366
Cell Junctions, Structure, Function, and Regulation
guanylate kinase (MAGUK) also contain
three to fve PDZ domains and an SH3 do-
main. OF these proteins, the most closely
studied group is the zonula occluding
proteins (ZO-1, ZO-2, ZO-3). The zonula
occluding proteins all bind to the claudins
via their PDZ domains and can attach
to actin flaments, thereby anchoring the
tight junction to the actin cytoskeleton.
ZO-1 and ZO-2 have also been Found
in AJs, presumably due to their abil-
ity to bind to
α
-catenin; however, their
presence in the AJ may only occur in
the absence oF TJs. In addition, these
proteins serve a scaFFolding, role local-
izing transcription Factors and signaling
proteins to the tight junction plaque.
±or example, ZONAB (ZO-1-associated
nucleic acid binding protein) is a tran-
scription Factor that acts as a repressor
oF Erb-2 promoter. ZONAB Function is
regulated, in part, by the sequestration
oF ZONAB at TJs through its binding
to ZO-1.
Attachment to the actin cytoskeleton
has been implicated as a possible control
point For the regulation oF tight junction
Function. A number oF proteins located
in the tight junction plaque can directly
link claudin to the actin cytoskeleton as
described For ZO proteins. Interestingly,
occludin has been Found to directly link
to actin flaments. The tight junction
may also serve as a site regulating cy-
toskeletal dynamics. Indeed, myosin II
is localized to the tight junction plaque
through its association with cingulin. The
structure oF cingulin contains a globu-
lar N-terminus linked to a coiled–coiled
domain that allows For the Formation oF
dimers. The N-terminus mediates bind-
ingtoZO
-1
,ZO
-2
,JAM
,andac
t
in
.The
C-terminus has been shown to bind non-
muscle myosin II. Other proteins that
act to bundle actin flaments, such as
cortactin, are also localized to the tight
junction plaque. Although it is clear that
the tight junction is associated with the
actin cytoskeleton, the Functional signiF-
icance oF this attachment is not clear.
Studies have attempted to disrupt actin
interaction through the expression oF mu-
tant proteins; however, these studies are
hampered by the endogenous levels oF
these proteins and/or by the ability oF
other proteins to compensate For the lost
protein Function. A major area For Future
research will be to determine how the in-
teraction oF the plaque proteins with the
actin cytoskeleton regulates
de novo
assem-
bly, reorganization, and acute regulation oF
the paracellular permeability oF the tight
junction.
2.5.3
Regulation of Tight Junction
Assembly/Disassembly
The close association between tight junc-
tion Function and the actin cytoskeleton
implicates the small GTPases (Rho, Rac,
and Cdc42) in the regulation oF the bar-
rier Function oF tight junctions. A number
oF studies have used the expression oF
dominant negative or constitutively ac-
tive Forms oF these proteins and Found
that the expression oF either Form de-
creases TER, increases paracellular soluble
flux, and decreases Fence Function. These
fndings suggest that the activity oF Rho
GTPases needs to be tightly regulated,
as either increased or decreased activity
will disrupt tight junction Function. Al-
ternatively, localized activation oF GTPase
activity may be an important Factor in
regulating changes in TJ Function. Local
changes in activity could be controlled by
guanine nuclear exchange Factors (GE±s)
associated with the tight junction plaque
proteins. GE±-H1/LFc has recently been
Found to localize in the TJ and overexpres-
sion oF wild-type GE±-H1/LFc increased
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