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* Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston;
Department of Biochemistry and Molecular Biology, Medical and Health Science Center, The University of Debrecen, Hungary;
Isis Pharmaceuticals Inc., Molecular Pharmacology, Carlsbad, California;
IRSP, SAIC Frederick Cancer Research and Development Center, Maryland;
|| Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School at Houston; and
# Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
Correspondence: Dr. Robert A. Kirken, University of Texas Health Science Center at Houston, Department of Integrative Biology, MSB Room 4.218, Houston, TX 77030. E-mail: Robert.A.Kirken{at}uth.tmc.edu
Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G1-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.
Key Words: T lymphocytes • signal transduction • Janus tyrosine kinase • oligodeoxynucletide • mTor
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