Interaction of calcineurin with substrates and targeting proteins.

Calcineurin is a calcium activated protein phosphatase with a major role in calcium signaling in diverse cells and organs and clinical importance as the target of the immunosuppressive drugs cyclosporin A and tacrolimus (FK506). Cell biology studies have focused mainly on the role of calcineurin in transcriptional signaling. Calcium entry in response to extracellular stimuli results in calcineurin activation, and signal transmission from the cytosol into the nucleus through dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT). This initiates a cascade of transcriptional events involved in physiological and developmental processes. Molecular analyses of the calcineurin-NFAT interaction have been extended recently to encompass the interaction of calcineurin with other substrates, targeting proteins and regulators of calcineurin activity. These studies have increased our understanding of how this essential calcium activated enzyme orchestrates intracellular events in cooperation with other signaling pathways, and have suggested a link between altered calcineurin signaling and the developmental anomalies of Down syndrome.