354
Cell Junctions, Structure, Function, and Regulation
proteins, such as
α
-actinin, vinculin, or
ZO-1.
Disruption
of
the
binding
of
β
-ca-
tenin/plakoglobin to either cadherin or
α
-
catenin regulates changes in the strength
of cell–cell adhesion and has been sug-
gested as playing a physiological role in cell
functions requiring dynamic changes in
cell–cell adhesion, such as the migration
of leukocytes through the endothelium
lining the blood vessel wall. In addi-
tion, disruption of cadherin attachment
to the actin cytoskeleton has been im-
plicated in disease states such as cancer.
Tumor cells deFcient in
α
-catenin, but ex-
pressing E-cadherin and
β
-catenin, have
a high rate of proliferation and display
a highly invasive phenotype. Expression
of
α
-catenin in these cells will restore
the attachment of cadherins to the actin
cytoskeleton and reverse the proliferative
and invasive phenotype. Attachment to the
actin cytoskeleton also is important for the
contraction of epithelial cell sheets, a pro-
cess that is required for the formation
of various structures during development.
Indeed, mutations in
α
-catenin result in
trophoblast malformation and inhibition
of development at the blastula stage due to
loss of intercellular adhesion.
In addition to performing structural and
regulatory roles at the AJ, catenins have
also been implicated in transcriptional
regulation of gene expression. A number
of catenins including p120 family mem-
bers, plakoglobin, and
β
-catenin have been
found in the nucleus. Although the role of
many of these catenins in the nucleus is
not fully understood, transcriptional reg-
ulation by
β
-catenin has been shown to
be part of the TC±/LE± signaling pathway.
The majority of the
β
-catenin in a cell is
foundintheAJandanyfree
β
-catenin is
usually rapidly degraded through a com-
plex series of reactions that lead to the
ubiquitin-proteasome pathway. However,
activation of the Wnt signaling pathway
results in the stabilization of cytoplasmic
β
-catenin that then translocates into the
nucleus. Once in the nucleus,
β
-catenin
complexes with LE±/TC± transcription
factors, and activates the LE±/TC± tar-
get genes that encode proteins involved
in cell proliferation, apoptosis, and remod-
eling of the extracellular matrix. Increases
in
β
-catenin nuclear signaling, owing to
a loss of AJs coupled with activation of
the Wnt pathway, have been implicated
in cancer progression. Although a simi-
lar pathway has not been elucidated for
other catenins, many have been found to
bind to transcription factors, suggesting
that they may also participate in transcrip-
tional activation and further support the
association between the AJ and regulation
of gene expression.
2.3.3
Regulation of Cadherin–Catenin
Complex
The
phosphorylation
of
serine,
threo-
nine, or tyrosine residues on
β
-catenin,
plakoglobin, and the CBD of cadherin
has also been implicated in regulating
the association of cadherins with the
actin cytoskeleton. A number of studies
have found that receptor tyrosine phos-
phatases such as PTP
µ
are part of the
cadherin–catenin complex, possibly bind-
ing directly to cadherins. Activation of Src
kinases, interaction with receptor tyrosine
kinases, such as Erb-2 and EG± receptors,
or the addition of phosphatase inhibitors,
all result in an increase in the phos-
phorylation of
β
-catenin or plakoglobin.
Numerous studies have found that in-
creases
in
the
phosphorylation
of
β
-
catenin, plakoglobin and cadherin are
associated with decreases in cell–cell adhe-
sion and a disruption of cadherin
β
-catenin
α
-catenin complex. However, these studies
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