Cellular adhesion molecules
and the extracellular matrix
Cellular adhesion molecules fall
into four major families
Depending on the family, binding
can be homophilic or heterophilic
Cadherins
Cadherins are responsible for Ca++dependent cell-cell adhesion
• Extracellular domains – homophilic binding
• Homophilic binding allows cells that express the same
type of cadherin to recognize and attach to each other
• Intracellular domains – attach to actin cytoskeleton
through catenins – so extracellular connections can
affect intracellular organization
• Mutation or downregulation of cadherin is associated
with metastasis in cancer.
• Mechanical agitation in Ca++-free solution is a useful
experimental technique to separate tissues into
individual cells
Cadherins attach
to the actin-based
cytoskeketon
through anchor
proteins including
catenins
Cadherins connect cells at a desmosome
Cadherins join adjacent epithelial cells to one
another
Role of cadherins in organizing a
synapse
• The next slide shows the events of
synaptogenesis
• A target cell puts out outgrowths called filopodia
– as one of them approaches a potential
presynaptic neuron’s axon, the two cells
become linked by cadherins.
• In the presynaptic cell, catenins organize a
release zone for synaptic vesicles with docking
site proteins
• In the postsynaptic cell, catenins form a corral in
which receptors collect
Ig-like cellular adhesion
molecules
Immunoglobulin-like cellular
adhesion proteins
• Extracellular domain contains multiple
subdomains that resemble those of
antibody molecules or immunoglobulins
• Structure of the subdomains is stabilized
by disulfide bonds rather than Ca++, as in
cadherins.
The recognition proteins of the immune
system arose from cell adhesion proteins
• A true specific immune system is largely a
vertebrate invention – but metazoans have
had cell adhesion molecules for a long
time
• antibodies and T-cell receptors evolved
from Ig-cell adhesion molecules through
– splice variations that lacked a membrane
anchor – antibodies
– Highly variable extracellular domains –
antibodies and T-cell receptors
Selectins
Selectins recognize the carbohydrate portion
of cell surface and matrix glycoproteins
• Binding is Ca++-dependent
• Selectins have a major role in
inflammation and hemostasis
Integrins
• Integrins are dimers consisting of non-covalently
bound α and β subunits.
– In mammals, there are 18 different α and 8 different β subunits
that combine to form 24 different dimers with different ligandbinding properties.
• Integrins mediate both ‘outside-in’ and ‘inside-out’
signaling:
– Outside-in: integrin binding to extracellular matrix activates 2nd
messenger pathways
– Inside-out: integrins can change between low-affinity and high
affinity in response to binding of regulatory proteins (vinculin,
talin, paxillin, many others) to their short cytoplasmic domains.
For some integrins, this can occur on a second-to-second time
scale.
Integrin activation involves a
conformational change
Integrins mediate focal contacts temporary attachments to the substrate
The Extracellular Matrix
A complex mixture of non-living
material that fills the spaces
between cells
Functions of the extracellular matrix
• Tissue integrity
• Tissue differentiation
• Intercellular communication
What is the extracellular matrix?
• Extracellular space is filled with a mesh of
proteins and polysaccharides organized
and assembled by the cells.
• Two main classes of molecules
– Glucoseaminoglycans associated with
protein to form proteoglycans
– fibrous proteins - the major fibrous proteins
are collagens – there are 24 of them
• Ultimately, matrix molecules make up such
gross structures as ligaments and tendons
Fibroblasts are specialized for
collagen production
Notice that the collagen strands are laid out in a criss-cross
fashion that confers maximum strength
The ECM has a complex role in regulating
behavior, survival, shape and function of
the cells associated with it.
An example – cultured cells
• Immortalized epithelial cells – for example
mammary tumor cells - can be raised in primary
cell culture
• If they are kept suspended in medium, they look
and act just like amoebas
• If they are allowed to settle on a glass or plastic
surface, they spread and multiply until a
confluent layer is formed, but this layer doesn’t
look like or function as an epithelium
• If they are allowed to settle on a collagen
surface, they form an artificial epithelium with
tight junctions and apical-basal polarity, and
begin to indulge in ion and fluid transport.
Typically, cells have and use
multiple types of adhesion
molecules
Example 1 – Leukocyte migration in response to
chemokines
Events from previous slide
• Step 2. Inflammatory mediators cause vascular
endothelial cells at site of infection to express
selectins that adhere to leukocyte cell surface (a
similar interaction causes platelets to adhere to a
damaged endothelium to initiate blood clotting)
• Step 3. Binding of selectins to the leukocyte causes
it to activate integrins – these attach it to Ig family
adhesion molecules on endothelial surface
• Step 4. Leukocyte behavior changes – it begins to
creep like an amoeba through the junctions
between endothelial cells
• Once in the extracellular space, leukocyte migrates
toward source of chemokines –using focal contacts
to attach to the extracellular matrix
Example 2: Onset, maintenance
and termination of mammary
gland function
First, some definitions
• Basal lamina, secreted by epithelial cells
• Reticular lamina, formed by fibroblasts
• Together make up the basement
membrane, the form of extracellular matrix
associated with epithelial and endothelial
tissues
Prolactin sustains lactation by manipulating
the interaction of alveolar cells and
basement membrane
• During pregnancy, steroid hormones estradiol
and progesterone from the placenta, stimulate
proliferation of mammary alveolar and duct cells
• After delivery, prolactin, a protein hormone from
the pituitary, initiates milk secretion: integrinlaminin interaction stimulates expression of milk
proteins by alveolar cells. The same interaction
also promotes cell survival and proliferation.
• End of lactation is initiated by drop in prolactin
secretion. Matrix metalloproteases (MMPs)
disassemble the matrix, removing survival
signals. Most mammary alveolar cells undergo
apoptosis, and milk production stops.