Tight junctions and human diseases

Abstract

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. 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. On the other hand, 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. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, 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. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.

Identification of a stem cell candidate in the normal human prostate gland

“…Consistent with this concept, we demonstrated that Ck6a+ cells were able to co-express cytokeratin 19 or ZO-1. ZO-1, a tight junctional protein (Sawada et al, 2003), is only expressed by terminally differentiated luminal cells but not by basal cells in the normal adult prostate. This suggests that the Ck6a+ cells that co-express ZO-1 are transient amplifying cells that are committed for terminal differentiation, and which later may lose cytokeratin 6a expression.…”

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

“…Tumors exhibit a loss of organization associated with a decrease in TJ integrity (Swisshelm et al, 2005), potentially allowing diffusion of nutrients and other growth factors, and facilitating the escape of the tumor cells into the vasculature (Sawada et al, 2003). Thus, the regulation of TJs is of significant interest in cancer biology, and claudins in particular, have been the focus of some attention, as these proteins are frequently upregulated and mislocalized in cancer, suggesting abnormal processing (reviewed in Morin, 2005).…”

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

“…In addition, tight junctions block the free diffusion of proteins and lipids between the apical and basolateral domains of the plasma membrane, therefore maintaining cell polarity (fence function). 1,2 Tight junctions are composed of transmembrane and cytoplasmic protein complexes and appear on electron micrographs as series of fusion points between the outer leaflets of plasma membranes of adjacent cells. At these so-called 'kissing points', the intercellular space is eliminated remarkably.…”

“…5 The cytoplasmic N-and C-terminal domains contain several phosphorylation sites and interact with various proteins. 1,2 The exact role of occludin in tight junctions function is unclear, although a regulatory function is speculated. 1 Claudins are integral membrane proteins that have, similar to occludin, four transmembrane domains and two extracellular loops.…”

“…1,2 The exact role of occludin in tight junctions function is unclear, although a regulatory function is speculated. 1 Claudins are integral membrane proteins that have, similar to occludin, four transmembrane domains and two extracellular loops. 6,7 However, unlike occludin, the first loop is longer than the second one.…”