The Stat1 binding motif of the interferon-gamma receptor is sufficient to mediate Stat5 activation and its repression by SOCS3.
Signal transduction via the interferon-gamma (IFN-gamma) receptor requires the tyrosine phosphorylation of signal transducers and activators of transcription (Stats). Whereas tyrosine phosphorylation of Stat1 occurs in all cells, activation of Stat5 by IFN-gamma is cell type-restricted. Here we investigated the mechanism of Stat5 activation by the IFN-gamma receptor. In transfection assays both Stat5 isoforms, Stat5a and Stat5b, were phosphorylated on tyrosine in response to IFN-gamma. Stat5 activation required the presence of tyrosine 420 (Tyr-420) in the murine IFNGR1 receptor chain, which also serves as the Stat1 binding site. Moreover, a peptide including Tyr-440, the Stat1 binding site of the human IFNGR1 chain, conferred the ability upon a synthetic receptor to activate Stat5. Suppressor of cytokine signaling 3 (SOCS3) inhibited the activation of Stat5 by the IFN-gamma receptor, and the Tyr-440-containing peptide stretch was sufficient for repression. SOCS3 expression had little effect on the activity of Jak kinases not associated with cytokine receptors. In IFN-gamma-treated, Stat1-deficient fibroblasts Stat5 was inefficient in inducing transcription of a Stat-dependent reporter gene, suggesting it does not per se make a major contribution to the expression of IFN-gamma-responsive genes.
Woldman
I
I
Vienna Biocenter, Institute of Microbiology and Genetics, Dr. Bohr-Gasse 9, A1030 Vienna, Austria.
Varinou
L
L
Ramsauer
K
K
Rapp
B
B
Decker
T
T
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008894:Milk Proteins; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017471:Receptors, Interferon / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D011506:Proteins; D017471:Receptors, Interferon; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma