Cell Junctions, Structure, Function, and Regulation
359
membrane, whereas the Dsg cytoplasmic
tail acts as a dominant negative that
prevents the formation of desmosomes.
The dominant negative activity of the
Dsg cytoplasmic tail can be reversed by
mutating the CBD. The mechanism of this
response is not known but the indications
are that the interaction of Dsg/Dsc with
intermediate Flaments is more complex
than just direct structural connections
through plaque proteins.
As described previously, plakoglobin is a
member of the armadillo family of pro-
teins, which links type I and type II
cadherins to
α
-catenin, thereby support-
ing attachment to the actin cytoskeleton.
In desmosomes, plakoglobin binds to the
CBD of Dsc and Dsg. Interestingly, the
binding site for Dsc/Dsg on plakoglobin
overlaps with the binding site for
α
-catenin
(the Frst ARM repeat); thus, the binding
of plakoglobin prevents the association
of
α
-catenin with the desmosomal cad-
herins. Instead of binding to
α
-catenin,
plakoglobin binds directly to DP, and ap-
pears to play an important role in linking
the desmosomal cadherins to DP and the
intermediate Flament cytoskeleton. The
C-terminus of plakoglobin has also been
found to play a role in regulating desmo-
some structure, as mutation of this region
results in desmosome fusion and the for-
mation of desmosomes that cover a large
area of the plasma membrane. The im-
portance of plakoglobin to the function
of desmosomes
in vivo
has been demon-
strated by gene ablation experiments in
mice. Plakoglobin-null mice exhibit early
embryonic lethality due to mechanical de-
fects in the heart that render the organ
unable to withstand the hemodynamic
forces generated by cardiac muscle con-
traction. At the ultrastructural level, there
is a loss of intercalated disc integrity, and
the normal organization of desmosomal
structures is disrupted. Interestingly, the
plakoglobin-null phenotype is not fully
penetrant, and survivors exhibit skin de-
fects (fragility and blistering) even though
desmosomes in most tissues appear mor-
phologically normal.
In addition to plakoglobin, a second fam-
ily of armadillo proteins is found in desmo-
somes. The plakophilins (PKP) are ARM
proteins belonging to the p120 subfam-
ily. In humans, three distinct plakophilin
isoforms arise from three different genes.
The Frst human genetic disorder to be
attributed to a desmosomal gene was a
mutation in plakophilin-1. Plakophilin-1
mutations lead to a skin fragility and
dysplasia syndrome, resulting in epider-
mal blistering. The plakophilins exhibit
a tissue- and differentiation-speciFc ex-
pression pattern and, depending on the
tissue, the plakophilins can localize to
both desmosomes and to the nucleus. In
desmosomes, PKP-1 is found in the upper,
most differentiated layers of stratiFed ep-
ithelia, and PKP-2 is found in the basal cell
layers of stratiFed epithelia. PKP-2 is also
found in some single-layered epithelia. Re-
cently, plakophilin 3 has been implicated
as playing a central role in desmosomal
structure owing to its multiple binding
partners and its widespread distribution in
different epithelial cells. PKP-3 has been
foundtobindtoallthreeDsgsandtoDsc3a
and 3b, as well as to Dsc1a and Dsc2a.
In addition, PKP-3 was found to bind to
plakoglobin, DP, and epithelial keratin-18.
Interestingly, this study was unable to Fnd
PKP-3 in the nucleus, suggesting that it
may play a more structural role than PKP-
1 and -2. In contrast, plakophilin-1 and
-2 exhibit strong nuclear localization, and
plakophilin-2 has been shown to interact
with the RNA polymerase III. ±urther-
more, PKP-2 has recently been found to
participate in transcriptional regulation in
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