The calcineurin–NFAT (nuclear factor of activated T cells) signalling pathway controls many physiological processes, including T-cell activation and cardiac cell growth. Regulator of calcineurin 1 (RCAN1) is a conserved regulator of this signalling network, but its functional role is hotly debated because, although it inhibits calcineurin–NFAT signalling in some experimental systems, it facilitates signalling in others. To resolve this debate, Kwang-Hyun Cho, Won Do Heo and colleagues (p. ) have used a new approach in which they combine in silico simulations and single-cell live imaging experimentation. The authors' approach reveals a hidden incoherent regulation switch that is formed by cross-talk signals mediated through extracellular signal-regulated protein kinase and glycogen synthase kinase-3. This switch, they report, diverts negative regulation by RCAN1 to positive regulation, which leads to a dose-dependent biphasic response. Specifically, RCAN1 functions as an inhibitor when its levels are low, but as a facilitator when its levels are high. The authors conclude that the discovery of this incoherent regulation switch, which can induce apparently opposite responses depending on conditions, provides an explanation for the different roles of RCAN1 in calcineurin–NFAT signalling that have been suggested in previous studies.
