Cell Junctions, Structure, Function, and Regulation
355
did not examine the effect of phosphory-
lation of speciFc amino acid residues on
the disassembly of the cadherin–catenin
complex. More recent investigations have
begun to examine the role of individual
amino acids of
β
-catenin. Mutation of tyro-
sine 654 in
β
-catenin was found to prevent
the dissociation of
β
-catenin E-cadherin
complexes triggered by exposure to the
phosphatase inhibitor sodium orthovana-
date, thereby demonstrating a cause-and-
effect relationship between phosphoryla-
tion of this residue and cadherin binding.
Similarly, phosphorylation of
β
-catenin on
Tyr142 was found to decrease its asso-
ciation with
α
-catenin. Interestingly, this
tyrosine residue is phosphorylated by ±er
or ±yn tyrosine kinases that can both bind
to p120. Thus, p120 may regulate
β
-catenin
α
-catenin association by recruiting these
kinases to cadherin complexes. The fur-
ther study of recombinant cadherins and
catenins with mutations that target individ-
ual tyrosine, serine, and theosine residues
will provide important insights into how
phosphorylation regulates cell–cell adhe-
sion at the AJ.
Rho, Rac, and Cdc42 are members of the
Rho GTPase family that regulate changes
in the actin cytoskeleton and play a major
role in cell processes that require actin re-
organization. Given the close association
of cadherin function with attachment to
the actin cytoskeleton, it is not surpris-
ing that the small GTPases Rac, Rho, and
Cdc42 have all been implicated in reg-
ulating cadherin-mediated adhesion. Use
of dominant negative or constitutively ac-
tive forms of these small GTPases has
shown that each can influence the state
of cadherin-mediated adhesion, with Rho
and Rac being required for stable local-
ization of cadherins at cell–cell contacts
in epithelial cells. Recent investigations
have also begun to elucidate the role of
Rho GTPases in signaling pathways ini-
tiated by cadherin binding. These studies
have found that Rac is activated upon en-
gagement of cadherins and is recruited
to nascent cadherin-mediated adhesion
sites. Rac is eventually lost from AJs
as they mature, indicating that although
Rac is activated upon contact formation,
it is not continually activated by cad-
herins. Rac may increase the strength of
cadherin-mediated cell–cell adhesion via
its influence on IQGAP. IQGAP is local-
ized to the cell–cell junction by binding
to
β
-catenin at the same site as
α
-catenin,
suggesting that binding of IQGAP pre-
vents attachment to the actin cytoskeleton.
Activation of Rac disrupts the binding of
IQGAP to
β
-catenin resulting in an in-
crease in
α
-catenin
β
-catenin association
and an increase in cadherin attachment
to the actin cytoskeleton. In addition, Rac
activation also results in the localization of
the Arp 2/3 complex at cadherin-mediated
cell–cell junctions. The Arp 2/3 complex
initiates actin assembly and may be re-
quired for actin polymerization that results
in the expansion of cell–cell contacts.
The function of Rho has been more
elusive. Studies have reported that Rho
is activated upon cadherin binding while
others have found inhibition of activity
with cadherin binding. This discrepancy
may be due to the different cell types used
in these studies, as the effect of small
GTPases on cadherin-mediated junctions
is dependent on cellular context. ±or
example, VE-cadherin does not require
Rac or Rho activity to localize to the
cell–cell
junction
in
endothelial
cells.
However, when VE-cadherin is expressed
in CHO cells, localization of VE-cadherin
to cell–cell junctions is Rho-dependent.
This study underscores the difference
between endothelial cell and epithelial
cell junctions and shows the importance
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