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Signalling to and from tight junctions

Key Points

  • Tight junctions (TJs) have long been regarded as simple barriers that separate compartments of different compositions, but recent research indicates that different types of signalling proteins and transduction pathways are associated with these junctions. They receive and convert signals from the cell interior to regulate junction assembly and function, and transmit signals to the cell interior to modulate gene expression and cell behaviour.

  • TJs are the most apical intercellular junctions in epithelia. Their classical functions are the regulation of paracellular permeability and the restriction of apical–basolateral intramembrane diffusion of lipids.

  • TJs are composed of a set of transmembrane proteins that are connected to cytoplasmic components and the actin cytoskeleton. Many of the cytoplasmic junctional components are signalling proteins or exhibit sequence similarities with tumour suppressors, and so might function in receiving signals from, or transmitting signals to, the cell interior.

  • The evolutionarily conserved partitioning defective (PAR)3–PAR6–atypical protein kinase C pathway regulates TJ assembly and is regulated by cell-division control protein 42 (Cdc42), a key regulator of cell polarity.

  • Rho signalling is a main pathway of regulation of TJs and involves TJ-specific activators of Rho and, possibly, several effector pathways.

  • A second evolutionarily conserved signalling complex at TJs is related to the Drosophila Stardust–Discs lost–Crumbs complex (equivalent to the mammalian Pals1–PATJ–Crumbs complex), indicating that TJs might be involved in signalling processes that regulate epithelial differentiation.

  • Several mechanisms that are or have been proposed to be involved in the regulation of proliferation are based on TJ-associated proteins that include transcription factors, cell-cycle regulators and lipid phosphatases, which indicates that TJs could have a proliferation suppressive function.

Abstract

Tight junctions have long been regarded as simple barriers that separate compartments of different compositions, but recent research indicates that different types of signalling proteins and transduction pathways are associated with these junctions. They receive and convert signals from the cell interior to regulate junction assembly and function, and transmit signals to the cell interior to modulate gene expression and cell behaviour.

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Figure 1: Epithelial intercellular junctions.
Figure 2: The composition of tight junctions.
Figure 3: Intercellular junctions in vertebrates and insects.
Figure 4: Signal transduction to and from tight junctions.
Figure 5: Signalling by aPKC and assembly of the junctional complex.
Figure 6: Regulation of paracellular permeability by Rho.
Figure 7: Assembly of epithelial tight junctions and regulation of proliferation and differentiation.

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Acknowledgements

The research in the authors' laboratories is supported by The Wellcome Trust, Cancer Research UK, the Biotechnology and Biological Sciences Research Council, the Medical Research Council and Fight for Sight.

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Correspondence to Karl Matter or Maria S. Balda.

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DATABASES

Swiss-Prot

afadin

ASH1

Cdc42

CDK4

Crumbs

Crumbs 3

Discs lost

E-cadherin

Elk1

ErbB2

GEF-H1

MAGI-1

MAGI-2

MAGI-3

MEK1

MUPP1

occludin

Pals1

PAR3

PAR6

PTEN

SAF-B

Stardust

ZO-1

ZO-2

ZO-3

FURTHER INFORMATION

Karl Matter's laboratory

Maria S. Balda's laboratory

Glossary

APICAL DOMAIN

The domain of an epithelial cell that faces the lumen of a cavity or tube, or the outside of the organism.

BASOLATERAL DOMAIN

The domain of an epithelial cell that adjoins underlying tissue.

GAP JUNCTION

A communicating junction (permeant to molecules up to 1 kDa) between adjacent cells that is composed of 12 connexin protein subunits, 6 of which form a connexon or hemichannel that is contributed by each of the coupled cells.

DESMOSOMES

These patch-like intercellular junctions are found in vertebrate tissue, and are particularly abundant in tissues undergoing mechanical stress. The central plaque contains adhesion molecules, and is an anchorage point for cytoskeletal filaments of the intermediate filament type.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains cadherins and catenins that are attached to cytoplasmic actin filaments.

INTERMEDIATE FILAMENT

A cytoskeletal filament, which is typically 10 nm in diameter, that is present in higher eukaryotic cells.

ACTIN BELT

A ring of actin filaments that circumvents many absorptive epithelial cells (for example, intestinal epithelial cells) at the level of the junctional complex.

TROPHECTODERM

The outer epithelial layer of the blastocyst.

FREEZE-FRACTURE

A method of visualizing the interior of cell membranes. Cells are frozen at the temperature of liquid nitrogen in the presence of antifreeze and the frozen block is then cracked with a knife blade. The fracture plane often passes through the hydrophobic middle of lipid bilayers, thereby exposing the interior of cell membranes. The resulting fracture faces are shadowed with platinum, the organic material is dissolved away and the replicas are floated off for electron microscopy.

ADAPTOR PROTEINS

Proteins that augment cellular responses by recruiting other proteins to a complex. They usually have several protein–protein interaction domains.

PDZ DOMAIN

A protein interaction domain that is often present in scaffolding proteins and is named after the founding members of this protein family (PSD-95, Discs-large A and ZO-1).

SEPTATE JUNCTION

A junction that is basal to the zonula adherens in Drosophila epithelial cells.

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It blocks the function of Gi proteins by catalysing ADP ribosylation of the α-subunit.

GTPγS

A non-hydrolysable analogue of GTP.

GUANINE NUCLEOTIDE EXCHANGE FACTOR

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

MAGUK PROTEINS

Scaffold proteins that contain PSD-95–Discs-large A–Zonula occludens-1 (PDZ), Src-homology-3 (SH3) and guanylate kinase domains.

SH3 DOMAINS

(Src-homology-3 domain). Protein sequences of about 50 amino acids that recognize and bind sequences that are rich in proline.

Y-BOX

A promoter element that generally contains a central ATTGG sequence and interacts with a family of transcription factors that are known as Y-box binding proteins.

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Matter, K., Balda, M. Signalling to and from tight junctions. Nat Rev Mol Cell Biol 4, 225–237 (2003). https://doi.org/10.1038/nrm1055

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