Calcineurin (CaN) assists T-cell activation, growth and differentiation of skeletal and cardiac myocytes, memory, and apoptosis. It also activates transcription of the nuclear factor of activated T-cells (NFAT) family including hypertrophic target genes. It has been reported that the modulatory calcineurin-interacting protein (MCIP) inhibits the CaN activity and thereby reduces the hypertrophic response. However, it has been shown that MCIP facilitates or permits the hypertrophic response under some stress conditions such as isoproterenol infusion or pressure overload by transverse aortic constriction. As there is no direct experimental evidence that can explain these paradoxical phenomena, there has been a controversy concerning the functional role of MCIP in developing the hypertrophic response. It is therefore crucial to establish a hypothesis that can clearly explain these phenomena. Towards this end, we propose in this paper a hypothesis that is based on available experimental evidence as well as mathematical modeling and computer simulations. We hypothesize that there is a threshold in the nuclear NFAT concentration above which MCIP is switched on. Below this threshold, the inhibition of active CaN by MCIP is negligible, while the activated protein kinase increases the dissociation rate of the CaN/MCIP complex. This leads to an augmentation of active CaN. This mechanism realizes the positive effect (i.e., removing any negative feedback) of MCIP in the hypertrophic response. On the other hand, the over-expression of active CaN increases nuclear NFAT to values above the threshold, while CaN is inhibited through binding of MCIP (expressed by the nuclear NFAT). This mechanism realizes the introduction of a negative feedback mechanism. To unravel this switching feedback mechanism, we have developed a mathematical model for which computer simulations are in agreement with the existing experimental data. The simulations demonstrate how the apparently paradoxical behavior can emerge as a result of cellular conditions. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.