Cell Science at a Glance 3677

Tight junctions at a also includes adherens junctions and differentiation. Several types of protein
desmosomes – see poster) and are components of TJs have been identified, and
glance connected to the actin cytoskeleton. In these have revealed a basic architectural
Maria S. Balda and Karl Matter freeze-fracture electron microscopy, TJs principle in which transmembrane proteins
appear as intramembrane strands that form are linked to a cytoplasmic plaque that is
Department of Cell Biology, UCL Institute of
Ophthalmology, University College London, 11-43 a net-like meshwork that encircles cells (see formed by a network of scaffolding and
Bath Street, London EC1V 9EL, UK poster). TJs contribute to the formation of adaptor proteins, signalling components and
e-mails: m.balda@ucl.ac.uk; k.matter@ucl.ac.uk polarised epithelial and endothelial barriers actin-binding cytoskeletal linkers (see
Journal of Cell Science 121, 3677-3682
by controlling the extent and selectivity of poster). Recent work into the cellular
Published by The Company of Biologists 2008 diffusion along the paracellular pathway functions of these proteins has started to
doi:10.1242/jcs.023887 (the gate function) and by forming an reveal how TJs are formed and which of
apical/basolateral intramembrane diffusion their components contribute to their
Tight junctions (TJs) are morphologically barrier in the outer leaflet of the plasma characteristic morphological appearance, as
distinct and highly regulated areas of close membrane (the fence function) (Cereijido well as how they are regulated and how they
contact between the plasma membranes of et al., 2008). Exciting research in recent signal to regulate changes in epithelial cells.
neighbouring epithelial and endothelial years has also linked TJs to intracellular Moreover, defects in TJ components, as
cells. They are the most apical component signalling mechanisms that guide well as dysregulation of their expression,
of the epithelial junctional complex (which epithelial-cell proliferation, polarisation and contribute to inherited diseases and to
cancer, and several TJ proteins are targeted
by viruses, bacteria and other pathogens.
This suggests that TJ-associated processes
have an important role in the pathogenesis
of a wide range of diseases. Here, we give
a brief review of some of the recently
Journal of Cell Science

r described components of TJs, and discuss

how they are thought to contribute to TJ
structure and function.

Components of TJs
Transmembrane proteins
TJs contain two principal types of
transmembrane components – tetraspan and
single-span transmembrane proteins. The
Actin tetraspan proteins are occludin, tricellulin
and the claudins, all of which are associated
with the junctional intramembrane strands
described above and are thought to have the
same membrane topology (both the N- and
C-termini in the cytosol). Tetraspan proteins
form the paracellular permeability barrier
t
and determine the capacity and the
selectivity of the paracellular diffusion
pathway (see below).

Claudins
The claudins, which constitute a family of
Tetraspan
at least 24 members, are expressed in a
ZO-1 occludin, claudins, JAMs, Bves, ZO-1, ZO-2, ZO-3,
JAM-A, TGFβ receptor type I, ZO-1, ZO-2, ZO-3, cingulin, Yes,
PI3K, aPKC, ERK1, casein kinase 1ε, PP1, PP2A, Itch, F-actin
ZO-1
ZO-1, ZO-2, ZO-3, MUPP1, PATJ, WNK4, OAP1, EphA2,
cingulin, ZONAB, Gα12, Apg2, Tuba, Shroom2, α-actinin 4, ARVCF,
α-catenin, AF6, α-dystrobrevin, connexins 30, 36, 43, 45, 47 and 50,
tissue-specific manner. They are thought to
F-actin, Helicobacter pylori CagA
Clostridium perfringens enterotoxin, hepatitis C virus
ZO-2 occludin, claudins, ZO-1, cingulin, F-actin, ARVCF, α-catenin,
4.1R, hScrib, connexin 43, SAFB, C/EBP
be the main structural components of
Jun, Fos, Myc, Csk, papillomavirus E6, adenovirus type 9 E4-ORF1, AP1
occludin, ZO-1, cingulin, PAR3, MUPP1, MAGI1, AF6, CASK, LFA-1, PICK1
reovirus, adenovirus, coxsackievirus
Pals1, PATJ, PAR6
ZO-1
ZO-3
Cingulin
occludin, claudins, ZO-1, cingulin, PATJ, AF6, p120 catenin, F-actin
JAMs, ZO-1, ZO-2, ZO-3, GEF-H1, myosin, F-actin
intramembrane strands (Furuse and
JACOP F-actin

Signalling proteins
Pals1
PATJ
CRB3, PATJ, PAR6, LIN7, MPP4
CRB3, Pals1, ZO-3, TSC2, MASCOT, JEAP, angiomotin, papillomavirus E6
Tsukita, 2006). The claudin composition of
aPKC
GEF-H1/Lfc
CDK4
G proteins
occludin, PAR3, PAR6
cingulin, RhoA, PAKs, PAR1, neurabins, microtubules
ZONAB, D-type cyclins
ZO-1 (Gα12)
PAR3/ASIP

PAR6
JAMs, PAR6, aPKC, TIAM1, 14-3-3 proteins,
KIF3A, PTEN, phospholipase C β, nectin
CRB3, PAR3, aPKC, Cdc42, Rac1, Pals1, mLgl, TGFβ receptors, Smurf; phospholipase Cβ, ECT2
a junction determines the ion selectivity of
PTEN
RPTPβ
Yes
Tuba
MAGI1, MAGI2, MAGI3, PAR3
MAGI3
occludin
ZO-1, Cdc42
MAGI1

MAGI2
PTEN, JAMs, synaptopodin, MASCOT, α-actinin 4, Rap GEP,
papillomavirus E6, adenovirus E4-ORF1
PTEN, β1 adrenergic receptor
the paracellular pathway, because changes
PP1
PP2A
Rab3b
Rab13
occludin
occludin
Noc2, pIgR, calmodulin
protein kinase A, MICAL-L2
MAGI
MUPP1
Shroom2
PTEN, RPTPβ, pro-TGFα, leukemia virus type 1 Tax oncoprotein
JAMs, claudins, CAR, Kit, NG2; TAPP1/2, papillomavirus E6, adenovirus E4-ORF1
ZO-1, myosin VIIa
in claudin expression correlate with
WNK4 claudins

Transcriptional and post-transcriptional regulators

JEAP
Sec6/8
LYRIC
PATJ
basolateral transport machinery
unknown
alterations in conductivity for specific
ZONAB
Symplekin
AP1
CDK4, ZO-1, symplekin, RalA
polyadenylation factor CstF, HSF1, ZONAB
ZO-2
PILT
Barmotin
unknown
unknown ions. Via their C-terminal cytoplasmic
huASH1 unknown

domains, claudins interact with several

Abbreviations: AF6, afadin; aPKC, atypical PKC; ARVCF, Armadillo-repeat protein deleted in velocardiofacial syndrome; Bves, blood-vessel epicardial substance; CAR, coxsackievirus and adenovirus receptor; CASK, Ca2+/calmodulin-dependent serine
protein kinase; CLMP, CAR-like membrane protein; CRB3, Crumbs homologue 3; Csk, Src tyrosine kinase; D, desmosomes; ECT2, epithelial-cell transforming sequence 2 oncogene; ESAM, endothelial-cell-selective adhesion molecule; Eph, ephrin; F-actin,
filamentous actin; GEF-H1, guanine-nucleotide exchange factor H1; HSF1, heat shock transcription factor 1; JACOP, junction-associated coiled-coil protein; JAM, junctional adhesion molecule; JEAP, junction-enriched and -associated protein; LFA-1, lympho-
cyte function-associated antigen 1; LYRIC, lysine-rich CEACAM1 co-isolated protein; MASCOT, MAGI1-associated coiled-coil tight junction protein; MAGI, membrane-associated guanylate kinase; mLgl, mammalian LETHAL giant larvae homologue; MPP4,
PSD95–DlgA–ZO-1 homology (PDZ)-
membrane palmitoylated protein subfamily member 4; MUPP1, multiple PDZ-domain protein; Noc2, no C2 domains protein; OAP1, OSP/claudin-11-associated protein 1; PAK, p21-activated kinase; PATJ, Pals1-associated tight-junction protein; PI3K, phos-
phoinositide 3-kinase; plgR, polymeric immunoglobulin receptor; PP, protein phosphatase; PTEN, phosphatase and tensin homologue; RPTPβ, receptor tyrosine phosphatase β; SAFB, scaffold attachment factor B; TAPP, tandem PH-domain-containing
protein; TIAM, T-cell lymphoma invasion and metastasis; TJ, tight junction; TSB2, tuberous sclerosis 2; WNK, with-no-K (Lys); ZO, zonula occludens; ZONAB, ZO-1-associated nucleic-acid protein
Journal of Cell Science 2008 (121, pp. 3677-3682)
domain-containing cytosolic proteins and
these interactions are thought to be
(See poster insert) important for junction assembly. The
 3678 Journal of Cell Science 121 (22)
extracellular loops of claudins have been
proposed to create charge-selective
paracellular aqueous pores that permit the
passive diffusion of ions between cells
(Krause et al., 2008; Van Itallie and
Anderson, 2006); however, structural
evidence for such pores is still missing and
it is not clear how the extracellular
domains of different claudin molecules
cooperate to assemble continuous, ion-
conductive pores.
Occludin
Similar to the claudins, occludin is
associated with intramembrane strands,
although it is not required for their
assembly. It regulates the paracellular
diffusion of small hydrophilic molecules,
has been linked to the formation of the
intramembrane diffusion barrier and
regulates the transepithelial migration of
neutrophils (Aijaz et al., 2006). Either one
of its N- and C-terminal cytosolic domains
is sufficient to anchor the protein in the
Journal of Cell Science
junction and to ensure a continuous
junctional distribution. Although both
domains interact with components of the
cytosolic plaque, they have different
functional properties – the N-terminal
domain regulates neutrophil transmigration
and the C-terminal domain regulates the
paracellular diffusion of small hydrophilic
tracers as well as targeting of occludin to
the basolateral membrane. Similarly, the
two extracellular loops of occludin regulate
its accumulation at junctions as well as
paracellular permeability. Occludin has also
been linked to the regulation of various
subcellular signalling pathways, such as
MAP-kinase-dependent pathways and
RhoA signalling. In the case of the
regulation of Raf1 and TGFβ, this
signalling function involves the second
(more C-terminal) extracellular domain
(Barrios-Rodiles et al., 2005; Wang et al.,
2005; Yu et al., 2005). However, the
underlying molecular mechanisms of many
of the processes to which occludin has been
linked remain to be determined and the
functional relevance of most of its
biochemical interactions is still unknown.
Tricellulin
Tricellulin was first identified as a protein
that is downregulated by the zinc-finger
transcription factor Snail (Ikenouchi et al.,
2005). In contrast to occludin and the
claudins, tricellulin is enriched at the
junctions between three epithelial cells.
The suppression of tricellulin expression
by RNA interference impairs the barrier
function of TJs, which suggests that it is
required for junction formation (Ikenouchi
et al., 2005). In its C-terminal cytoplasmic
domain, tricellulin shares a conserved
domain with occludin that mediates
binding to the tight junction protein 1
(TJP1, hereafter referred to as ZO-1), a
cytosolic component of TJs (see below)
(Riazuddin et al., 2006). Although this
domain is affected in mutations that cause
deafness, the role of the interaction of
tricellulin with ZO-1 in the formation of
junctions is unknown.
Single-span transmembrane
proteins
Most of the single-span transmembrane
proteins that are associated with TJs,
including the junctional adhesion
molecules (JAMs), are members of
the CTX/VH-C2 family of adhesion
proteins. These proteins contain two
immunoglobulin folds in their extracellular
domain, one of the VH- and one of the
C2-type (Bazzoni, 2003). Four JAMs –
JAM-A, -B, -C and -D – have been
identified, and all four can mediate
homotypic cell-cell adhesion. Several of the
JAM proteins, as well as the related
proteins coxsackievirus and adenovirus
receptor (CAR), CAR-like membrane
protein (CLMP) and the endothelial-cell-
selective adhesion molecule (ESAM),
associate with TJs and interact with adaptor
proteins of the cytoplasmic plaque
(Bazzoni et al., 2000; Ebnet et al., 2003;
Ebnet et al., 2000; Raschperger et al., 2004;
Wegmann et al., 2004). JAMs regulate
adhesion between leukocytes and
endothelial cells, as well as the paracellular
transmigration of leukocytes across the
endothelium, and have been shown to
regulate the development of cell polarity by
binding to the evolutionarily conserved
complex between PAR3, PAR6 and
atypical PKC (aPKC) (Bradfield et al.,
2007; Ebnet et al., 2004; Weber et al.,
2007). The role of JAMs in cell polarisation
is also important during spermatogenesis,
because JAM-C-deficient spermatids fail to
polarise and differentiate.
Another type of single-span membrane
protein that is associated with TJs is
Crumbs homologue 3 (CRB3), one of the
three vertebrate homologues of the
Drosophila melanogaster protein Crumbs
(Lemmers et al., 2004; Makarova et al.,
2003; Roh et al., 2003). CRB3 is present
across the entire apical membrane and only
a minor fraction of the entire cellular pool
is associated with TJs. The cytoplasmic
domain of CRB3 interacts with cytosolic
adaptor proteins such as Pals1, which link
it to the cellular machinery that regulates
epithelial polarisation (Hurd et al., 2003;
Lemmers et al., 2004). Consequently, the
overexpression of CRB3 leads to delayed
TJ formation in monolayers of Madin-
Darby canine kidney (MDCK) cells and to
disruption of epithelial morphogenesis.
CRB3 also localises to the primary cilium
and regulates ciliary morphogenesis (Fan
et al., 2007).
Finally, Bves (a member of the
Popeye-domain-containing family of
transmembrane proteins), also localises to
TJs in polarised epithelia and associates
with ZO-1-based complexes (see below)
(Osler et al., 2005). The downregulation
of Bves in cultured cells reduces
transepithelial resistance and junctional
protein localisation at the membrane,
which suggests that Bves contributes to the
establishment and/or maintenance of
epithelial integrity (Osler et al., 2005);
however, the role of Bves in TJs is poorly
understood and little is known about its
interaction partners.
The cytoplasmic plaque
Intercellular junctions have similar
building principles in different cell types
and often share components. For example,
many of the components that are associated
with epithelial junctions are also found at
neuronal synapses (Yamada and Nelson,
2007). These components often have
similar functions, such as the regulation of
the cytoskeleton to guide the assembly and
disassembly of the junction or synapse. A
major structural feature of junctions is that
they contain a cytoplasmic plaque, which
forms an interface between the junctional
membrane and the cytoskeleton. In TJs, the
cytoplasmic plaque functions in the
regulation of adhesion and paracellular
permeability, as well as in the transmission
of signals from the junction to the cell
interior to regulate cellular processes such
as migration and gene expression. The
cytoplasmic plaque is formed by a
complex network of adaptors, scaffolding
and cytoskeletal proteins that crosslink
junctional membrane proteins and connect
TJs to the actin cytoskeleton (see poster).
The TJ plaque also recruits an array of
signalling components that includes
classical signalling proteins, such as
kinases and phosphatases, as well as dual-
localisation proteins that can reside at

junctions as well as in the nucleus and
provide a mechanism by which TJs can
regulate gene expression (Guillemot et al.,
2008; Matter and Balda, 2007; Paris et al.,
2008).
ZO-1, the first TJ protein to be identified,
is one of the most-studied TJ plaque
components. It has the typical functional
properties and domain structure of a
scaffolding protein – it contains several
protein-protein interaction domains,
including three PDZ domains, one SH3
domain and one guanylate kinase
homology (GUK) domain), as well as an
F-actin-binding domain. ZO-1 interacts
with claudins through its first PDZ domain,
with ZO-2 or ZO-3 (two other TJ adaptors
of the same protein family as ZO-1)
through its second PDZ domain, with
occludin through the GUK domain, and
with actin and α-catenin through its large
C-terminal domain (Fanning, 2001;
Umeda et al., 2006). In addition, ZO-1
Journal of Cell Science
binds through its SH3 domain to several
signalling proteins such as a of paracellular permeability, as well as in
serine/threonine protein kinase, the Y-box
transcription factor ZONAB and the heat-
shock protein Apg2, as well as Gα12, an α
subunit of heterotrimeric G proteins
(Matter and Balda, 2007; Meyer et al.,
2002). These interaction partners can
regulate each other; for example, Apg2
regulates the interaction between ZO-1 and
ZONAB during the heat-shock response,
which results in the nuclear accumulation
and activation of ZONAB.
Other junctional proteins are present as
components of evolutionarily conserved
signalling complexes, which are based on
the adaptors PAR3 and PAR6, or Pals1 and
PATJ (Assemat et al., 2007; Wang and
Margolis, 2007). Both of these complexes
are found in both vertebrates and
invertebrates and are crucial for the
development of cell polarity and for
epithelial morphogenesis. Both complexes
bind to TJ membrane proteins: the PAR3-
PAR6 complex binds to JAMs and the
Pals1-PATJ complex binds to CRB3. The
complexes are not independent but, instead
interact with each other. For example,
PAR6 also binds to Pals1 and CRB3 (Hurd
et al., 2003; Lemmers et al., 2004), and
ZO-3 – an interaction partner of ZO-1 –
binds to PATJ (Michel et al., 2005; Roh et
al., 2002). However, in most cases in which
such interactions between components of
different complexes have been identified, it
has not yet been determined how common
Journal of Cell Science 121 (22)
such interactions are and how they
contribute to junction assembly and
function.
Functions of TJs
The classical functions of TJs are the
regulation of paracellular permeability and
the formation of an apical-basolateral
intramembrane diffusion barrier that helps
to maintain cell-surface polarity. More
recently, TJs have been linked to various
signalling mechanisms that guide gene
expression, proliferation and differentiation.
TJ components also form complexes with
the cellular machinery that regulates
basolateral cell-surface transport (the Sec6-
Sec8 complex); however, this does not
appear to be an exclusive property of TJ
proteins because these complexes also
contain adherens-junction components,
such as E-cadherin and nectin 2 (Yeaman et
al., 2004). The actual structure that forms
the intramembrane diffusion barrier is
poorly understood; hence, we limit our
discussion to the role of TJs in the regulation
signalling during epithelial proliferation and
differentiation.
Paracellular permeability
TJs allow the passive selective diffusion of
ions and small hydrophilic molecules
through the paracellular pathway across
epithelia and endothelia. The molecular
mechanisms that are responsible for
selective ion permeability and for diffusion
of small hydrophilic molecules are distinct,
as many manipulations and regulatory
mechanisms specifically affect only one of
the two processes, or downregulate one
while activating the other (Aijaz et al.,
2006). For example, the overexpression of
occludin or certain occludin mutants in
cultured epithelial cells stimulates the
paracellular diffusion of small hydrophilic
molecules but increases transepithelial
electrical resistance (a measure of
transepithelial ion permeability) (Aijaz
et al., 2006).
Occludin, tricellulin and the claudins are
the main TJ membrane components that
are involved in paracellular permeability.
On the basis of observations in human
disease, mouse models and cultured cell
lines, it has been suggested that the claudin
composition of TJs is a major determinant
of the permeability properties of a tissue
(Furuse and Tsukita, 2006; Van Itallie and
Anderson, 2006). Absence of specific
claudins can cause organ-specific defects,
3679
such as neurological, reproductive and
renal defects. For example, mice that lack
claudin 1 die after birth because of water
loss across the skin, and the absence of
claudin 5 causes leakage of small tracers
across the brain endothelium (Furuse and
Tsukita, 2006). Experiments with epithelial
cell lines further suggest that different
claudins favour paracellular diffusion of
specific ions and, as mentioned above,
these have lead to a model in which
claudins form homo- and hetero-oligomers
that engage in intercellular interactions to
form paracellular aqueous pores. The ion-
selectivity of these pores is determined by
their claudin composition (Krause et al.,
2008; Van Itallie and Anderson, 2006).
The process that mediates the paracellular
diffusion of small hydrophilic molecules is
less well understood and the actual
mechanism by which such molecules
permeate the junction is not known.
However, the process is regulated by RhoA
signalling and seems to require
actinomyosin-driven processes (Aijaz et al.,
2006; McKenzie and Ridley, 2007; Nusrat
et al., 2000; Utech et al., 2006). It is
therefore possible that dynamic
rearrangements of intramembrane strands
lead to paracellular diffusion. Occludin has
been linked to the regulation of paracellular
permeability of small hydrophilic
molecules across cultured epithelial
monolayers (Balda and Matter, 2000;
Schneeberger and Lynch, 2004); it is
thought that this regulatory mechanism
involves phosphorylation events as well as
the actin cytoskeleton because the
C-terminal domain of occludin binds to
protein kinases and lipid kinases, as well as
to actin filaments and cytoskeletal linkers
(Aijaz et al., 2006; Schneeberger and
Lynch, 2004). Strikingly, live-cell-imaging
experiments using GFP-tagged occludin
have recently suggested that occludin
diffuses within the junction, suggesting that
occludin dynamics might contribute to
paracellular diffusion (Shen et al., 2008).
However, because the experiment involved
an N-terminal GFP-tag and blocking the N-
terminus is known to interfere with
anchoring of occludin within the junction,
it is not clear whether the observed dynamic
properties indeed reflect physiological
occludin behaviour (Huber et al., 2000).
Cell proliferation, polarity and
differentiation
The regulation of cell proliferation and
polarisation is crucial for the development
 3680 Journal of Cell Science 121 (22)
of differentiated tissues. Several studies
have linked TJs to the regulation of cell
proliferation and cell polarity. Similar to
adherens junctions, TJs function in the
suppression of proliferation (Gonzalez-
Mariscal et al., 2007; Matter and Balda,
2007). Occludin suppresses oncogenic
Raf-1 signalling (Wang et al., 2005) and
ZO-1 interacts with ZONAB, thereby
regulating gene expression, cell
proliferation and epithelial morphogenesis
(Matter and Balda, 2007; Sourisseau et al.,
2006). ZO-2 localises to the nucleus and
interacts with the DNA-binding protein
scaffold attachment factor B (SAFB) as
well as with several transcription factors
(Gonzalez-Mariscal et al., 2007; Huerta et
al., 2007; Traweger et al., 2003). TJs have
also been linked to the regulation of RhoA-
dependent proliferation through the
junction-associated guanine-nucleotide
exchange factor GEF-H1 and the
junctional scaffolding protein cingulin,
which binds to and inhibits GEF-H1 (Aijaz
Journal of Cell Science
et al., 2005; Guillemot and Citi, 2006). It
remains to be determined, however,
whether and how these different TJ-
associated signalling mechanisms are
connected with each other and by which
transmembrane proteins they are regulated.
Strikingly, deficiencies in ZO-1 or ZO-2
expression are embryonic lethal in mice,
which suggests that the two TJ proteins are
important for development (Katsuno et al.,
2008; Xu et al., 2008). Whether any of the
signalling mechanisms that have been
identified in cell culture experiments
contribute to these phenotypes in vivo,
however, is not clear.
Two evolutionarily conserved cell-polarity
signalling pathways reside at TJs. Similar to
D. melanogaster, the CRB3-Pals1-PATJ
pathway regulates junction assembly and
biogenesis of the apical membrane in
vertebrate epithelial cells (Shin et al., 2006).
The signalling pathway downstream of the
complex has not yet been elucidated. The
second conserved signalling module is the
PAR3-PAR6-aPKC complex, which was
originally described as a regulator of
cytoplasmic partitioning in the early embryo
of Caenorhabditis elegans. PAR3 associates
with the cytoplasmic domain of JAMs,
which results in the recruitment of the
PAR3-PAR6-aPKC complex to cell-cell
junctions (Bradfield et al., 2007; Ebnet et
al., 2004; Weber et al., 2007). The complex
functions as an effector of Cdc42, a Rho-
family GTPase that is essential for
epithelial-cell polarity and becomes
activated during junction formation –
binding of the complex to GTP-bound
Cdc42 stimulates activation of aPKC and,
consequently, the formation of mature TJs
(Ebnet et al., 2004; Shin et al., 2006). In
agreement with these observations, Cdc42
is crucial for the establishment of epithelial
polarity during early mammalian
development, and the aPKC isoforms PAR3
and PAR6 are necessary for the formation
of the epidermal barrier (Helfrich et al.,
2007; Wu et al., 2007). Interestingly, PAR3
also suppresses the activation of Rac1,
another member of the RhoGTPase family,
during junction formation by binding the
guanine nucleotide exchange factor TIAM1
(Chen and Macara, 2005). This function,
however, does not require PAR6 or aPKC,
which suggests that PAR3 can act
independently of PAR6 and aPKC.
TJs in disease
Defects in permeability
TJ transmembrane proteins are affected in
several inherited diseases, which suggests
that the selectivity of the junctional
diffusion barrier is physiologically
important. For example, mutations in
claudin 16 (which was originally called
paracellin-1) and claudin 19 cause
hypomagnesaemia (renal magnesium
wasting) owing to a deficiency in
paracellular magnesium resorption in the
kidney (Konrad et al., 2006; Simon et al.,
1999). The two proteins interact and are
thought to form a paracellular cation pore.
Similarly, mutations in claudin 14 and
tricellulin cause hereditary deafness, which
is likely to be the result of alterations in
paracellular permeability (Riazuddin et al.,
2006; Wilcox et al., 2001).
The WNK (with-no-K[Lys]) kinases
WNK4 and WNK1, mutations in which
cause hypertension (pseudohypo-
aldosteronism type II) because of their
effects on renal salt reabsorption and K+
excretion (Wilson et al., 2001), are also
thought to act through claudins. Disease is
caused by WNK4 alleles that have gain-of-
function mutations and therefore
hyperstimulate claudin phosphorylation,
which results in increased paracellular
Cl– permeability and, subsequently,
hypertension (Kahle et al., 2004; Yamauchi
et al., 2004; Richardson and Alessi, 2008).
The expression of several TJ components
is affected in various carcinomas. For
example, the expression levels of ZO-1 and
ZO-2 are dysregulated in different types of
cancers and, in the case of breast cancer, low
expression of ZO-1 has been correlated with
a poor prognosis (Chlenski et al., 2000;
Chlenski et al., 1999; Hoover et al., 1998;
Kleeff et al., 2001; Martin et al., 2004;
Morita et al., 2004; Resnick et al., 2005;
Takai et al., 2005). Similarly, several
junctional scaffolding proteins are bound
and inactivated by viral oncogenes
(Glaunsinger et al., 2001; Latorre et al.,
2005). By contrast, ZONAB and its
activating protein Apg2 are both
upregulated in hepatocellular carcinomas,
which suggests that this proliferation-
promoting pathway is stimulated (Arakawa
et al., 2004; Gotoh et al., 2004; Hayashi et
al., 2002).
To what extent these alterations are a cause
or a consequence of carcinogenesis is
generally not clear. Nevertheless, claudin 1
has been shown to promote transformation
and metastatic behaviour in colon cancer
(Dhawan et al., 2005). The underlying
molecular mechanism by which claudin 1
regulates migration is not clear. However,
it might involve the association of
claudin 1 with integrin-based complexes,
similar to the role of claudin 11 in cell
migration (Tiwari-Woodruff et al., 2001).
TJ proteins as targets of pathogens
TJ proteins are targeted by several types of
pathogens, and these interactions often
lead to junctional dissociation and the loss
of epithelial barrier function. For example,
proteolytic enzymes from pollen and dust
mites, as well as enterotoxin from
Clostridium perfringens, attack junctional
membrane proteins, which results in
paracellular leakage (Runswick et al.,
2007; Sonoda et al., 1999; Wan et al.,
1999). In addition, several TJ
transmembrane proteins function as
receptors for viruses. For example,
claudin 1 functions as a co-receptor for the
hepatitis C virus and is required for virus
entry (Evans et al., 2007). Similarly,
several of the TJ-associated members of
the CTX-protein family, such as the
coxsackievirus and adenovirus receptor
(CAR) and JAM-A (which binds to
reovirus), also act as viral receptors
(Barton et al., 2001; Cohen et al., 2001;
Walters et al., 2002). In some cases (e.g.
hepatitis C virus), binding of virus to the
TJ protein favours its entry into cells,
whereas in other cases the interaction helps
to overcome the junctional diffusion
barrier to enable the virus to access its
actual receptor (e.g. rotavirus) or to

promote the release of virus from the
epithelium (e.g. adenovirus) (Evans et al.,
2007; Nava et al., 2004; Walters et al.,
2002). Another striking example is
provided by the bacterium Helicobacter
pylori, which causes gastric ulcers and
cancer (Pritchard and Crabtree, 2006).
H. pylori translocates a protein called
CagA into host cells. CagA associates with
the ZO-1–JAM-A complex, which is
thought to contribute to corruption of the
gastric epithelial barrier (Amieva et al.,
2003). Because the binding of CagA causes
the redistribution of ZO-1 complexes, it is
possible that ZO-1-associated signalling
mechanisms contribute to the development
of H. pylori-induced pathologies.
Conclusions and perspectives
A complex network of TJ-associated
proteins has been identified over the last 20
years. Despite this, we have only begun to
understand how these proteins interact with
each other and cooperate to perform various
Journal of Cell Science
junctional functions. Thus, the identification
of specific TJ-associated molecular
mechanisms remains a major challenge for
the future. For example, many junctional
proteins can bind to several other proteins
and it seems unlikely that they associate
with all of them at once; it will therefore be
important to identify the role of particular
interactions for junction assembly, and to
determine when they occur and for which
functions of TJs they are important.
Moreover, substantial evidence indicates the
existence of mechanisms that permit the
paracellular permeation of specific ions and
small hydrophilic molecules; however, the
underlying molecular structure and
machinery are only poorly understood and
there is little structural information. Only a
few animal models that are deficient in
specific TJ proteins have thus far been
generated and most have not been analysed
in great detail. Moreover, TJ junctions will
have to be studied in different species in the
future, because the example of ZO-3 has
shown that deficiency of a specific protein
can lead to different phenotypes in different
animal models (Adachi et al., 2006; Kiener
et al., 2008; Xu et al., 2008). To understand
the role of TJ-associated signalling
mechanisms and junctional barrier
properties, it will be crucial to determine the
role of TJ-associated proteins in
development and their importance for
normal organ function. Finally, TJ proteins
appear to contribute to many diseases,
ranging from viral infections to cancer. The
understanding of TJs at a molecular level,
Journal of Cell Science 121 (22)
and of how they contribute to such diseases,
should provide therapeutic opportunities for
a wide range of disorders.
We apologise to anyone whose work and publications
could not be cited due to the limited available space.
M.S.B. and K.M. are supported by the Medical
Research Council, the Biotechnology and Biological
Sciences Research Council, the Association for
International Cancer Research, Fight for Sight and the
Wellcome Trust. The electron micrograph of the
junctional complex in kidney epithelial cells is
reprinted from Huber et al. (Huber et al., 1998), with
permission. The electron microscopic image of a
freeze-fracture replica from intestinal epithelial cells
was kindly provided by Peter Munro, UCL Institute
of Ophthalmology, London, UK.
References
Adachi, M., Inoko, A., Hata, M., Furuse, K., Umeda, K.,
Itoh, M. and Tsukita, S. (2006). Normal establishment of
epithelial tight junctions in mice and cultured cells lacking
expression of ZO-3, a tight-junction MAGUK protein. Mol.
Cell. Biol. 26, 9003-9015.
Aijaz, S., D’Atri, F., Citi, S., Balda, M. S. and Matter, K.
(2005). Binding of GEF-H1 to the tight junction-associated
adaptor cingulin results in inhibition of Rho signaling and
G1/S phase transition. Dev. Cell 8, 777-786.
Aijaz, S., Balda, M. S. and Matter, K. (2006). Tight
junctions: molecular architecture and function. Int. Rev.
Cytol. 248, 261-298.
Amieva, M. R., Vogelmann, R., Covacci, A., Tompkins,
L. S., Nelson, W. J. and Falkow, S. (2003). Disruption of
the epithelial apical-junctional complex by Helicobacter
pylori CagA. Science 300, 1430-1434.
Arakawa, Y., Kajino, K., Kano, S., Tobita, H., Hayashi,
J., Yasen, M., Moriyama, M. and Hino, O. (2004).
Transcription of dbpA, a Y box binding protein, is positively
regulated by E2F1: implications in hepatocarcinogenesis.
Biochem. Biophys. Res. Commun. 322, 297-302.
Assemat, E., Bazellieres, E., Pallesi-Pocachard, E., Le
Bivic, A. and Massey-Harroche, D. (2007). Polarity
complex proteins. Biochim Biophys Acta. 1778, 614-630.
Balda, M. S. and Matter, K. (2000). Transmembrane
proteins of tight junctions. Sem. Cell Dev. Biol. 11, 281-289.
Barrios-Rodiles, M., Brown, K. R., Ozdamar, B., Bose,
R., Liu, Z., Donovan, R. S., Shinjo, F., Liu, Y., Dembowy,
J., Taylor, I. W. et al. (2005). High-throughput mapping of
a dynamic signaling network in mammalian cells. Science
307, 1621-1625.
Barton, E. S., Forrest, J. C., Connolly, J. L., Chappell,
J. D., Liu, Y., Schnell, F. J., Nusrat, A., Parkos, C. A. and
Dermody, T. S. (2001). Junction adhesion molecule is a
receptor for reovirus. Cell 104, 441-451.
Bazzoni, G. (2003). The JAM family of junctional adhesion
molecules. Curr. Opin. Cell Biol. 15, 525-530.
Bazzoni, G., Martinez-Estrada, O. M., Orsenigo, F.,
Cordenonsi, M., Citi, S. and Dejana, E. (2000).
Interaction of junctional adhesion molecule with the tight
junction components ZO-1, cingulin, and occludin. J. Biol.
Chem. 275, 20520-20526.
Bradfield, P. F., Nourshargh, S., Aurrand-Lions, M. and
Imhof, B. A. (2007). JAM family and related proteins in
leukocyte migration (Vestweber series). Arterioscler.
Thromb. Vasc. Biol. 27, 2104-2112.
Cereijido, M., Contreras, R. G., Shoshani, L., Flores-
Benitez, D. and Larre, I. (2008). Tight junction and
polarity interaction in the transporting epithelial phenotype.
Biochim. Biophys. Acta 1778, 770-793.
Chen, X. and Macara, I. G. (2005). Par-3 controls tight
junction assembly through the Rac exchange factor Tiam1.
Nat. Cell Biol. 7, 262-269.
Chlenski, A., Ketels, K. V., Tsao, M. S., Talamonti, M.
S., Anderson, M. R., Oyasu, R. and Scarpelli, D. G.
(1999). Tight junction protein ZO-2 is differentially
expressed in normal pancreatic ducts compared to human
pancreatic adenocarcinoma. Int. J. Cancer 82, 137-144.
Chlenski, A., Ketels, K. V., Korovaitseva, G. I.,
Talamonti, M. S., Oyasu, R. and Scarpelli, D. G. (2000).
Organization and expression of the human zo-2 gene (tjp-2)
3681
in normal and neoplastic tissues. Biochim. Biophys. Acta
1493, 319-324.
Cohen, C. J., Shieh, J. T., Pickles, R. J., Okegawa, T.,
Hsieh, J. T. and Bergelson, J. M. (2001). The
coxsackievirus and adenovirus receptor is a transmembrane
component of the tight junction. Proc. Natl. Acad. Sci. USA
98, 15191-15196.
Dhawan, P., Singh, A. B., Deane, N. G., No, Y., Shiou, S.
R., Schmidt, C., Neff, J., Washington, M. K. and
Beauchamp, R. D. (2005). Claudin-1 regulates cellular
transformation and metastatic behavior in colon cancer. J.
Clin. Invest. 115, 1765-1776.
Ebnet, K., Schulz, C. U., Meyer Zu Brickwedde, M. K.,
Pendl, G. G. and Vestweber, D. (2000). Junctional
adhesion molecule interacts with the PDZ domain-
containing proteins AF-6 and ZO-1. J. Biol. Chem. 275,
27979-27988.
Ebnet, K., Aurrand-Lions, M., Kuhn, A., Kiefer, F.,
Butz, S., Zander, K., Meyer zu Brickwedde, M. K.,
Suzuki, A., Imhof, B. A. and Vestweber, D. (2003). The
junctional adhesion molecule (JAM) family members JAM-
2 and JAM-3 associate with the cell polarity protein PAR-
3: a possible role for JAMs in endothelial cell polarity. J.
Cell Sci. 116, 3879-3891.
Ebnet, K., Suzuki, A., Ohno, S. and Vestweber, D. (2004).
Junctional adhesion molecules (JAMs): more molecules
with dual functions? J. Cell Sci. 117, 19-29.
Evans, M. J., von Hahn, T., Tscherne, D. M., Syder, A.
J., Panis, M., Wolk, B., Hatziioannou, T., McKeating, J.
A., Bieniasz, P. D. and Rice, C. M. (2007). Claudin-1 is a
hepatitis C virus co-receptor required for a late step in entry.
Nature 446, 801-805.
Fan, S., Fogg, V., Wang, Q., Chen, X. W., Liu, C. J. and
Margolis, B. (2007). A novel Crumbs3 isoform regulates
cell division and ciliogenesis via importin beta interactions.
J. Cell Biol. 178, 387-398.
Fanning, A. S. (2001). Organization and the regulation of
the tight junction by the actin-myosin cytoskeleton. In Tight
Junctions (ed. J. M. Anderson and M. Cereijido), pp. 265-
284. Boca Raton, FL: CRC Press.
Furuse, M. and Tsukita, S. (2006). Claudins in occluding
junctions of humans and flies. Trends Cell Biol. 16, 181-
188.
Glaunsinger, B. A., Weiss, R. S., Lee, S. S. and Javier, R.
(2001). Link of the unique oncogenic properties of
adenovirus type 9 E4-ORF1 to a select interaction with the
candidate tumor suppressor protein ZO-2. EMBO J. 20,
5578-5586.
Gonzalez-Mariscal, L., Lechuga, S. and Garay, E.
(2007). Role of tight junctions in cell proliferation and
cancer. Prog. Histochem. Cytochem. 42, 1-57.
Gotoh, K., Nonoguchi, K., Higashitsuji, H., Kaneko, Y.,
Sakurai, T., Sumitomo, Y., Itoh, K., Subjeck, J. R. and
Fujita, J. (2004). Apg-2 has a chaperone-like activity
similar to Hsp110 and is overexpressed in hepatocellular
carcinomas. FEBS Lett. 560, 19-24.
Guillemot, L. and Citi, S. (2006). Cingulin regulates
claudin-2 expression and cell proliferation through the small
GTPase RhoA. Mol. Biol. Cell 17, 3569-3577.
Guillemot, L., Paschoud, S., Pulimeno, P., Foglia, A. and
Citi, S. (2008). The cytoplasmic plaque of tight junctions:
a scaffolding and signalling center. Biochim. Biophys. Acta
1778, 601-613.
Hayashi, J., Kajino, K., Umeda, T., Takano, S.,
Arakawa, Y., Kudo, M. and Hino, O. (2002). Somatic
mutation and SNP in the promoter of dbpA and human
hepatocarcinogenesis. Int. J. Oncol. 21, 847-850.
Helfrich, I., Schmitz, A., Zigrino, P., Michels, C., Haase,
I., le Bivic, A., Leitges, M. and Niessen, C. M. (2007).
Role of aPKC isoforms and their binding partners Par3 and
Par6 in epidermal barrier formation. J. Invest. Dermatol.
127, 782-791.
Hoover, K. B., Liao, S. Y. and Bryant, P. J. (1998). Loss
of the tight junction MAGUK ZO-1 in breast cancer:
relationship to glandular differentiation and loss of
heterozygosity. Am. J. Pathol. 153, 1767-1773.
Huber, D., Balda, M. S. and Matter, K. (1998).
Transepithelial migration of neutrophils. Invasion
Metastasis 18, 70-80.
Huber, D., Balda, M. S. and Matter, K. (2000). Occludin
modulates transepithelial migration of neutrophils. J. Biol.
Chem. 275, 5773-5778.
Huerta, M., Munoz, R., Tapia, R., Soto-Reyes, E.,
Ramirez, L., Recillas-Targa, F., Gonzalez-Mariscal, L.
 3682 Journal of Cell Science 121 (22)
and Lopez-Bayghen, E. (2007). Cyclin D1 is
transcriptionally down-regulated by ZO-2 via an E box and
the transcription factor c-Myc. Mol. Biol. Cell 18, 4826-
4836.
Hurd, T. W., Gao, L., Roh, M. H., Macara, I. G. and
Margolis, B. (2003). Direct interaction of two polarity
complexes implicated in epithelial tight junction assembly.
Nat. Cell Biol. 5, 137-142.
Ikenouchi, J., Furuse, M., Furuse, K., Sasaki, H. and
Tsukita, S. (2005). Tricellulin constitutes a novel barrier at
tricellular contacts of epithelial cells. J. Cell Biol. 171, 939-
945.
Kahle, K. T., Macgregor, G. G., Wilson, F. H., Van Hoek,
A. N., Brown, D., Ardito, T., Kashgarian, M., Giebisch,
G., Hebert, S. C., Boulpaep, E. L. et al. (2004).
Paracellular Cl- permeability is regulated by WNK4 kinase:
insight into normal physiology and hypertension. Proc.
Natl. Acad. Sci. USA 101, 14877-14882.
Katsuno, T., Umeda, K., Matsui, T., Hata, M., Tamura,
A., Itoh, M., Takeuchi, K., Fujimori, T., Nabeshima, Y.
I., Noda, T. et al. (2008). Deficiency of ZO-1 causes
embryonic lethal phenotype associated with defected yolk
sac angiogenesis and apoptosis of embryonic cells. Mol.
Biol. Cell 19, 2465-2475.
Kiener, T. K., Selptsova-Friedrich, I. and Hunziker, W.
(2008). Tjp3/zo-3 is critical for epidermal barrier function
in zebrafish embryos. Dev. Biol. 316, 36-49.
Kleeff, J., Shi, X., Bode, H. P., Hoover, K., Shrikhande,
S., Bryant, P. J., Korc, M., Buchler, M. W. and Friess, H.
(2001). Altered expression and localization of the tight
junction protein ZO-1 in primary and metastatic pancreatic
cancer. Pancreas 23, 259-265.
Konrad, M., Schaller, A., Seelow, D., Pandey, A. V.,
Journal of Cell Science
Waldegger, S., Lesslauer, A., Vitzthum, H., Suzuki, Y.,
Luk, J. M., Becker, C. et al. (2006). Mutations in the tight-
junction gene claudin 19 (CLDN19) are associated with
renal magnesium wasting, renal failure, and severe ocular
involvement. Am. J. Hum. Genet. 79, 949-957.
Krause, G., Winkler, L., Mueller, S. L., Haseloff, R. F.,
Piontek, J. and Blasig, I. E. (2008). Structure and function
of claudins. Biochim Biophys Acta 1778, 631-645.
Latorre, I. J., Roh, M. H., Frese, K. K., Weiss, R. S.,
Margolis, B. and Javier, R. T. (2005). Viral oncoprotein-
induced mislocalization of select PDZ proteins disrupts tight
junctions and causes polarity defects in epithelial cells. J.
Cell Sci. 118, 4283-4293.
Lemmers, C., Michel, D., Lane-Guermonprez, L.,
Delgrossi, M. H., Medina, E., Arsanto, J. P. and Le Bivic,
A. (2004). CRB3 binds directly to Par6 and regulates the
morphogenesis of the tight junctions in mammalian
epithelial cells. Mol. Biol. Cell 15, 1324-1333.
Makarova, O., Roh, M. H., Liu, C. J., Laurinec, S. and
Margolis, B. (2003). Mammalian Crumbs3 is a small
transmembrane protein linked to protein associated with
Lin-7 (Pals1). Gene 302, 21-29.
Martin, T. A., Watkins, G., Mansel, R. E. and Jiang, W.
G. (2004). Loss of tight junction plaque molecules in breast
cancer tissues is associated with a poor prognosis in patients
with breast cancer. Eur. J. Cancer 40, 2717-2725.
Matter, K. and Balda, M. S. (2007). Tight junctions, gene
expression and nucleo-junctinal interplay. J. Cell Sci. 120,
1505-1511.
McKenzie, J. A. and Ridley, A. J. (2007). Roles of
Rho/ROCK and MLCK in TNF-alpha-induced changes in
endothelial morphology and permeability. J. Cell Physiol.
213, 221-228.
Meyer, T. N., Schwesinger, C. and Denker, B. M. (2002).
Zonula occludens-1 is a scaffolding protein for signaling
molecules. Galpha(12) directly binds to the Src homology
3 domain and regulates paracellular permeability in
epithelial cells. J. Biol. Chem. 277, 24855-24858.
Michel, D., Arsanto, J. P., Massey-Harroche, D., Beclin,
C., Wijnholds, J. and Le Bivic, A. (2005). PATJ connects
and stabilizes apical and lateral components of tight
junctions in human intestinal cells. J. Cell Sci. 118, 4049-
4057.
Morita, K., Tsukita, S. and Miyachi, Y. (2004). Tight
junction-associated proteins (occludin, ZO-1, claudin-1,
claudin-4) in squamous cell carcinoma and Bowen’s
disease. Br. J. Dermatol. 151, 328-334.
Nava, P., Lopez, S., Arias, C. F., Islas, S. and Gonzalez-
Mariscal, L. (2004). The rotavirus surface protein VP8
modulates the gate and fence function of tight junctions in
epithelial cells. J. Cell Sci 117, 5509-5519.
Nusrat, A., Turner, J. R. and Madara, J. L. (2000).
Molecular physiology and pathophysiology of tight
junctions. IV. regulation of tight junctions by extracellular
stimuli: nutrients, cytokines, and immune cells. Am. J.
Physiol. Gastrointest. Liver Physiol. 279, G851-G857.
Osler, M. E., Chang, M. S. and Bader, D. M. (2005). Bves
modulates epithelial integrity through an interaction at the
tight junction. J. Cell Sci. 118, 4667-4678.
Paris, L., Tonutti, L., Vannini, C. and Bazzoni, G. (2008).
Structural organization of the tight junctions. Biochim.
Biophys. Acta 1778, 646-659.
Pritchard, D. M. and Crabtree, J. E. (2006). Helicobacter
pylori and gastric cancer. Curr. Opin. Gastroenterol. 22,
620-625.
Raschperger, E., Engstrom, U., Pettersson, R. F. and
Fuxe, J. (2004). CLMP, a novel member of the CTX family
and a new component of epithelial tight junctions. J. Biol.
Chem. 279, 796-804.
Resnick, M. B., Konkin, T., Routhier, J., Sabo, E. and
Pricolo, V. E. (2005). Claudin-1 is a strong prognostic
indicator in stage II colonic cancer: a tissue microarray
study. Mod. Pathol. 18, 511-518.
Riazuddin, S., Ahmed, Z. M., Fanning, A. S., Lagziel, A.,
Kitajiri, S., Ramzan, K., Khan, S. N., Chattaraj, P.,
Friedman, P. L., Anderson, J. M. et al. (2006). Tricellulin
is a tight-junction protein necessary for hearing. Am. J.
Hum. Genet. 79, 1040-1051.
Richardson, C. and Alessi, D. R. (2008).The regulation of
salt transport and blood pressure by the WNK-SPAK/OSR1
signalling pathway. J. Cell Sci. 121, 3293-3304.
Roh, M. H., Liu, C. J., Laurinec, S. and Margolis, B.
(2002). The carboxyl terminus of zona occludens-3 binds
and recruits a mammalian homologue of discs lost to tight
junctions. J. Biol. Chem. 277, 27501-27509.
Roh, M. H., Fan, S., Liu, C. J. and Margolis, B. (2003).
The Crumbs3-Pals1 complex participates in the
establishment of polarity in mammalian epithelial cells. J.
Cell Sci. 116, 2895-2906.
Runswick, S., Mitchell, T., Davies, P., Robinson, C. and
Garrod, D. R. (2007). Pollen proteolytic enzymes degrade
tight junctions. Respirology 12, 834-842.
Schneeberger, E. E. and Lynch, R. D. (2004). The tight
junction: a multifunctional complex. Am. J. Physiol. 286,
C1213-C1228.
Shen, L., Weber, C. R. and Turner, J. R. (2008). The tight
junction protein complex undergoes rapid and continuous
molecular remodeling at steady state. J. Cell Biol. 181, 683-
695.
Shin, K., Fogg, V. C. and Margolis, B. (2006). Tight
junctions and cell polarity. Annu. Rev. Cell Dev. Biol. 22,
207-235.
Simon, D. B., Lu, Y., Choate, K. A., Velazquez, H., Al-
Sabban, E., Praga, M., Casari, G., Bettinelli, A., Colussi,
G., Rodriguez-Soriano, J. et al. (1999). Paracellin-1, a
renal tight junction protein required for paracellular Mg2+
resorption. Science 285, 103-106.
Sonoda, N., Furuse, M., Sasaki, H., Yonemura, S.,
Katahira, J., Horiguchi, Y. and Tsukita, S. (1999).
Clostridium perfringens enterotoxin fragment removes
specific claudins from tight junction strands: Evidence for
direct involvement of claudins in tight junction barrier. J.
Cell Biol. 147, 195-204.
Sourisseau, T., Georgiadis, A., Tsapara, A., Ali, R. R.,
Pestell, R., Matter, K. and Balda, M. S. (2006). Regulation
of PCNA and cyclin D1 expression and epithelial
morphogenesis by the ZO-1-regulated transcription factor
ZONAB/DbpA. Mol. Cell. Biol. 26, 2387-2398.
Takai, E., Tan, X., Tamori, Y., Hirota, M., Egami, H. and
Ogawa, M. (2005). Correlation of translocation of tight
junction protein Zonula occludens-1 and activation of
epidermal growth factor receptor in the regulation of
invasion of pancreatic cancer cells. Int. J. Oncol. 27, 645-
651.
Tiwari-Woodruff, S. K., Buznikov, A. G., Vu, T. Q.,
Micevych, P. E., Chen, K., Kornblum, H. I. and
Bronstein, J. M. (2001). OSP/claudin-11 forms a complex
with a novel member of the tetraspanin super family and
beta1 integrin and regulates proliferation and migration of
oligodendrocytes. J. Cell Biol. 153, 295-305.
Traweger, A., Fuchs, R., Krizbai, I. A., Weiger, T. M.,
Bauer, H. C. and Bauer, H. (2003). The tight junction
protein ZO-2 localizes to the nucleus and interacts with the
heterogeneous nuclear ribonucleoprotein scaffold
attachment factor-B. J. Biol. Chem. 278, 2692-2700.
Umeda, K., Ikenouchi, J., Katahira-Tayama, S., Furuse,
K., Sasaki, H., Nakayama, M., Matsui, T., Tsukita, S.
and Furuse, M. (2006). ZO-1 and ZO-2 independently
determine where claudins are polymerized in tight-junction
strand formation. Cell 126, 741-754.
Utech, M., Bruwer, M. and Nusrat, A. (2006). Tight
junctions and cell-cell interactions. Methods Mol. Biol. 341,
185-195.
Van Itallie, C. M. and Anderson, J. M. (2006). Claudins
and epithelial paracellular transport. Annu. Rev. Physiol. 68,
403-429.
Walters, R. W., Freimuth, P., Moninger, T. O., Ganske,
I., Zabner, J. and Welsh, M. J. (2002). Adenovirus fiber
disrupts CAR-mediated intercellular adhesion allowing
virus escape. Cell 110, 789-799.
Wan, H., Winton, H. L., Soeller, C., Tovey, E. R.,
Gruenert, D. C., Thompson, P. J., Stewart, G. A., Taylor,
G. W., Garrod, D. R., Cannell, M. B. et al. (1999). Der p
1 facilitates transepithelial allergen delivery by disruption of
tight junctions. J. Clin. Invest. 104, 123-133.
Wang, Q. and Margolis, B. (2007). Apical junctional
complexes and cell polarity. Kidney Int. 72, 1448-1458.
Wang, Z., Mandell, K. J., Parkos, C. A., Mrsny, R. J. and
Nusrat, A. (2005). The second loop of occludin is required
for suppression of Raf1-induced tumor growth. Oncogene
24, 4412-4420.
Weber, C., Fraemohs, L. and Dejana, E. (2007). The role
of junctional adhesion molecules in vascular inflammation.
Nat. Rev. Immunol. 7, 467-477.
Wegmann, F., Ebnet, K., Du Pasquier, L., Vestweber, D.
and Butz, S. (2004). Endothelial adhesion molecule ESAM
binds directly to the multidomain adaptor MAGI-1 and
recruits it to cell contacts. Exp. Cell Res. 300, 121-133.
Wilcox, E. R., Burton, Q. L., Naz, S., Riazuddin, S.,
Smith, T. N., Ploplis, B., Belyantseva, I., Ben-Yosef, T.,
Liburd, N. A., Morell, R. J. et al. (2001). Mutations in the
gene encoding tight junction claudin-14 cause autosomal
recessive deafness DFNB29. Cell 104, 165-172.
Wilson, F. H., Disse-Nicodeme, S., Choate, K. A.,
Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel,
M., Milford, D. V., Lipkin, G. W., Achard, J. M. et al.
(2001). Human hypertension caused by mutations in WNK
kinases. Science 293, 1107-1112.
Wu, X., Li, S., Chrostek-Grashoff, A., Czuchra, A.,
Meyer, H., Yurchenco, P. D. and Brakebusch, C. (2007).
Cdc42 is crucial for the establishment of epithelial polarity
during early mammalian development. Dev. Dyn. 236,
2767-2778.
Xu, J., Kausalya, P. J., Phua, D. C., Ali, S. M., Hossain,
Z. and Hunziker, W. (2008). Early embryonic lethality of
mice lacking ZO-2, but Not ZO-3, reveals critical and
nonredundant roles for individual zonula occludens proteins
in mammalian development. Mol. Cell. Biol. 28, 1669-1678.
Yamada, S. and Nelson, W. J. (2007). Synapses: sites of
cell recognition, adhesion, and functional specification.
Annu. Rev. Biochem. 76, 267-294.
Yamauchi, K., Rai, T., Kobayashi, K., Sohara, E.,
Suzuki, T., Itoh, T., Suda, S., Hayama, A., Sasaki, S. and
Uchida, S. (2004). Disease-causing mutant WNK4
increases paracellular chloride permeability and
phosphorylates claudins. Proc. Natl. Acad. Sci. USA 101,
4690-4694.
Yeaman, C., Grindstaff, K. K. and Nelson, W. J. (2004).
Mechanism of recruiting Sec6/8 (exocyst) complex to the
apical junctional complex during polarization of epithelial
cells. J. Cell Sci. 117, 559-570.
Yu, A. L., McCarthy, K. M., Francis, S. A., McCormack,
J. M., Lai, J., Rogers, R. A., Lynch, R. D. and
Schneeberger, E. E. (2005). Knock down of occludin
expression leads to diverse phenotypic alterations in
epithelial cells. Am. J. Physiol. Cell Physiol. 288, C1231-
C1241.
Cell Science at a Glance on the Web
Electronic copies of the poster insert are
available in the online version of this article
at jcs.biologists.org. The JPEG images can
be downloaded for printing or used as
slides.