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JBC:控制Stat5b S193的磷酸化可能会遏制造血系统恶性肿瘤

在外部细胞因子及内部的酪氨酸激酶刺激的信号网络下游,信号传导及转录激活因子5b(Stat5b)是一个关键性的位点。Stat5b的最大转录活化需要Ser和Tyr的磷酸化。虽然Tyr磷酸化调节机制以及Stat5b的激活机制已经被广泛的研究,但是Ser磷酸化的作用机制还需要被完全阐明。近日,美国德克萨斯大学阿尔帕索分校的Robert A. Kirken等人研究发现了一个新的可以调节Stat5与DNA结合以及转录活性的磷酸化位点。相关研究发表在3月22日的美国《生化周刊》(Journal of Biological Chemistry)上。

STAT(Signal transducers and activators of transcription)即信号传导及转录激活因子,含有SH2和SH3结构域,可与特定的含磷酸化酪氨酸的肽段结合。当STAT被磷酸化后,发生聚合成为同源或异源二聚体形式的活化的转录激活因子,进入胞核内与靶基因启动子序列的特定位点结合,促进其转录。

使用质谱和磷酸化特异抗体研究,研究人员发现Ser193是人类Stat5b中一个新发现的由细胞因子诱导的磷酸化位点。在应答于几种常见细胞因子包括白细胞介素2,7,9和15时,Stat5b pS193被发现于激活的PBMCs或者是淋巴细胞系。运动及空间分析表明:Stat5b S193的磷酸化是迅速并且短暂的,而且在Stat5b转位到核内之前就已经在细胞的胞质室内发生了。此外,可诱导的Stat5b S193磷酸化对抑制剂哺乳动物雷帕霉素靶蛋白(mTOR)敏感,而抑制蛋白磷酸酶2A(PP2A)后会引起S193的磷酸化。在HEK293细胞的重构分析、定点突变和EMSA研究表明:Stat5b的最高转录活化需要S193的磷酸化。事实上,在几种淋巴瘤细胞系、原发性白血病和淋巴瘤病人肿瘤细胞中都发现了Stat5b S193的组成性磷酸化。

总的来说,IL-2家族通过雷帕霉素敏感机理紧密控制Stat5b S193的磷酸化。而且,S193组成性磷酸化与Stat5b原癌活性有关,因此Stat5b S193很可能会成为造血系统恶性肿瘤的新型治疗靶点。(生物谷Deepblue编译)


参考文献:


Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a novel cytokine induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies

DOI:doi: 10.1074/jbc.M111.319756
AUTHORS:Abhisek Mitra1, Jeremy A. Ross, Georgialina Rodriguez, Zsuzsanna S. Nagy, Harry L. Wilson and Robert A. Kirken.
ABSTRACT:Signal transducer and activator of transcription 5b (Stat5b) is a critical node in the signaling network downstream of external (cytokines or growth factors) or internal (oncogenic tyrosine kinases) stimuli. Maximum transcriptional activation of Stat5b requires both tyrosine and serine phosphorylation. Although the mechanisms governing tyrosine phosphorylation and activation of Stat5b have been extensively studied, the role of serine phosphorylation remains to be fully elucidated.Using mass spectrometry and phospho-specific antibodies, we identified S193 as a novel site of cytokine induced phosphorylation within human Stat5b. Stat5b pS193 was detected in activated primary human PBMCs or lymphoid cell lines in response to several gamma common cytokines, including interleukin (IL)-2, -7, -9, and -15. Kinetic and spatial analysis indicated that Stat5b S193 phosphorylation was rapid, transient and occurred in the cytoplasmic compartment of the cell prior to Stat5b translocation to the nucleus. Moreover, inducible Stat5b S193 phosphorylation was sensitive to inhibitors of mammalian target of rapamycin (mTOR), whereas inhibition of protein phosphatase 2A (PP2A) induced phosphorylation of S193. Reconstitution assays in HEK293 cells in conjunction with site-directed mutagenesis, EMSA and reporter assays, indicated that pS193 is required for maximal Stat5b transcriptional activity. Indeed, Stat5b S193 was found constitutively phosphorylated in several lymphoid tumor cell lines as well as primary leukemia and lymphoma patient tumor cells.Taken together, IL-2 family cytokines tightly control Stat5b S193 phosphorylation through a rapamycin sensitive mechanism. Furthermore, constitutive S193 phosphorylation is associated with Stat5b proto-oncogenic activity and therefore may serve as a novel therapeutic target for treating hematopoietic malignancies.

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