Cell Junctions, Structure, Function, and Regulation
The interaction of the JMD with p120
catenin has been implicated in regulat-
ing lateral clustering and the strength
of cadherin-mediated cell–cell adhesion.
p120 is a member of the p120 family,
which includes p120, p0071,
-catenin, and
AVRCF. These proteins have greater than
45% identity in the ARM domains and
bind to cadherins via the interaction of
the ARM domain with a highly conserved
region in the JMD. The most extensively
studied member of this family to date is
p120. Initial studies presented conflicting
results concerning the effect of p120 on
cadherin function with one study show-
ing that the p120 cadherin interaction
was required for lateral clustering and en-
hanced the strength of cell adhesion, while
a second study presented contrasting data
suggesting that the JMD and its interaction
with p120 had a negative effect on cell–cell
adhesion. This discrepancy was attributed
to differences in the phosphorylation state
of p120 in the different cell types that were
used for these studies. Indeed, phospho-
rylation of p120 on serine and threonine
residues in the N-terminus results in a
decrease in cell–cell adhesion, whereas
inhibition of phosphorylation of these
residues using staurosporin, or deletion
of the N-terminus results in an increase
in cadherin-mediated cell–cell adhesion.
In addition to containing serine/threonine
phosphorylation sites, the N-terminus of
p120 also contains a number of tyro-
sine phosphorylation sites. Although the
phosphorylation of p120 has been shown
to alter cadherin function, the molecular
mechanism responsible for the change in
cadherin function with phosphorylation of
p120 has not been reported.
The interaction of p120 with the JMD has
been implicated in mediating a number
of functions in addition to cadherin clus-
tering. For example, the juxtamembrane
region of VE-cadherin has been implicated
in excluding N-cadherin from cell–cell
junctions in cells expressing these two
cadherins, which may be why N-cadherin
endothelial cells. The interaction of JMD
with p120 has also been shown to protect
E-cadherin from degradation. The colon
tumor cell line SW48 possesses a defect
in the p120 gene that prevents expression
of p120. These cells show minimal expres-
sion of E-cadherin and have poor cell–cell
adhesion. Interestingly, restoring the lev-
els of p120 increased both the E-cadherin
levels and E-cadherin-mediated cell–cell
adhesion. We have found similar results
in endothelial cells, where a decrease in
the level of p120 results in a decrease in
the level of VE-cadherin and a decrease
in endothelial monolayer integrity. Thus,
interaction of p120 with the JMD region of
at least some cadherins is required for the
expression at the plasma membrane.
The C-terminus of the cytoplasmic tail
contains the CBD and mediates attach-
ment to the actin cytoskeleton through
binding to
-catenin, plakoglobin (also
Plakoglobin and
-catenin share a simi-
lar structure containing 12 ARM repeats
found in the central ARM domain that
is flanked on either side by N-terminal
and C-terminal domains. The binding of
-catenin and plakoglobin to cadherins is
mediated through the ARM domains, and
these two proteins bind to the CBD in
a mutually exclusive fashion. Attachment
to the cytoskeleton is then achieved by the
binding of
-catenin to the N-terminus and
the ±rst ARM repeat of plakoglobin or
catenin and to actin. In addition to binding
directly to the actin cytoskeleton,
can also mediate attachment to micro-
±laments by binding to actin-associated
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