336
Cell Junctions, Structure, Function, and Regulation
their ligands is tightly regulated. In these
cells, intracellular signals trigger confor-
mational changes in integrins that regulate
the ability of their extracellular domains
to bind to their ligands. This is referred
to as integrin ‘‘inside-out’’ signaling and
is most prevalent in circulating blood
cells, including platelets and leukocytes,
such as neutrophils, monocytes and T-
lymphocytes. The best-studied examples
of inside-out signaling are the regulation
of
α
IIb
β
3
integrin on platelets and
β
2
inte-
grins and leukocytes. As mentioned above,
the
α
IIb
β
3
integrin promotes platelet ag-
gregation by binding to soluble Fbrinogen.
Although platelet aggregation is impor-
tant in preventing excessive bleeding when
blood vessels are injured, inappropriate
platelet aggregation can lead to thrombo-
sis. Thus, the
α
IIb
β
3
integrin is inactive
on resting platelets, and when platelets
become activated at sites of blood vessel in-
jury, intracellular signaling events activate
α
IIb
β
3
.The
α
IIb
β
3
integrin is then able to
bind to soluble Fbrinogen with high afFn-
ity and promote the formation of platelet
aggregates or plugs to stop bleeding.
Similarly, the activity of
β
2
integrins
(Table 4)
is
also
tightly
regulated
to
prevent the inappropriate activation of an
immune response. The activation of
β
2
integrins involves conformational changes
that increase the afFnity of ligand binding;
however, changes in the avidity with which
β
2
integrins interact with their ligands is
also important. Signals that increase the
avidity of
β
2
integrin-ligand interactions
promote the diffusion and clustering of
β
2
integrins on the cell surface. In the case
of inactivated T-lymphocytes,
β
2
integrins
are tethered to the actin cytoskeleton in
an inactive state. Signals that activate T-
lymphocytes release
β
2
integrins from
the cytoskeleton.
β
2
integrins are then
free to diffuse on the plasma membrane,
cluster and form new attachments to the
cytoskeleton at adhesion sites.
Both inside-out and outside-in inte-
grin signaling are mediated by confor-
mational changes in the integrin het-
erodimer. Interestingly, the characteriza-
tion of conformation-dependent antibod-
ies to integrins has indicated that the con-
formations of activated and ligand-bound
integrins are similar. Recent electron mi-
croscopy, X-ray crystallography, NMR, and
mutational studies have provided impor-
tant insight into the conformational reg-
ulation of integrin activity. These studies
suggest that integrins in the low afFn-
ity state (inactive) have a bent, closed
conformation with their globular ligand
binding heads bent toward the plasma
membrane and their
α
-and
β
-subunits
closely associated (±ig. 4). In contrast, in-
tegrins in the high afFnity state (fully
active) have straightened and opened com-
formations with their
α
-and
β
-subunits
separated and their globular domains ex-
tended away from the plasma membrane
for ligand binding (±ig. 4). Integrins in
the intermediate afFnity state have their
ligand-binding domains extended from the
plasma membrane; however, their con-
formations are not fully opened. Current
evidence suggests that these integrin con-
formations are in dynamic equilibrium
and that conditions that inactivate or acti-
vate integrins shift this equilibrium.
1.3.4
Integrin-associated Proteins
The ability of integrins to mediate adhe-
sion and to activate signals depends on
their interaction with other cellular pro-
teins (Table 5). Most integrins associate
with the cytoskeleton and signaling com-
plexes by protein interactions mediated by
their
β
-subunit cytoplasmic domain (
β
-
tail). In fact, clustering isolated
β
1
and
β
3
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