Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression

Complete activation of signal transducer and activator of transcription 1 ( STAT1) requires phosphorylation at both Y701 and a conserved PMS727P sequen ce. S727 phosphorylation of STAT1 in interferon-gamma (IFN-gamma)-treated m ouse fibroblasts occurred without a need for p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 or c-Jun kina ses, and required both an intact SH2 domain and phosphorylation of Y701, In contrast, UV irradiation-induced STAT1 phosphorylation on S727 required p3 8MAPK, but no SH2 domain-phospho-tyrosine interactions. Mutation of S727 di fferentially affected IFN-gamma target genes, at the level of both basal an d induced expression. particularly strong effects were noted for the GBP1 a nd TAP1 genes. The PMS727P motif of STAT3 was phosphorylated by stimuli and signaling pathways different from those for STAT1 S727, Transfer of the ST AT3 C-terminus to STAT1 changed the stimulus and pathway specificity of STA T1 S727 phosphorylation to that of STAT3, Our data suggest that STAT C-term ini contribute to the specificity of cellular responses by linking individu al STATs to different serine kinase pathways and through an intrinsically d ifferent requirement for serine phosphorylation at different target gene pr omoters.