352
Cell Junctions, Structure, Function, and Regulation
cells but not a mixture of the two. Muta-
tional studies demonstrated that the EC1
domain and the amino acids surrounding
the HAV peptide play an important role
in homophilic trans-cadherin adhesion.
Further studies using domain-swapping
approaches, antibodies or peptides to the
EC1 domain con±rmed these ±ndings. In-
terestingly, recent studies have suggested
that cadherins may not be restricted to ho-
mophilic binding, but may also interact
with each other in a heterophilic man-
ner. This is particularly true of the type II
cadherins. The members of this family of
cadherins have been shown to bind in a
heterophilic manner to other members of
the same family. For example, cadherin 8
can bind to cadherin 11 allowing for the
formation of cell aggregates with strong
cell–cell adhesion. One should remem-
ber that type II cadherins do not contain
the HAV sequence and do not bind at all
to type I cadherins. Recent studies have
found that heterophilic binding may also
occur within the type I cadherin family;
however, the studies have suggested that
these heterophilic interactions are weaker
than homophilic interactions. As the stud-
ies demonstrating heterophilic binding of
cadherins have been performed only in
cell culture systems, the physiological rele-
vance of heterophilic binding in tissue and
organ function is unknown.
2.3.2
Cytoplasmic Domain: Lateral
Clustering and Cytoskeletal Attachment
Changes in the strength of cadherin-
mediated adhesion are necessary for the
dynamic cellular movements found during
processes such as angiogenesis and tissue
morphogenesis. Environmental signals,
such as growth factors, act to modulate the
strength of cadherin-mediated adhesion by
changing the association of cadherin with
the actin cytoskeleton and by disrupting
cadherin clustering. Both of these pro-
cesses are regulated through the cadherin
cytoplasmic tail. The cytoplasmic tail of
cadherin contains two important domains,
the juxtamembrane domain (JMD) and
the C-terminal catenin binding domain
(CBD), both of which bind to the catenins
to form a cadherin–catenin complex. The
catenins are a family of related proteins
that share a central domain called the
armadillo-repeat domain (ARM domain).
This domain contains 10 to 13 armadillo
repeats, so named because of their se-
quence homology to the armadillo gene
product ±rst identi±ed in
Drosophila
.The
ARM repeats have been shown to have a
tertiary structure that results in the forma-
tion of a groove that contains a number of
positively charged residues. Proteins that
bind to the ARM region do not possess a
single consensus sequence, but do possess
many negatively charged amino acids that
bind within the positively charged groove
created by the ARM domain.
The extracellular domain of cadherin can
support cell–cell adhesion independent of
the cytoplasmic tail, but the strength of
adhesion is considerably weaker than that
supported by the full-length molecule. The
binding mediated by the extracellular do-
main of cadherins can be increased by
clustering cadherin extracellular domains
on the cell surface. This was shown using
chimeric cadherin molecules containing
an intracellular regulatable oligomeriza-
tion motif connected to the extracellular
and transmembrane domain of cadherins.
Under normal conditions, the JMD of
the cytoplasmic tail is believed to regu-
late cadherin clustering. Deletion mutants
of cadherin that contain the JMD, but not
the CBD, were found to cluster and me-
diate strong adhesion demonstrating the
importance of the JMD in regulating cad-
herin function.
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