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J Biol Chem, Vol. 275, Issue 14, 10247-10255, April 7, 2000

Stat5a Serine Phosphorylation
SERINE 779 IS CONSTITUTIVELY PHOSPHORYLATED IN THE MAMMARY GLAND, AND SERINE 725 PHOSPHORYLATION INFLUENCES PROLACTIN-STIMULATED IN VITRO DNA BINDING ACTIVITY^*

Iwan Beuvink, Daniel Hess, Horst Flotow, Jan Hofsteenge, Bernd Groner^§, and Nancy E. Hynes^¶

From the Friedrich Miescher Institute, P. O. Box 2543, CH-4002 Basel, Switzerland,  Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts, AL7 3AY, United Kingdom, and ^§ Georg Speyer Haus, Paul Ehrlich Strasse 42-44, 60596 Frankfurt, Germany

The activity of transcription factors of the Stat family is controlled by phosphorylation of a conserved, carboxyl-terminal tyrosine residue. Tyrosine phosphorylation is essential for Stat dimerization, nuclear translocation, DNA binding, and transcriptional activation. Phosphorylation of Stats on specific serine residues has also been described. We have previously shown that in HC11 mammary epithelial cells Stat5a is phosphorylated on Tyr⁶⁹⁴ in a prolactin-sensitive manner, whereas serine phosphorylation is constitutive (Wartmann, M., Cella, N., Hofer, P., Groner, B., Xiuwen, L., Hennighausen, L., and Hynes, N. E. (1996) J. Biol. Chem. 271, 31863-31868). By using mass spectrometry and site-directed mutagenesis, we have now identified Ser⁷⁷⁹, located in a unique Stat5a SP motif, as the site of serine phosphorylation. By using phospho-Ser⁷⁷⁹-specific antiserum, we have determined that Ser⁷⁷⁹ is constitutively phosphorylated in mammary glands taken from different developmental stages. Stat5a isolated from spleen, heart, brain, and lung was also found to be phosphorylated on Ser⁷⁷⁹. Ser⁷²⁵ in Stat5a has also been identified as a phosphorylation site (Yamashita, H., Xu, J., Erwin, R. A., Farrar, W. L., Kirken, R. A., and Rui, H. (1998) J. Biol. Chem. 273, 30218-30224). Here we show that mutagenesis of Ser⁷²⁵, Ser⁷⁷⁹, or a combination of Ser^725/779 to an Ala had no effect on prolactin-induced transcriptional activation of a -casein reporter construct. However, following prolactin induction the Ser⁷²⁵ mutant displayed sustained DNA binding activity compared with that of wild type Stat5a. The results suggest that Ser⁷²⁵ phosphorylation has an impact on signal duration.

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