340
Cell Junctions, Structure, Function, and Regulation
domain; there is some evidence that this
interaction promotes cell migration.
Recently, phosphotyrosine-binding (PT-
B) domains have been shown to be in-
volved in some protein interactions with
integrin
β
-tails. The PTB domain repre-
sents another conserved protein–protein
interaction domain. PTB domains bind to
NPXY and NPXF motifs found in many
proteins, including most integrin
β
-tails.
Recent studies have indicated that the re-
gion of talin that binds to integrins has
a three-dimensional structure similar to a
PTB domain. Talin’s PTB domain has been
shown to bind to the membrane-proximal
NPXY motif in the integrin
β
-tail. Inter-
estingly, this
β
-tail motif is required for
most aspects of integrin function. Some
PTB domains bind NPXY motifs when
the tyrosine residue is phosphorylated.
However, talin-integrin
β
-tail interactions
do not require tyrosine phosphorylation.
ICAP-1 also interacts with the integrin
β
1
cytoplasmic domain via a PTP do-
main, but requires the C-terminal NPXY
motif of the
β
1
tail. Recently, PTB do-
mains from several other proteins have
been shown to bind to integrin
β
-tails, al-
though the functional signi±cance of these
interactions is not yet known. Nonetheless,
since NPXY/F motifs are highly conserved
among the different
β
-tails, as well as
across species, it is likely that
β
-tail–PTB
domain interactions will play central roles
in integrin function. The binding of some
PTP domain-containing proteins to indi-
vidual
β
-tails may require the tyrosine
phosphorylation of the NPXY, motifs fur-
ther increasing the diversity of protein
interactions with
β
-tails and the mecha-
nisms that regulate them.
Several proteins have been identi±ed
that bind to
α
-subunit cytoplasmic do-
mains (Table 5). The functional signi±-
cance of the interaction of paxillin with
the
α
4
tail has been established. This asso-
ciation modulates cell migration mediated
by integrins containing
α
4
tails. Addition-
ally, serine phosphorylation of
α
4
tails
has been shown to inhibit the binding of
paxillin. Thus, paxillin-
α
4
tail association
and
α
4
integrin-dependent cell migration
are likely to be regulated by signaling
pathways that modulate the phosphory-
lation of the
α
4
tail. Paxillin has also
b
e
e
ns
h
ow
nt
ob
i
n
dt
ot
h
e
α
9
tail to
regulate
α
9
β
1
-dependent cell migration.
The ability of paxillin to regulate mi-
gration by this mechanism is likely to
be important for
α
4
β
1
4
β
7
,an
d
α
9
β
1
function during development and
α
4
β
1
and
α
4
β
7
function during the immune
response.
Integrins also associate with other trans-
membrane proteins, including caveolin,
tetraspanins (TM4 proteins) and CD47
(also known as integrin-associated pro-
tein, IAP). Caveolin binds to the
α
-subunit
of several integrin heterodimers, includ-
ing
α
5
β
1
and links these integrins to
Fyn, an Src family kinase that can cou-
ple integrins to the Ras/ERK MAP kinase
pathway, which is important for cell pro-
liferation. Several members of the TM4
family have been shown to bind to inte-
grin
α
-subunit extracellular domains. The
strongest association appears to be be-
tween CD151 and
α
3
β
1
. The cytoplasmic
domain of CD151 recruits the signaling
proteins phosphatidylinositol 4-kinase and
protein kinase C to CD151-integrin com-
plexes. These signaling proteins regulate
the actin cytoskeleton and cell spreading.
Interestingly, mutations that inhibit the
association of CD151 and
α
3
β
1
also inhibit
cell spreading, indicating that this asso-
ciation is functionally signi±cant. CD47
is also an important regulator of inte-
grin function. CD47 associates with
β
1
,
β
2
,
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