Cell Junctions, Structure, Function, and Regulation
345
domain. Finally, BP230 is recruited. The
recruitment of BP230 requires
α
6
β
4
adhe-
sions containing both BP180 and plectin.
Thus, plectin appears to function in the
assembly of hemidesmosomes by facilitat-
ing the interaction of BP230 and BP180
with the
β
4
cytoplasmic domain and also
by stabilizing the association of keratin
±laments with hemidesmosomes.
1.5.2
Signaling by
α
6
β
4
Like other integrins,
α
6
β
4
can function as a
signaling receptor.
α
6
β
4
signaling impacts
the survival, proliferation, and migration
of epithelial cells.
α
6
β
4
activates ERK MAP
kinase that plays a critical role in regulat-
ing cell proliferation and survival. The
β
4
cytoplasmic domain becomes phosphory-
lated on tyrosine residues when
α
6
β
4
binds
to laminin 5. These phosphorylations are
important in linking
α
6
β
4
engagement to
the activation of intracellular signals. Al-
though
α
6
β
4
cans
igna
linep
i
the
l
ia
lce
l
ls
that do not form hemidesmosomes, it is
not yet known whether
α
6
β
4
integrins can
activate signals when associated with in-
termediate ±laments at hemidesmosomes.
However, the activation of the epidermal
growth factor (EGF) receptor can trigger
the phosphorylation of the
β
4
cytoplasmic
domain resulting in the disassembly of
hemidesmosomes, which is likely to be
important for cell migration and prolifer-
ation. The
α
6
β
4
integrin has been found
to play a role in promoting cell migra-
tion and invasion of some carcinomas
by activating PI 3-kinase, and the small
GTP-binding proteins Rac and Rho. In
cell culture models,
α
6
β
4
integrin can
promote cell migration on laminin 1 by
associating with the micro±lament cy-
toskeleton and stabilizing the adhesion
of lamellipodia and ±lopodia to laminin1,
suggesting that
α
6
β
4
can function in
both intermediate ±lament-associated and
actin-micro±lament-associated
cell–mat-
rix adhesions. The
α
6
β
4
integrin is also
expressed by the endothelial cells and
neuronal cells. The adhesion complexes
formed by
α
6
β
4
in these cell types have
not been fully characterized. However, it
is known that
α
6
β
4
associates with the
intermediate ±lament cytoskeleton in en-
dothelial cells and is likely to do so in
neuronal cells as well.
In summary, members of the integrin
family of cell adhesion receptors play
important roles in most physiological pro-
cesses. Integrins regulate these processes
by providing a transmembrane connection
between the various integrin ligands and
components of the cell’s cytoskeletal net-
works, and also functioning as signaling
receptors in cooperation with other cell
surface receptors.
2
Cell–Cell Junctions
2.1
Overview
Cell–cell junctions serve to bind cells to-
gether allowing for these cells to act as a
tissue and mediate physiological functions
within an organism. For example, cell–cell
junctions in endothelial cells, which line
the walls of all blood vessels, allow en-
dothelial cells to regulate the movement of
fluid, macromolecules, and immune cells
from the vascular space to the extravas-
cular space of tissues. Cell junctions are
separated into groups according to their
functions, and these groups include ad-
hesive junctions, occlusive junctions and
junctions that allow direct communica-
tion between cells. These junctions have
been extensively studied in epithelial cells
and are shown in Fig. 9. Adhesive junc-
tions include desmosomes and adherens
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