Cell Junctions, Structure, Function, and Regulation
365
barrier of the skin. Importantly, removal
of one claudin isoform does not result in
the complete loss of tight junction strands
in the affected tissue, thereby demonstrat-
ing that it is the combined function of
different claudin isoforms that creates the
selectivity of the tight junction.
Two other transmembrane components
have been found to play a major role in
the formation and regulation of TJs, oc-
cludin and junctional adhesion molecule
(JAM). Occludin was the Frst protein to
be isolated from tight junction enriched
fractions. Immunofluorescent and immu-
noelectron microscopic analysis showed
that this protein was localized to the tight
junction strand. Like claudins, occludins
contain four transmembrane regions with
two extracellular loops, and their amino
and carboxyterminal tails are located in
the cytoplasm. Initial studies found that
overexpression of occludin in MDCK cells
would increase the number of tight junc-
tion strands and elevate TER. However, by
generating occludin-deFcient embryonic
stem cells and occludin-knockout mice,
it was shown that functional tight junction
strands could be formed in the absence of
occludin. Histological examination of cer-
tain tissues did show some abnormalities
such as chronic inflammation and hyper-
plasia of the gastric epithelium, suggesting
that occludin plays a regulatory role rather
than establishing the barrier itself. This
is supported by studies that have corre-
lated changes in occludin phosphorylation
with changes in barrier function. JAM is
a single membrane-spanning protein with
two IgG-like domains in its extracellular re-
gion that mediate homotypic binding. JAM
is not integrated into the tight junction
strand; however, studies have shown that
JAM is involved in tight junction forma-
tion and barrier function possibly through
an interaction with occludin.
2.5.2
Plaque Proteins of Tight Junctions
Like desmosomes and AJs, TJs also have
a cytoplasmic plaque region containing
proteins that serve both structural and
signaling roles (Table 7). The plaque re-
gion of the tight junction is made up of a
large number of proteins containing PDZ
domains, named from the Frst three pro-
teins Frst identiFed within this domain
[P
SD-95-postsynaptic density protein 95;
D
lg-discs large proteinan; Z
onula (ZO)
occludins-1]. The PDZ domain mediates
interaction with other proteins, including
other PDZ proteins or transmembrane
proteins containing the S/T-X-V in their
C-terminus. As seen in Table 7, the PDZ
containing proteins found in the tight
junction can be divided into two subsets
based on whether the protein contains a
guanylate kinase homology region. Pro-
teins containing the membrane-associated
Tab. 7
Tight junction plaque proteins.
Type
Protein name
PDZ (MAGUK)
ZO-1
ZO-2
ZO-3
MAGI/BAP1
PDS (non-MAGUK)
PAR-3 (ASIP)
PAR-6
AF-6
Non-PDZ
Cingulin
Symplekin
ZONAB
ASH1
4.1R
Cytoskeletal
Actin
Spectrin
Signaling
RAB13, RAB3B
Atypical protein kinase C
(
ζ
,
λ
)
ZAK
Other
Sec6/8
7H6
BG9.1
19B1
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