How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

Abstract

NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to, activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifically signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to maintain robustness against hypertonic or hypotonic stress. Core tip: NFAT5 is critical for kidney functions. Its disregulation results in or is associated with the renal diseases and disorders. More than a dozen of kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. The present review is focused on how these kinases regulate NFAT5 activity under the context of hypertonicity or hypotonicity. Understanding these regulatory mechanisms will have therapeutic implications. A precedent example is that recognition of the cyclosporine immunosuppressive effect resulted from inhibition of the phosphatase calcineurin-dependent activation of NFAT1 allows combination use of cyclosporine with other mechanistically different immunosuppressants to improve their therapeutic efficacy and reduce their side effects.Zhou X. How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5? World J Nephrol 2016; 5(1): 20-32 Available from:

NFAT5 Has a Job in the Brain

“…CDK5, c-Abl, and ATM promote the nuclear localization of NFAT5, and, in contrast, CK1 inhibits its nuclear accumulation [19]. There are many other factors that influence the activation and expression of NFAT5, such as inflammatory cytokines [16, 77], microRNAs [50, 62, 78, 79], and transcription factors [80-83].…”

“…Like many other biological processes, activation of NFAT5 is determined by its phosphorylation sites. Hypertonicity and hypoxia promptly increased the phosphorylation of NFAT5, and it could be phosphorylated at many sites [17-19]. Furthermore, the phosphorylation and nuclear location of NFAT5 were regulated by several kinases, such as p38 [20], ATM [21], GSK-3β [22], CDK5 [23], and CK1 [24].…”

NFAT5‐sensitive Orai1 expression and store‐operated Ca 2+ entry in megakaryocytes

“…NFAT5 expression is known to be upregulated by hypertonicity (1, 2) and dehydration (13). Accordingly, increase in osmolarity by the addition of 40 mM NaCl to culture medium of MEG‐01 cells and water deprivation of mice increased NFAT5 expression, an effect paralleled by increase of Orai1 expression.…”

“…Nuclear factor of activated T cells 5 (NFATS) or tonicity responsive enhancer (TonE) binding protein (TonEBP), was originally cloned as a cell volume–regulated transcription factor upregulated by osmotic cell shrinkage (1, 2). NFAT5‐sensitive genes include serum and glucocorticoid‐inducible kinase 1 (SGK1) (3), which in turn leads to phosphorylation and thus degradation of the inhibitor protein IkBα resulting in nuclear translocation of the transcription factor NFkB (4).…”

NFAT5 moves to Fat City

“…Furthermore, how changes in tonicity are converted into functional outputs via NFAT5 remains elusive. More than a dozen protein kinases have been identified that contribute to tonicity-dependent regulation of NFAT5 [3]. Hypertonicity activates NFAT5 by increasing its nuclear localization and by transactivating its activity in the early phase and protein abundance in the late phase of activation.…”