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

SnapShot: Epithelial tight junctions.

Tight junctions form a morphological and functional border between the apical and basolateral cell surface domains that serves as a paracellular diffu...
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