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首页> 外文期刊>Cellular Signalling >Mutational analysis reveals separable DNA binding and trans-activation of Drosophila STAT92E
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Mutational analysis reveals separable DNA binding and trans-activation of Drosophila STAT92E

机译：突变分析显示果蝇STAT92E可分离的DNA结合和反式激活

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In the canonical model of JAK/STAT signalling STAT transcription factors are activated by JAK mediated tyrosine phosphorylation following pathway stimulation by external cytokines. Activated STAT molecules then homo- or heterodimerise before translocating to the nucleus where they bind to DNA sequences within the promoters of pathway target genes. DNA-bound STAT dimers then activate transcription of their targets via interaction with components of the basal transcription machinery. Here we describe a missense mutation in the SH2 domain of the single Drosophila STAT92E homologue which results in an amino-acid substitution conserved in both the canonical SH2 domain and STAT-like molecules previously identified in C elegans and the mosquito Anopheles gambiae. This mutation leads to nuclear accumulation and constitutive DNA binding of Drosophila STAT92E even in the absence of JAK stimulation. Strikingly, this mutant shows only limited transcriptional activity in tissue culture based assays and functions as a dominant-negative at both the phenotypic and molecular levels in vivo. These features represent aspects of both dominant gain-of-function and dominant-negative activities and imply that the functions of DNA binding can be functionally separated from the role of STAT92E as a transcriptional activator. It is thus possible that an alternative post-translational modification, in addition to tyrosine phosphorylation, may be required to allow STAT to act as a transcriptional activator and suggests the existence of an alternative mechanism by which STAT transcriptional activity may be regulated in vivo. (c) 2005 Elsevier Inc. All rights reserved.
机译：在JAK / STAT信号转导的经典模型中，STAT转录因子在外部细胞因子途径刺激后被JAK介导的酪氨酸磷酸化激活。然后，活化的STAT分子在转移至细胞核之前与同二聚体或异源二聚体结合，在细胞核中与途径靶基因启动子内的DNA序列结合。然后，DNA结合的STAT二聚体通过与基础转录机制的成分相互作用来激活其靶标的转录。在这里，我们描述了单个果蝇STAT92E同源物的SH2域中的一个错义突变，该突变导致在经典SH2域和先前在秀丽隐杆线虫和冈比亚按蚊中鉴定出的STAT样分子中均保守的氨基酸取代。即使没有JAK刺激，这种突变也导致果蝇STAT92E的核积累和组成性DNA结合。令人惊讶的是，该突变体在基于组织培养的分析中仅显示出有限的转录活性，并且在体内的表型和分子水平上均起显性负性作用。这些特征代表着显性功能获得性和显性负性活性的方面，并且暗示DNA结合的功能可以在功能上与STAT92E作为转录激活因子的作用分开。因此，可能需要除酪氨酸磷酸化以外的另一种翻译后修饰，以使STAT充当转录激活剂，并暗示存在另一种机制，通过该机制可以在体内调节STAT的转录活性。 （c）2005 Elsevier Inc.保留所有权利。

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