Cell Junctions, Structure, Function, and Regulation
335
stress fbers and Focal adhesions to regu-
late cell–matrix adhesion and contractility.
±AK and paxillin are important reg-
ulators oF cell spreading and cell mi-
gration. ±AK/Src complexes trigger the
phosphorylation oF p130Cas. Phosphory-
lated p130Cas recruits additional signaling
proteins including the adaptor protein
CrkII, and Dock180, which is a guanine
exchange Factor (GE±) that activates Rac.
Integrin-mediated adhesion is suFfcient to
activate Rac, and is also required For the
membrane targeting oF activated Rac and
its association with downstream eFFectors.
Thus, even when Rac is activated by signals
From other cell surFace receptors, such as
growth Factor receptors, integrin-mediated
adhesion is still required For Rac to activate
downstream signaling pathways. Activated
±AK/Src complexes also trigger the tyro-
sine phosphorylation oF paxillin, which can
also lead to the recruitment oF CrkII and
potential activation oF Rac by similar path-
ways. However, current evidence suggests
that paxillin regulates migration by bind-
ing oF paxillin-kinase linker (PKL). PKL is
an ArF GTPase activating protein (GAP)
that regulates vesicular traFfcking. In ad-
dition, PKL binds to the Cdc42/Rac GE±,
PAK interacting exchange Factor (PIX), an-
o
therGE±ForRac
.PKLa
lsob
indstothe
serine/threonine kinase PAK, which is ac-
tivated by Rac to promote cell migration.
Thus, paxillin-PKL association may pro-
vide the appropriately localized scaFFold
For the activation oF signaling complexes
that are required to direct cell migration.
In addition, stable integrin-mediated ad-
hesion cooperates with other cell surFace
receptors such as growth Factor recep-
tors to regulate cell behavior, such as
proliFeration, survival, and diFFerentiation.
Numerous studies have demonstrated an
important role For integrins in the regu-
lation oF cell proliFeration. Most normal
cells require integrin-mediated adhesion
to specifc components oF the ECM For cell
proliFeration; activation oF growth Factor re-
ceptorsisnotsuFfcient.Integrinspromote
cell proliFeration by regulating the activi-
ties oF the G1 cyclin-dependent kinases
(Cdk4/6 and Cdk2). Integrin-mediated ad-
hesion is necessary For the transcription
oF cyclin D1, which is required For the ac-
tivation oF the cyclin-dependent kinase(s)
Cdk4/6. The cyclin D1 promoter is reg-
ulated by transcription Factors that are
phosphorylated and activated by ERK.
Integrin-mediated adhesion is required For
integrin- and growth Factor-activated ERK
to be translocated to the nucleus and For
the sustained ERK activity that is necessary
to induce transcription From the cyclin D1
promoter. Integrin signaling is also re-
quired For the activation oF cyclin E-Cdk2.
Integrin-mediated adhesion promotes cy-
clin E-Cdk2 activity by contributing to the
downregulation oF the Cdk inhibitors, p21
and p27.
In
some
cell
types,
the
ability
oF
cell–matrix adhesion to promote cell pro-
liFeration is dependent upon the inte-
grin heterodimer mediating adhesion. The
α
5
β
1
-mediated endothelial cell adhesion
to fbronectin promotes proliFeration in
response to growth Factors, whereas
α
2
β
1
-
mediated endothelial adhesion to laminin1
does not. Interestingly, this regulation is
at the level oF cyclin D1 translation and
depends on Rac signaling, which occurs
eFfciently when cells are adhered to f-
bronectin, but not to laminin1. Thus,
integrin signaling not only promotes the
transcription oF cyclin D1, but can also
regulate the translation oF cyclin D1 by
modulating the activation oF Rac signaling.
‘‘Inside-out’’ integrin signaling provides
cells with a mechanism to rapidly reg-
ulate
integrin
Function.
In
some
cell
types, the ability oF integrins to bind
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