIOC 212
Thomas Duchaine

Lecture 15: Integrins (February 10, 2012) Lecture 14 (continued) Cadherins Cadherin diversity in the CNS  Nerve tissue cadherins have distinct yet overlapping expression patterns  Cadherins o Found in the brain of a mouse are the classical cadherins  E-cadherin  R-cadherin  Cadherin-6 o Are thought to have a role in synapse formation and stabilization of nerve cells.  Proto-cadherins in the brain o They are like antibodies o They can create a variety of cadherins because  They differ in their N-terminal region  Variable region exons o Encode for the extracellular region of one type of transmembrane proto-cadherin protein o Many promoters associated with each variable exon that are used to generate many transcripts.  They are identical in their C-terminal regions  Constant region exons o Encoded by separate exons  They are arranged on a proto-cadherin gene cluster  Variability is a result of a combination of differential promoter regions and alternative RNA splicing o This is very different in comparison to the antibody diversification, which is done by site-specific recombination.  Figure B, Slide 16, Lecture 14 o The arrangement of exons that encode the members of one of the three known proto- cadherin families of non-classical cadherins in humans can be seen in the figure above. o All of the proto-cadherins encoded by this cluster share the same cytoplasmic tail.  Cytoplasmic tail is is encoded by the three constant-region exons C1, C2, and C3. Linkage and signaling of classical cadherins • Most cadherins link the actin cytoskeleton of neighboring cells • Cytoplasmic tail of cadherins • Highly conserved • Interact with actin filaments by intracellular anchor proteins called catenins & another protein called p120 (120kDA big) • Alpha & beta catenins • Essential interaction to hold cells together • Cadherins • Are important for cell-cell contact • Regulate intracellular mechanisms • Desmosomes • Are formed by non-classical cadherins • Interact with IF, rather than with actin filaments. • Their cytoplasmic domains bind different anchor proteins • Signal transduction • Performed by some cadherins • Example: Vascular endothelial cadherin (VE-cadherin) • Mediates adhesion of EC cells and VEGF binds to its receptor and uses VE-cadherin as a co-receptor. • Figure on the left, Slide 17, Lecture 14 • The linkage of classical cadherins to actin filaments. • The cadherins are coupled indirectly to actin filaments by the anchor proteins alpha-catenin and beta-catenin. • A third intracellular protein, called p120, also binds to the cadherin cytoplasmic tail and regulates cadherin function. • Figure on the top right, Slide 17, Lecture 14 • Mode of activation of Rac1 by the formation of E-cadherin- mediated cell–cell adhesions. • Before the establishment of E-cadherin-mediated cell–cell adhesions, Rho GDI seizes GDP · Rac1 in the cytosol. • When cadherin-mediated homophilic interactions occur, GDP · Rac1 is dissociated from Rho GDI by an unknown mechanism and is targeted to the plasma membrane. • GDP · Rac1 is converted to GTP · Rac1 through the action of a GEF (e.g., Tiam1) downstream of PI3k. • Activated Rac1 then positively regulates E-cadherin-mediated cell–cell adhesions. • Figure on the bottom right, Slide 17, Lecture 14 • Activated Rac-1 protein – make more actin filament signalling occurs • Net result is the extension of actin filament (polymerization) • More cadherins can interact with each other & tightening of the adhesion can occur • Rac - GTP • A binding signalling molecule • PI3K • Phosphoinositide 3-kinase • GEF • Guanine nucleotide exchange factors • Promote the exchange of GDP for GTP • GDI • GDP dissociation inhibitors • Interact with GDP-bound small GTPases Journal of Cell Biology • Inhibit the exchange of GDP for GTP, • Sequester the small GTPases into the cytosol Selectin Structure of Selectins  White blood cells o Need to move between the tissue and the blood stream  This requires special adhesive properties  Selectins are used  Selectins o Calcium dependent for structure & function o Transmembrane protein o Lectin domain  Cell-surface oligosaccharide-binding domain which causes weak interactions o Anchor proteins which interact with actin filaments o Mediate a variety of transient Ca dependent cell-cell adhesion interactions in the bloodstream o 3 types  L-selectin - white blood cells (lymphocytes)  P-selectin - platelets and endothelial cells that have been activated by inflammatory response. (Figure on slide 18, Lecture 14)  E-selectin on activated endothelial cells. Function of Selectins (Slide 19, Lecture 14) • Selectins and integrins mediate the cell–cell adhesions for white blood cell migration out of the bloodstream into a tissue • Binding white blood cells to endothelial cell linings • Migrate out of the bloodstream into the tissue • In lymphoid organ • Endothelial cells (EC) express oligosaccharides recognized by L- selectin on lymphocytes • The cells then become trapped • At the inflammation site • EC express selectins recognize the oligosaccharides on lymphocytes & flag for help. • Selectins & integrins • Together strengthen the binding of blood cells to the endothelium. • Cell-cell adhesion mediated by them together is a heterophilic type: • Selectins bind to specific oligosaccharides on glycoproteins and glycolipids
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