Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression
Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression
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DOI：
10.1093/emboj/20.1.91
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发表时间：
2001-01-15
期刊：
影响因子：
11.4
通讯作者：
Decker, T
中科院分区：
文献类型：
--
作者：
Kovarik, P;Mangold, M;Decker, T
信号转导和转录激活因子1（STAT 1）的完全激活需要在Y 701和一个保守的PMS 727 P序列的磷酸化。干扰素-γ中STAT 1的S727磷酸化（IFN-γ）处理的小鼠成纤维细胞在不需要p38促分裂原活化蛋白激酶（MAPK）、细胞外信号调节激酶1和2或c-Jun激酶的情况下发生，并且需要完整的SH 2结构域和Y 701的磷酸化。相反，UV照射诱导的S727上的STAT 1磷酸化需要p38 MAPK，但没有SH 2结构域-磷酸-酪氨酸相互作用。S727的突变在基础和诱导表达水平上差异地影响IFN-γ靶基因。对于GBP 1和TAP 1基因注意到特别强的作用。STAT 3的PMS 727 P基序被不同于STAT 1 S727的刺激和信号通路磷酸化。STAT 3 C-末端转移到STAT 1改变了STAT 1 S727磷酸化的刺激和通路特异性，我们的数据表明，STAT C-末端通过将单个STAT与不同的丝氨酸激酶途径连接，并通过对不同的丝氨酸激酶途径的内在不同要求，不同靶基因启动子的丝氨酸磷酸化。
Complete activation of signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Y701 and a conserved PMS727P sequence. S727 phosphorylation of STAT1 in interferon-gamma (IFN-gamma)-treated mouse fibroblasts occurred without a need for p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 or c-Jun kinases, and required both an intact SH2 domain and phosphorylation of Y701, In contrast, UV irradiation-induced STAT1 phosphorylation on S727 required p38MAPK, but no SH2 domain-phospho-tyrosine interactions. Mutation of S727 differentially affected IFN-gamma target genes, at the level of both basal and induced expression. particularly strong effects were noted for the GBP1 and TAP1 genes. The PMS727P motif of STAT3 was phosphorylated by stimuli and signaling pathways different from those for STAT1 S727, Transfer of the STAT3 C-terminus to STAT1 changed the stimulus and pathway specificity of STAT1 S727 phosphorylation to that of STAT3, Our data suggest that STAT C-termini contribute to the specificity of cellular responses by linking individual STATs to different serine kinase pathways and through an intrinsically different requirement for serine phosphorylation at different target gene promoters.