Chapter 6 – Regulation of Claudins by Posttranslational Modifications and Cell-Signaling Cascades

Publisher Summary Claudins are the main constituents of tight junction (TJ) filaments, and their function is regulated by several posttranslational modifications including phosphorylation, palmitoylation, and signaling through cytokines, prostaglandins, and hormones. This chapter describes the putative phosphorylation sites present in the claudin family of proteins and analyze those phosphorylations that trigger a specific cellular response. The chapter also describes how cytokines, transforming growth factor β, prostaglandin E 2 , and progesterone promote the development of leakier TJs in epithelia by reducing the expression of claudins that act as cation barriers and increasing the appearance of those that function as cation pores. In contrast, epithelial growth factor (EGF), the follicle-stimulating hormones, testosterone, and aldosterone, induce the generation of tighter TJs by increasing the expression of claudins that block the paracellular passage of cations. Loss of TJs and barrier function in transformed tissues has long been recognized. Hence, the observation that certain cancers like breast, colon, esophagus, ovary, pancreas, and prostate are characterized for overexpressing certain TJ proteins, including claudin-3 and -4, throws up an interesting enigma. The answer to this riddle might be in the posttranslational modifications that these proteins exhibit in the transformed tissues that allow them to be expressed but not to exert their barrier function or to localize at the TJ.