Abstract
Nuclear import of the NF-AT transcription factors during T-cell activation requires the calcium-activated phosphatase calcineurin, which unmasks nuclear-location signals on NF-AT (1–5). We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1 (6–8). Calcineurin suppresses this futile cycling by a non-catalytic mechanism involving the masking of nuclear export signals on NF-AT targeted by Crm1. This clustering of binding sites for calcineurin and Crm1 on NF-AT establishes an inherent competition between these molecules that imparts exquisite calcium sensitivity to the shuttling dynamics of the NF-AT transcription factors. Such a balance between nuclear import and export may regulate the action of other transcription factors.
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Acknowledgements
We thank A. Yang and T. Rapoport for helpful discussions and comments on this manuscript, and G. Grosveld, R. Reed and B. Wolff for reagents used in this study. This work was supported by grants from the NIH and the American Cancer Society.
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Zhu, J., McKeon, F. NF-AT activation requires suppression of Crm1-dependent export by calcineurin. Nature 398, 256–260 (1999). https://doi.org/10.1038/18473
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DOI: https://doi.org/10.1038/18473
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