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J Biol Chem, Vol. 273, Issue 46, 30218-30224, November 13, 1998
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From the Transcription factors of the Stat family are
controlled by protein kinases. Phosphorylation of a positionally
conserved tyrosine residue is obligatory for Stat dimerization, nuclear
translocation, and specific DNA binding. Studies of Stat1 and Stat3
have suggested that serine phosphorylation may also regulate function.
We now identify serine residues located in a conserved PSP motif of
Stat5a (Ser725) and Stat5b (Ser730) as
major phosphorylation sites, using mutagenesis, phosphoamino acid
analysis, and site-specific anti-Stat5-phosphoserine antibodies. Unexpectedly, phosphorylation control of this PSP motif differed between the highly homologous Stat5a and Stat5b proteins. Whereas Ser725 of Stat5a was constitutively phosphorylated both in
COS-7 cells and Nb2 lymphocytes, phosphorylation of Ser730
of Stat5b was markedly stimulated by prolactin. The data also suggested
the existence of a second major serine phosphorylation site in Stat5a.
Interestingly, constitutive phosphorylation of the PSP motif was
suppressed by PD98059 but not by staurosporine under conditions in
which both agents inhibited mitogen-activated protein kinases.
Furthermore, pretreatment of cells with staurosporine, PD98059, H7, or
wortmannin did not prevent either Stat5a or Stat5b from becoming
maximally serine-phosphorylated after prolactin exposure. We propose
that two pathways regulate Stat5 serine phosphorylation, one that is
prolactin-activated and PD98059-resistant and one that is
constitutively active and PD98059-sensitive and preferentially targets
Stat5a. Finally, phosphorylation of the PSP motif of Stat5a or Stat5b
was not essential for DNA binding or transcriptional activation of a
Department of Pathology, Uniformed Services
University of the Health Sciences, Bethesda, Maryland 20814, the
§ Department of Integrative Biology, Pharmacology, and
Physiology, University of Texas at Houston, Houston, Texas 77030, and
the ¶ Intramural Research Support Program, Division of Basic
Sciences,
-casein reporter gene in COS-7 cells, suggesting that serine kinase
control of Stat5 activity differs from that of Stat1 and Stat3.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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