Lecture 15: Integrins (February 10, 2012)
Lecture 14 (continued)
Cadherin diversity in the CNS
Nerve tissue cadherins have distinct yet overlapping expression patterns
o Found in the brain of a mouse are the classical cadherins
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
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
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
• Are important for cell-cell contact
• Regulate intracellular mechanisms
• 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
• 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
• Phosphoinositide 3-kinase
• Guanine nucleotide exchange factors
• Promote the exchange of GDP for GTP
• 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
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
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