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(Received for publication, January 8, 1997, and in revised form, March 21, 1997)
From the Many cytokines, hormones, and growth
factors activate Janus kinases to tyrosine phosphorylate select members
of the Stat transcription factors. For full transcriptional activation,
Stat1 and Stat3 also require phosphorylation of a conserved
serine residue within a mitogen-activated protein kinase
phosphorylation consensus site. On the other hand, two recently
identified and highly homologous Stat5a and Stat5b proteins lack this
putative mitogen-activated protein kinase phosphorylation site. The
present study set out to establish whether Stat5a and Stat5b are under
the control of an interleukin-2 (IL2)-activated Stat5 serine kinase. We
now report that IL2 stimulated marked phosphorylation of serine and
tyrosine residues of both Stat5a and Stat5b in human T lymphocytes and in several IL2-responsive lymphocytic cell lines. No Stat5a/b phosphothreonine was detected. Phosphoamino acid analysis also revealed
that Stat5a/b phosphotyrosine levels were maximized within 1-5 min of
IL2 stimulation, whereas serine phosphorylation kinetics were slower.
Interestingly, IL2-induced serine phosphorylation of Stat5a differed
quantitatively and temporally from that of Stat5b with Stat5a serine
phosphorylation leveling off after 10 min and the more pronounced
Stat5b response continuing to rise for at least 60 min of IL2
stimulation. Furthermore, we identified two discrete domains of IL2
receptor
Volume 272, Number 24,
Issue of June 13, 1997
pp. 15459-15465
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Independently Mediate IL2 Activation of a
PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b Serine Kinase
,
,
,
,
and
Intramural Research Support Program, Science
Applications International Corporation Frederick, Frederick,
Maryland, 21702-1201 ¶ Division of Basic Sciences, Cytokine
Molecular Mechanisms Section, Laboratory of Molecular
Immunoregulation, National Cancer Institute, Frederick Cancer
Research and Development Center, Frederick, Maryland 21702-1201, the 
Department of Pathology, F. E. Hébert School of
Medicine, Uniformed Services University of the Health Sciences,
Bethesda, Maryland 20814, and ** Laboratory of Biochemistry and
Metabolism, NIDDK, National Institutes of Health,
Bethesda, Maryland 28092
(IL2R) that could independently restore the ability of
a truncated IL2R mutant to mediate Stat5a/b phosphorylation and DNA
binding to the 
-activated site of the -casein gene promoter.
These observations demonstrated that there is no strict requirement for
one particular IL2R region for Stat5 phosphorylation. Finally, we
established that the IL2-activated Stat5a/b serine kinase is
insensitive to several selective inhibitors of known IL2-stimulated
kinases including MEK1/MEK2 (PD98059), mTOR (rapamycin), and
phosphatidylinositol 3-kinase (wortmannin) as determined by
phosphoamino acid and DNA binding analysis, thus suggesting that a
yet-to-be-identified serine kinase mediates Stat5a/b activation.
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