Calcineurin: a central controller of signalling in eukaryotes

Abstract

This meeting took place at the Juan March Foundation, Madrid, Spain, between 3 and 5 November 2003. It was sponsored by the Juan March Foundation and organized by E. Olson and J.M. Redondo. ![][1] Calcineurin is a serine‐ and threonine‐specific protein phosphatase that is conserved in all eukaryotes and is unique among phosphatases for its ability to sense Ca2+ through its activation by calmodulin. Identified and characterized in pioneering work by the Claude Klee and Philip Cohen laboratories in the late 1970s, calcineurin catapulted to centre stage when the groups of Stuart Schreiber and Irving Weissman discovered that it is the target of the immunosuppressants cyclosporin A and FK506. In the same year, the laboratory of Gerald Crabtree showed that cyclosporin blocks the nuclear import of the nuclear factor of activated T cell (NFAT) proteins and in 1993, the group of Anjana Rao showed that these proteins are dephosphorylated by calcineurin. These findings revealed a central pathway that coupled calcineurin to transcriptional regulation (Fig 1). Since then, calcineurin and NFAT proteins have been shown to participate in signalling cascades that govern the development and function of the immune, nervous, cardiovascular and musculoskeletal systems. Parallel advances made in microbial systems, including model yeasts and pathogenic fungi, have revealed that the basic mechanisms of action of calcineurin are conserved from unicellular to multicellular eukaryotes. Figure 1. Signal integration and coincidence detection by assembly of NFATc transcriptional complexes in the nucleus. A range of signalling pathways are integrated in the nucleus by the assembly of NFATc transcriptional complexes from calcineurin‐dependent NFATc subunits and inducible nuclear partners (NFATn), which regulate the affinity and specificity of NFATc DNA binding and ensure transcriptional activation in response to two signals. This mechanism allows the complexes to behave as coincidence detectors and signal integrators. CK1, casein kinase 1; Csp1, calcipressin … [1]: pending:yes