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
previous page 1007 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1009 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off