Why So Many Phosphates?

Science's STKE  03 Oct 2000:
Vol. 2000, Issue 52, pp. tw2
DOI: 10.1126/stke.2000.52.tw2

Regulation of protein function by phosphorylation is a common theme in signal transduction. However, in many cases it is not yet clear precisely how this covalent modification alters protein function. This is particularly true for molecules like the transcription factor NFAT in which no less than 21 serine residues are phosphorylated in unstimulated cells. In general, dephosphorylation of NFAT is correlated with its transport to the nucleus and activation of its transcriptional effects. Okamura et al. carefully analyzed the relation of phosphorylation to the localization and transcriptional activity of NFAT1. Their results indicate that dephosphorylation of 13 of 14 conserved serine residues is necessary to fully expose a nuclear localization signal (NLS) in NFAT. However, even fully phosphorylated NFAT1 entered the nucleus at a slow rate. Thus NFAT appears infrequently to assume an active conformation (with the NLS exposed), even in the fully phosphorylated state. Dephosphorylation also decreased nuclear export, through loss of or interference with a nuclear export signal. Although regulation of NFAT through localization has been emphasized, Okamura et al. found that transcriptional activity of NFAT is also potently stimulated by both dephosphorylation of sites in the regulatory domain and by increased phosphorylation of sites in the transactivation domain. The authors suggest that changes in phosphorylation state of NFAT modify the probability with which it assumes an active conformation. Further, they propose that the need for multiple dephosphorylation events required for full activity may be analogous to requirement of multiple phosphorylation events in T cell receptor stimulation, which establishes a threshold for full functional activation of the system.

Okamura, H., Aramburu, J., García-Rodríguez, C., Viola, J.P.B., Raghavan, A., Tahiliani, M., Zhang, X., Qin, J., Hogan, P.G., and Rao, A. (2000) Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol. Cell 6: 539-550. [Online Journal]