Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3

Abstract

Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.

ACKNOWLEDGMENTS

We thank A. Altman, T. Hoey, Y.-C. Liu, R. Maurer, A. Rao, and T. Soderling for providing reagents; T. Barrett and M. Sharma for technical assistance; and K. Gemme for administrative assistance.

C.-W. Chow is an Arthritis Foundation fellow. This work was supported in part by grants CA65861 and CA72009 from the National Cancer Institute. R.J.D. is an Investigator of the Howard Hughes Medical Institute.