992
Cell 157, May 8, 2014 ©2014 Elsevier Inc.
DOI http://dx.doi.org/10.1016/j.cell.2014.04.027
See online version for legend and references.
Junctional intramembrane strands
Size-selective diffusion: Strand dynamics?
Cell 2
P
Scrib Lgl Dlg
Par1
Par3
aPKC
Par3/6
aPKC
Par6
Crb3 Pals1 Patj
Cdc42
Dbl3
TJ
Lateral determinants
Apical/lateral border
Apical determinants
Apical marginal zone
Apical/lateral border and junction positioning
Extracellular space
Ezrin
Cell 1
Fluctuating pores Claudins
Selective paracellular permeability
E-cadherin
Nectins
Adherens junction
JAM-A,-B,-C; CAR
Angulins
Bves
Occludin Tricellulin MarvelD3
Claudins
Tight junction
A PICA L M AR GINAL ZONE
F-Actin
Crb3
Basal
Apical
Lateral
Shown as
α catenin β catenin p120catenin
AF-6
ZONAB/YB3; Symplekin
Shown as
Proliferation Differentiation Migration Survival Cell shape Cytoskeleton Gene expression
Signaling to cell
Transcriptional and posttranscriptional regulators
• GTP-binding proteins and their regulators: Rab13 and 3A, RhoGTPases; p114RhoGEF, GEF-H1, ARHGEF11, Tuba, Rich • Kinases and phosphatases: CDK4, MEKK1, Yes, WNK4; PP1, PP2A, PTEN
Signaling proteins
ZO-1,-2,-3; MAGI1-3; Pals1; Patj; MUPP1; Par3; Angiomotin; Cingulin; Paracingulin/JACOP
Shown as
Major cytoplasmic plaque proteins
Scaffolding proteins
Paracellular pathway
Microtubles
Major junctional transmembrane proteins
Adherens junction
Tight junction
Proteins and Organization
Karl Matter and Maria S. Balda Department of Cell Biology, Institute of Ophthalmology, University College London, EC1V 9EL London, UK
SnapShot: Epithelial Tight Junctions
Cyclin D1
RalA
RAS
GEF-H1
SAF-B
TEAD
YAP/TAZ
ERK
ERK
Rac PAK RAF
Myc
ZO-2
Rich
Elk1
AP-1
JNK1
MEKK1
MARVELD3
YAP/TAZ
ZO-1/2
Merlin AMOT Mst/LATS
PATJ Pals1
Crb3
Proliferation; migration; survival; differentiation
Transcription
Symplekin
ZONAB
CDK4
CDK4 ZONAB Symplekin
RhoA
Translation
ZONAB
Cingulin
ZO-1
APG-2
Regulation of gene expression
SnapShot: Epithelial Tight Junctions Karl Matter and Maria S. Balda Department of Cell Biology, Institute of Ophthalmology, University College London, EC1V 9EL London, UK
Tight junctions form a morphological and functional border between the apical and basolateral cell surface domains. Together with adherens junctions, they form the apical junctional complex. Both junctions are linked to the actin and microtubule cytoskeleton, which is important for junction assembly and regulation (Cereijido et al., 2008). Tight junctions form a paracellular diffusion barrier, enabling epithelial cells to separate compartments of different composition (Anderson and Van Itallie, 2009; Cereijido et al., 2008). This diffusion barrier is semipermeable, as it allows ion- and size-selective passive diffusion. Tight junctions also contribute to the generation and maintenance of cell polarity by harboring regulatory components that control apicobasal polarization by guiding vesicular traffic to the cell surface and by forming an intramembrane diffusion barrier in the exoplasmic leaflet of the plasma membrane. Finally, tight junctions regulate signaling mechanisms that guide cell behavior, shape, and gene expression. Composition Tight junctions are close contacts between the plasma membranes of neighboring cells and contain a network of intramembrane strands formed by transmembrane particles (Furuse and Tsukita, 2006). These particles are oligomers of transmembrane proteins that also mediate cell-cell contact and form the paracellular diffusion barrier. Members of the claudin family are the strands main component. They contain a second type of tetraspan membrane proteins whose transmembrane domains form a Marvel domain (i.e., occludin, tricellulin, and MarvelD3). The junction also contains adhesion proteins with immunoglobulin domains, such as JAMs, CAR, and angulins. Crb3, a transmembrane protein that specifies apical differentiation, also interacts with tight junctions, as well as Bves, an adhesion protein with three transmembrane domains. These transmembrane proteins interact with a complex cytosolic protein network called cytoplasmic plaque, formed by multivalent adaptor proteins, many of which contain multiple protein-protein interaction motifs such as PDZ and SH3 domains, and different types of signaling proteins, which include GTP-binding proteins and their regulators, as well as protein and lipid kinases and phosphatases. These signaling proteins receive signals from the cells to regulate junction assembly and function and transmit signals to the cells to guide cell behavior. The junctional protein network also recruits proteins that regulate transcription and translation. Some tight junction components can also interact with proteins that are concentrated at adherens junctions (e.g., ZO-1 can form complexes with α-catenin). It is thought that such interactions are important for junction assembly, as tight and adherens junctions mature from primordial junctions, induced by cadherins and nectins, that contain components of both types of adhesion complexes. Lastly, junctional components have binding sites for F-actin and microtubules, which serve to integrate tight and adherens junctions with each other and the cellular cytoskeleton (Cereijido et al., 2008; Yano et al., 2013). Selective Paracellular Permeability Tight junctions form a regulated semipermeable diffusion barrier that allows the passive diffusion of certain ions and small hydrophilic molecules along concentration gradients. Claudins are the main mediators of ion diffusion and are thought to form ion-selective pores that fluctuate between an open and closed state (Shen et al., 2011). As different tissues express different members of the claudin family, they also exhibit distinct paracellular ion selectivity. The slow diffusion of small hydrophilic molecules is less well understood but may involve the dynamic reorganization of tight junction strands, thereby allowing small soluble molecules to penetrate and cross the junction. Positioning of the Apical/Lateral Border Evolutionarily conserved signaling mechanisms guide cell polarization. Tight junctions form the apical/lateral border, and their positioning hence determines the relative size of the two cell surface domains. Positioning of this border is regulated by counteracting apical and lateral determinants. Initial junction formation stimulates the recruitment of the Par3/Par6/aPKC (atypical protein kinase C) complex, a pro-apical signaling complex. Ezrin/Dbl3-driven Cdc42 activation then leads to activation of aPKC, expansion of the apical domain, and dissociation of the Par3/Par6/aPKC complex (Zihni et al., 2014). Par3 remains at tight junctions, and Par6/aPKC become enriched in an apical marginal zone along with other apical determinants. Regulation of Gene Expression Formation of tight junction has been linked to the suppression of mechanisms that regulate gene expression and promote cell proliferation (Balda and Matter, 2009). As a consequence, tight junction formation contributes to the inhibition of proliferation in a cell-density-dependent manner. One such pathway relies on ZONAB, an RNA- and DNAbinding protein that regulates transcription and translation. ZONAB binds to the junctional adaptor ZO-1 and complexes with the cell-cycle kinase Cdk4. Ras stimulates GEF-H1/ RhoA activation and, subsequently, dissociation of ZONAB from junctions. Ras also stimulates RalA, which modulates ZONAB’s subcellular distribution. The Hippo pathway kinases Mst and LATS also associate with tight junctions and suppress activation of YAP and TAZ, two transcriptional coactivators. YAP also binds junctional proteins directly, which further contributes to its inhibition (Zhao et al., 2011). The adaptor protein AMOT plays a central role in the Hippo pathway and associates with the tumor suppressor Merlin to regulate Ras/ERK signaling via Rac. Regulation of YAP/TAZ activation is another mechanism of crosstalk between tight and adherens junctions, which also suppress this pathway. The more recently discovered MarvelD3 protein suppresses MEKK1/JNK activation and thereby the transcription factors Elk1 and AP-1 (Steed et al., 2014). Some tight junction proteins cycle between the nucleus and the junction. An example is the adaptor ZO-2, which binds and inhibits transcription factors in the nucleus (Gonzalez-Mariscal et al., 2012). These junctional signaling pathways have been shown to modulate the cellular stress response, suggesting that tight junctions act as sensors for tissue stress and damage. The localization of established tumor suppressors and oncogenes to tight junctions supports the physiological and pathological importance of this cellular signaling hub. References Anderson, J.M., and Van Itallie, C.M. (2009). Cold Spring Harb. Perspect. Biol. 1, a002584. Balda, M.S., and Matter, K. (2009). Biochim. Biophys. Acta 1788, 761–767. Cereijido, M., Contreras, R.G., Shoshani, L., Flores-Benitez, D., and Larre, I. (2008). Biochim. Biophys. Acta 1778, 770–793. Furuse, M., and Tsukita, S. (2006). Trends Cell Biol. 16, 181–188. Gonzalez-Mariscal, L., Bautista, P., Lechuga, S., and Quiros, M. (2012). Ann. NY Acad. Sci. 1257, 133–141. Shen, L., Weber, C.R., Raleigh, D.R., Yu, D., and Turner, J.R. (2011). Annu. Rev. Physiol. 73, 283–309. Steed, E., Elbediwy, A., Vacca, B., Dupasquier, S., Hemkemeyer, S.A., Suddason, T., Costa, A.C., Beaudry, J.B., Zihni, C., Gallagher, E., et al. (2014). J. Cell Biol. 3, 821–838. Yano, T., Matsui, T., Tamura, A., Uji, M., and Tsukita, S. (2013). J. Cell Biol. 203, 605–614. Zhao, B., Tumaneng, K., and Guan, K.L. (2011). Nat. Cell Biol. 13, 877–883. Zihni, C., Munro, P.M., Elbediwy, A., Keep, N.H., Terry, S.J., Harris, J., Balda, M.S., and Matter, K. (2014). J. Cell Biol. 204, 111–127.
992.e1 Cell 157, May 8, 2014 ©2014 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cell.2014.04.027