Cell Junctions, Structure, Function, and Regulation
369
role in most if not all physiological pro-
cesses. Much is already known about
the mechanisms regulating cell–matrix
and cell–cell adhesion. Important com-
ponents of cell junctions and their sig-
naling pathways have been identiFed and
characterized. Current evidence suggests
that there are many different junctional-
binding proteins providing alternative cy-
toskeletal linkages and signaling pathways
to mediate cell function. A challenge
for the future will be to determine the
signiFcance of individual linkages and
pathways in diverse physiological con-
texts. Additionally, most of what we know
about cell junctions has been gained from
two-dimensional (2D) cell culture mod-
els focusing on speciFc protein–protein
interactions. Although these studies have
provided important insights into the mech-
anisms regulating the functions of speciFc
proteins, a future task will be to determine
the role of these mechanisms in complex
biological systems. Gene knockout studies
have provided an important starting point.
However, cell adhesion and signaling pro-
teins have multiple interaction partners.
Thus, more information will be gained
from future ‘‘knockin’’ studies of these
proteins with mutations that inhibit indi-
vidual aspects of protein function.
Additionally, the view of cell–matrix and
cell–cell adhesions as sites of mechan-
otransduction is growing in momentum.
Multiple examples are available to demon-
strate the activation of integrin signaling by
changes in hemodynamic shear stress on
endothelial cells. Additionally, it has been
known for many years that the response
of cells to their ECM environment not
only depends on speciFc integrin–ligand
integrations
but
also
on
the
physical
state of these ECM ligands. The rigid-
ity of the ECM can dramatically affect
cell behavior. Changes in ECM rigidity
have been modeled experimentally us-
ing three-dimensional collagen matrices.
Rigid collagen matrices that are attached
to a culture provide resistance to cell-
generated contractile forces at cell–matrix
junctions, whereas nonrigid collagen ma-
trices that float in culture medium do
not. Interestingly, mammary epithelial
cells differentiate into aveolar-like struc-
tures containing basement membranes,
and secrete milk proteins when cultured
in nonrigid three-dimensional collagen
matrices. However, mammary cells fail
to differentiate and continue proliferating
when cultured in rigid three-dimensional
matrices. In contrast, the differentiation
of Fbroblasts into myoFbroblasts requires
the increase in ECM rigidity that ac-
companies wound healing. In culture,
Fbroblasts differentiate into myoFbrob-
l
a
s
t
swhencu
l
tu
redinr
ig
id
,bu
tno
tin
nonrigid, three-dimensional collagen ma-
trices. Clearly, identifying the molecular
mechanisms that govern mechanotrans-
duction at cell junctions is an important
area for future investigation.
±inally, in most instances, integrins and
cadherins regulate cell behavior by collabo-
rating with other cell surface receptors. ±or
example, the interaction of VE-cadherin
with VEG±-receptor 2 modulates VEG±-
induced signaling, perhaps by clustering
the VEG± receptor with phosphatases in
the AJ. In addition, evidence suggests that
E-cadherin may cocluster and activate the
EG± receptor resulting in activation of EG±
signaling independent of the EG± ligand.
Similar observations have been made in
studies examining the collaboration be-
tween integrin and growth factor receptor
signaling. Thus, the molecular mecha-
nisms governing the cross-talk between
cell junction proteins and other signal-
ing receptors will be a continuing area of
intense investigation.
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