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tight junctions

Wednesday 17 September 2003

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. Tight junctions are important for the permeability properties of epithelial and endothelial barriers as they restrict diffusion along the paracellular space.

Function

- The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis.

The fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity.

In epithelial barrier, intercellular tight junctions provide a barrier to the back-diffusion of hydrogen ions. Epithelial disruption is followed rapidly by restitution, in which existing cells migrate along the exposed basement membrane to fill in the defects and restore epithelial barrier integrity.

- epithelial proliferation and differentiation

Tight junctions also function in the regulation of epithelial proliferation and differentiation. They harbour evolutionarily conserved protein complexes that regulate polarisation and junction assembly.

Tight junctions also recruit signalling proteins that participate in the regulation of cell proliferation and differentiation.

These signalling proteins include components that affect established signalling cascades and dual localisation proteins that can associate with junctions as well as travel to the nucleus where they regulate gene expression.

Structure

Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins (CLDNs), and JAMs have been recently discovered.

Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP.

Molecular components: claudins, occludins, JAMs

Pathology

- mutations in the claudin-1 gene (CLDN1) in neonatal ichthyosis-sclerosing cholangitis syndrome (607626)

- mutations in the claudin-14 gene (CLDN14) in hereditary deafness

- mutations in the claudin-16 gene (CLDN16) resultand hereditary hypomagnesemia.

- some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases.

- mutations of TJP2 (coding for tight junction protein 2) in familial hypercholanemia

- aberrant expression of tight junction-related proteins ZO-1, claudin-1 (CLD1) and occludin in synovial sarcoma (#14704716#)

- germline mutations of MARVELD2 in 5q13.1 (MIM.610572) coding for tricellulin in autosomal recessive deafness locus 49 (DFNB49) (MIM.610153)

See also

- apical junctions
- tight junction proteins
- claudins (CLDNs)

References

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- Gasbarrini G, Montalto M. Structure and function of tight junctions. Role in intestinal barrier. Ital J Gastroenterol Hepatol. 1999 Aug-Sep;31(6):481-8. PMID: #10575567#

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- Denker BM, Nigam SK. Molecular structure and assembly of the tight junction. Am J Physiol. 1998 Jan;274(1 Pt 2):F1-9. PMID: #9458817#