Abstract
Regulator of calcineurin 1 (RCAN1) is a key regulator of the calcineurin-NFAT signaling network in organisms ranging from yeast to human, but its functional role is still under debate because different roles of RCAN1 have been suggested under various experimental conditions. To elucidate the mechanisms underlying the RCAN1 regulatory system, we used a systems approach by combining single-cell experimentation with in silico simulations. In particular, we found that the nuclear export of GSK3β, which switches on the facilitative role of RCAN1 in the calcineurin-NFAT signaling pathway, is promoted by PI3K signaling. Based on this, along with integrated information from previous experiments, we developed a mathematical model in which the functional role of RCAN1 changes in a dose-dependent manner: RCAN1 functions as an inhibitor when its levels are low, but as a facilitator when its levels are high. Furthermore, we identified a hidden incoherent regulation switch that mediates this role change, which entails negative regulation through RCAN1 binding to calcineurin and positive regulation through sequential phosphorylation of RCAN1.
Highlights
The calcineurin–nuclear factor of activated T-cells (NFAT) signaling pathway has essential roles in many physiological processes, including T-cell activation, memory formation and apoptosis in neurons, and growth and differentiation in skeletal muscle and cardiac cells (Rusnak and Mertz, 2000; Shin et al, 2006; Shin et al, 2008; Tomida et al, 2003)
Recent studies have shown that Regulator of calcineurin 1 (RCAN1) facilitates calcineurin–NFAT signaling under various experimental conditions, and this has led to controversy regarding the functional role of RCAN1 (Fox and Heitman, 2005; Sanna et al, 2006; Vega et al, 2003b) (Table 1)
Vega and colleagues suggested a dual role of RCAN1 in the development of cardiac hypertrophy (Vega et al, 2003b), whereas Sanna and co-workers insisted that RCAN1 functions only as a calcineurin facilitator and reasoned that previous experiments showing RCAN1 to be a calcineurin inhibitor might be due to sequestration effects resulting from an overexpression approach (Sanna et al, 2006)
Summary
The calcineurin–nuclear factor of activated T-cells (NFAT) signaling pathway has essential roles in many physiological processes, including T-cell activation, memory formation and apoptosis in neurons, and growth and differentiation in skeletal muscle and cardiac cells (Rusnak and Mertz, 2000; Shin et al, 2006; Shin et al, 2008; Tomida et al, 2003). The activated calcineurin dephosphorylates NFAT, leading to its nuclear localization and subsequent activation of its target genes (Liang et al, 2003; Rusnak and Mertz, 2000; Vega et al, 2003a). Regulator of calcineurin 1 (RCAN1), a protein encoded by one of the target genes of NFAT, binds and inhibits calcineurin (Chan et al, 2005; Vega et al, 2002). Vega and colleagues suggested a dual role of RCAN1 in the development of cardiac hypertrophy (Vega et al, 2003b), whereas Sanna and co-workers insisted that RCAN1 functions only as a calcineurin facilitator and reasoned that previous experiments showing RCAN1 to be a calcineurin inhibitor might be due to sequestration effects resulting from an overexpression approach (Sanna et al, 2006). That Hoeffer (Hoeffer et al, 2007) and Ryeom and colleagues (Ryeom et al, 2003) demonstrated an inhibitory role of RCAN1 in mouse knockout experiments
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
