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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways.
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Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways.

机译:白细胞介素2家族细胞因子刺激人T细胞中Stat5转录因子的Pro-Ser-Pro基序的磷酸化:抵抗多种丝氨酸激酶途径的抑制。

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摘要

Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G(1)-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.
机译:信号转导子和转录激活子(Stat)5a和Stat5b对于正常的免疫功能至关重要。 T细胞通过细胞周期的G(1)-S期进行过程需要Stat5a / b的T细胞受体(TCR)和/或细胞因子诱导的酪氨酸磷酸化。 Stat5a / b还可以以细胞依赖性方式在位于转录激活域内的Pro-Ser-Pro(PSP)基序上组成型或细胞因子诱导性磷酸化。 PSP基序的磷酸化是至少在某些启动子环境下通过Stat5进行最大转录激活所必需的。尚未在T细胞中确定Stat5a / b的基础和细胞因子诱导的丝氨酸磷酸化状态。使用原代人T细胞和T淋巴细胞细胞系,以及针对Stat5a或Stat5b中这种保守的磷酸丝氨酸基序的新型磷酸特异性抗体,我们报告:Stat5a和Stat5b在基础条件下在PSP基序上未磷酸化,并在响应于几种T细胞生长因子刺激物,包括白介素(IL)-2,-7,-9和-15和佛波酯12-肉豆蔻酸酯13-乙酸酯,但不包括TCR参与;诱导型Stat5a / b丝氨酸磷酸化在数量和时间上均存在差异。与可诱导的Stat3丝氨酸磷酸化相反,Stat5a / b丝氨酸磷酸化对促分裂原激活的蛋白激酶,磷脂酰肌醇3激酶和哺乳动物雷帕霉素靶标的抑制剂不敏感,或者通过Raf-A,-B或-C缺失反义寡核苷酸。我们得出结论,IL-2家族细胞因子通过不同于Stat3丝氨酸激酶的激酶来紧密控制Stat5丝氨酸磷酸化。

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