Cell Junctions, Structure, Function, and Regulation
333
(Table 4). For example, the platelet integrin
α
IIb
β
3
binds to soluble fbrinogen lead-
ing to platelet aggregation.
β
2
integrins
bind to counterreceptors on the sur±ace
o± other cells. For example, the
α
L
β
2
in-
tegrin expressed on T-lymphocytes binds
to its counterreceptor ICAM-1 expressed
on antigen-presenting cells, leading to the
±ormation o± the adhesion complex known
as the
immune synapse
, which is required
±or ±ull and sustained T-lymphocyte activa-
tion. The
α
L
β
2
integrin is also expressed on
neutrophils and monocytes/macrophages
and can bind to ICAM-1 expressed on
the endothelial cells that line blood ves-
sels. Similarly, the
α
4
β
1
and
α
4
β
7
inte-
g
r
in
se
xp
r
e
s
s
edonl
euk
o
c
y
t
e
sc
anb
ind
to their counterreceptor(s), VCAM-1 and
MadCAM-1 (
α
4
β
7
only) on endothelial
cells. The binding o± leukocyte integrins to
their counterreceptors on endothelial cells
is important to enable leukocytes to exit
the circulation in order to fght in±ection
in tissues in the case o± neutrophils and
monocyte/macrophages, or to enter lymp-
hoid tissues in the case o± T-lymphocytes.
1.3.3
Integrin Signaling
The most intriguing aspect o± integrin
biology is the ability o± integrins to ±unc-
tion as bidirectional signaling receptors.
Ligand binding to integrins induces trans-
membrane con±ormational changes that
transduce signals to integrin intracellu-
lar domains, resulting in the linkage o±
integrins to cytoskeletal networks and
signaling pathways that regulate cell be-
havior.
The
process
by
which
ligand
binding to integrins activates intracellular
signals is re±erred to as integrin ‘‘outside-
in’’ signaling.
Integrin ‘‘outside-in’’ signaling provides
cells with important in±ormation about
their ECM environment that allows them
to make decisions regarding proli±eration,
survival, migration, and di±±erentiation
in response to growth ±actors, cytokines,
chemokines, and morphogens. The ±orma-
tion o± integrin-ECM adhesions regulates
these processes by activating cascades
o± biochemical signals that regulate the
assembly o± cytoskeletal networks and
signaling complexes (Fig. 3). The ±orma-
tion o± signaling complexes is regulated
by protein–protein interactions. For ex-
ample, Src homology 2 (SH2) domains
bind to phosphorylated tyrosine residues
in proteins. Thus, the activation o± tyro-
sine kinase signaling generates binding
sites ±or SH2 domains, providing a mech-
anism to recruit proteins to signaling
complexes. Other protein interactions are
mediated by Src homology 3 (SH3) do-
mains; these domains bind to proline-rich
regions in other proteins. There are still
other conserved domains that mediate pro-
tein–protein interactions; these will be
described as they become relevant to the
discussion.
An early signaling event that ±ollows
integrin engagement in cell adhesion is
the activation o± the cytoplasmic tyrosine
kinase, ±ocal adhesion kinase (FAK). In-
tegrins trigger the autophosphorylation o±
FAK at tyrosine 397, which promotes the
association o± Src ±amily o± cytoplasmic ty-
rosine kinases and other signaling proteins
such as phosphoinositide (PI) 3-kinase and
phospholipase C
γ
via their SH2 domains.
Src kinases phosphorylate FAK’s kinase
domain and also tyrosine 925, increasing
FAK’s kinase activity and promoting the
binding o± SH2 domain containing sig-
naling proteins at tyrosine 925, including
Grb2, and Grb7. Activated FAK/Src kinase
complexes trigger a cascade o± protein
tyrosine phosphorylations, including the
phosphorylation o± the adaptor proteins
paxillin and p130Cas, which in turn pro-
motes the ±ormation o± protein complexes
