Cell Junctions, Structure, Function, and Regulation
351
Interestingly,
a
recent
crystallographic
study using C-cadherin has suggested a
third model in which cis-binding may
actually form lateral multimers through
interaction of EC-1/EC-2 domains on adja-
cent cadherins. Although the mechanism
of cis-interaction of cadherins remains
controversial, crystallographic, mutagen-
esis,
and
in
vitro
binding
studies
all
support a requirement for cis-dimerization
in cadherin-mediated cell–cell adhesion.
The structural basis involved in me-
diating homophilic binding of cadherins
on adjacent cells is also fraught with
controversy. As in cis-dimerization, trans-
dimerization, which is the binding of two
cadherins on different cells, has also been
shown to require the EC-1 domain. In one
model, the EC-1 domains of two cadherins
on opposing cells bind to form a zipper-
like structure as shown in Fig. 11. This
model is supported by studies that have
shown that the HAV motif and the amino
acids surrounding this peptide mediate the
speci±city of cadherin adhesion. However,
a trans-dimer with this structure seems too
long to be accommodated in the intercellu-
lar space observed by electron microscopy.
In a second model, the EC-1 domain of
one cadherin interacts with the EC-4 or
EC
-5doma
ino
fthecadher
inonanad
ja
-
cent cell. This model is consistent with the
distance between plasma membranes ob-
served by electron microscopy and is also
supported by studies showing that antibod-
ies to the EC-4 and EC-5 regions disrupt
cadherin-mediated binding. In addition,
direct force measurements would suggest
that a greater overlap of the cadherins
showninFig.11isrequiredformaximum
adhesive strength, and that interaction me-
diated only by the EC-1 domain would not
be strong enough to maintain cell–cell ad-
hesion. Nonetheless, both models support
the formation of a zipper-like structure
by the trans-interaction of cadherins on
opposing cells.
Understanding
the
mechanisms
of
cadherin-mediated adhesion has impor-
tant implications for therapeutic interven-
tions in processes such as tumor angio-
genesis. Monoclonal antibodies to the EC1
region of VE-cadherin have been shown
to prevent branching morphogenesis of
endothelial cells in culture and to inhibit
angiogenesis in a mouse cornea model.
Unfortunately, antibodies to the EC1 do-
main also cause a decrease in barrier
function of confluent endothelial monolay-
ers, particularly in the microcirculation of
the lung. However, monoclonal antibodies
to the EC4 domain inhibit angiogenesis,
without altering the barrier function of en-
dothelia with stable, well-structured AJs,
such as those found in the lung. These
results suggest that antibodies to the EC4
domain may be used to prevent angio-
genesis and thus inhibit the growth of
many tumors without having the adverse
side effect of changing vascular perme-
ability. These results further underscore
the importance of understanding struc-
ture–function relationships that govern
cadherin-mediated cell–cell adhesion.
Using cell culture aggregation assays,
it was demonstrated that the EC1 do-
main and the HAV region play essen-
tial roles in determining the speci±city
of homophilic binding of classical cad-
herins. In early studies, E-cadherin and
P-cadherin were expressed as recombinant
proteins in ±broblasts that normally do
not express these cadherins and do not
demonstrate calcium-dependent cell–cell
adhesion. These studies demonstrated that
when cells expressing E-cadherin were
mixed with cells expressing P-cadherin,
the resulting cell aggregates would con-
tain either E-cadherin cells or P-cadherin
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