Regulation of tonicity-dependent activation of NFAT5 by mitogen-activated protein kinases

Various tissues, most notably the kidney medulla, are normally exposed to a hypertonic environment. The transcription factor NFAT5 is essential for these tissues to survive and function properly by activating expression of the osmoprotective genes and genes that are unique for the functions of these tissues. Moreover, hypertonicity causes or is associated with certain diseases and disorders such as diabetes mellitus and inflammation. NFAT5 plays an important role in pathogenesis of these diseases and disorders. Hypertonicity activates NFAT5 through phosphorylation of signaling molecules or NFAT5 itself. More than a dozen of kinases have been identified. This mini-review will focus on mitogen-activated protein kinases (MAPKs), which include p38, ERK and JNK families, because they are the most studied kinases in regulation of NFAT5. p38α, ERK1/2 and some of their upstream kinases have been demonstrated to contribute to tonicity-dependent activation of NFAT5 by increasing its transactivating activity without significantly affecting its nuclear accumulation. However, many important questions remain. For example, hypotonicity, which inhibits NFAT5 activity, also activates p38 and ERK1/2, raising a question concerning how p38 and ERK1/2 relay the hypertonic signal to NFAT5. The present mini-review calls for attention to MAPKs isoforms, duration and strength of activation, cellular localization and interaction with specific scaffolds and other signaling molecules, when they are studied for their roles in regulation of NFAT5. Further, whether MAPKs regulate NFAT5 in the tissues remains to be addressed.