System-level investigation into the regulatory mechanism of the calcineurin/NFAT signaling pathway.

Calcineurn/nuclear factor of the activated T cell (CaN/NFAT) signaling pathway plays crucial roles in the development of cardiac hypertrophy, Down's syndrome, and autoimmune diseases in response to pathological stimuli. The aim of the present study is to get a system-level understanding on the regulatory mechanism of CaN/NFAT signaling pathway in consideration of the controversial roles of myocyte-enriched calcineurin interacting protein1 (MCIP1) for varying stress stimuli. To this end, we have developed an experimentally validated mathematical model and carried out computer simulations as well as cell-based experiments. Quantitative overexpression and knock-down experiments in C2C12 myoblasts have revealed that MCIP1 functions only as a calcineurin inhibitor. We have also observed a biphasic response of the NFAT activity with increasing stimuli of isoproterenol. Through extensive in silico simulations, we have discovered that the NFAT activity is primarily modulated by ERK5 and MCIP1 under mild isoproterenol stimuli whereas it is mainly modulated by atrogin1 (muscle atrophy F-box protein) under strong isoproterenol stimuli. This study shows that a system-level analysis may help understanding CaN/NFAT signaling-associated disease.