Nucleocytoplasmic shuttling and the control of NF-AT signaling

The nuclear factors of activated T cells (NF-ATs) constitute a family of transcription factors that transduce calcium signals in the immune, cardiac, muscular and nervous systems. Like their distant relatives of the Rel family, including NF-kappa B, NF-ATs are cytoplasmic in resting cells and activated by means of induced nuclear import. Unlike NF-kappa B, however, NF-ATs show highly dynamic nuclear shuttling properties that have important implications for graded signaling by these molecules. This review focuses on recent advances in deciphering mechanisms by which calcium signaling regulates the nucleo-cytoplasmic shuttling and therefore transactivation functions of the NF-ATs. These discoveries highlight the interplay between nuclear import and export signals on NF-ATs, and the roles of the calcium-activated phosphatase calcineurin and NF-AT kinases in controlling the activity of these signals. They also reveal that NF-ATs, as well as other transcription factors controlled at the level of nuclear import, face the very real prospect of futile cycling across the nuclear envelope as a consequence of conflicting nuclear import and export signals. We discuss the molecular mechanisms by which calcineurin suppresses futile cycling, as well as the major challenges to our understanding of NF-AT signaling in diverse biological systems.