Regulation of NFAT activation: a potential therapeutic target for immunosuppression

The NFAT family of transcription factors plays pivotal roles in the development and function of the immune system. Their activation process is tightly regulated by calcium-dependent phosphatase calcineurin and has been a target of the immunosuppressive drugs cyclosporin A and FK-506. Although the clinical use of these drugs has dramatically increased the success of organ transplantation, their therapeutic use is limited by severe side effects. Recent studies for the calcineurin/NFAT signaling pathway have identified a number of cellular proteins that inhibit calcineurin function. Specific peptide sequences that interfere with the interaction between calcineurin and NFAT have also been characterized. Moreover, diverse approaches to identify small organic molecules that modulate NFAT function have been performed. This review focuses on the recent advances in our understanding of the inhibitory modulation of NFAT function, which may open up the additional avenues for immunosuppressive therapy.