Non-canonical functions of claudin proteins: Beyond the regulation of cell-cell adhesions

Abstract

Tight junctions form a barrier to the diffusion of apical and basolateral membrane proteins thus regulating membrane polarity. They also regulate the paracellular movement of ions and water across epithelial and endothelial cells so that functionally they constitute an important permselective barrier. Permselectivity at tight junctions is regulated by claudins, which confer anion or cation permeability, and tightness or leakiness, by forming several highly regulated pores within the apical tight junction complex. One interesting feature of claudins is that they are, more often than not, localized to the basolateral membrane, in intracellular cytoplasmic vesicles, or in the nucleus rather than to the apical tight junction complex. These intracellular pools of claudin molecules likely serve important functions in the epithelium. This review will address the widespread prevalence of claudins that are not associated with the apical tight junction complex and discuss the important and emerging non-traditional functions of these molecules in health and disease.

Keywords: EMT; claudin; nuclear transcription; review.

Figure 1.

Confocal micrographs of the stomach mucosa stained for tight junction associated claudin-4 and basolateral membrane-associated claudin-18. Note the absence of green fluorescence signal at apical tight junctions in the surface of tissues stained for claudin-4 but the strong signal at apical tight junctions of epithelial cells in the neck and base (arrows). In contrast, claudin-18 is highly concentrated at the basolateral membrane of all epithelial cells (arrowheads) in the stomach mucosa with particularly robust expression in surface epithelial cells. MM, muscularis mucosa.

Figure 2.

Schematic diagram of potential functions for basolateral claudin molecules. (A) Basolateral claudins may function in the trafficking of endosomal vesicles (red circles) from the baolateral membrane to tight junctions for rapid remodeling. (B) Basolateral claudins may function as accessory pores to facilitate further discretion of ion transport at tight junctions (dotted arrow) and/or create signaling hubs via interaction with claudin/claudin complexes and the action cytoskeleton. EpCAM, epithelial cell adhesion molecule; TGN, trans-Golgi network.

Figure 3.

Schematic diagram of the cell/extracellular matrix interface in epithelial cells. Claudin molecules interact with integrin -α and -β subunits within the focal adhesion complex, which provides and anchor for cells to the extracellular matrix. The presence of claudins results in MAPK signaling through the focal adhesion kinase (FAK)/Src/p 130cas complex.