Regulation of Transcription Factor SP1 by the β-Catenin Destruction Complex Modulates Wnt Response
Regulation of Transcription Factor SP1 by the β-Catenin Destruction Complex Modulates Wnt Response
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DOI：
10.1128/mcb.00188-18
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发表时间：
2018-11-01
影响因子：
5.3
通讯作者：
Galande, Sanjeev
中科院分区：
文献类型：
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作者：
Mir, Rafeeq;Sharma, Ankita;Galande, Sanjeev
无处不在的转录因子特异性蛋白1 （SP1）在翻译后被大量修饰。这些修饰对于转换其功能和调节其转录活性以及DNA结合和稳定性至关重要。然而，通过细胞信号通路调控SP1稳定性的机制尚不清楚。在这里，我们提供了生化和功能证据，证明SP1是Wnt信号通路的一个组成部分。我们在SP1中发现了哺乳动物特有的磷酸化基序。在缺乏Wnt信号的情况下，糖原合成酶激酶3 β (GSK3 β)介导的磷酸化和β - trcp E3泛素连接酶介导的泛素化是诱导SP1降解的必要条件。当Wnt信号开启时，SP1以β -连环蛋白依赖的方式稳定下来。SP1直接与β -catenin相互作用，Wnt信号通过阻碍SP1与β - trcp和axin1（破坏复合物的组分）的相互作用诱导SP1稳定。Wnt信号抑制SP1的泛素化和随后的蛋白体降解。此外，SP1调控wnt依赖性β -catenin的稳定性，它们的相互稳定对靶基因表达至关重要，提示存在反馈机制。稳定后，SP1和β -catenin共同占据TCFL2/ β -catenin靶基因的启动子。总的来说，本研究揭示了SP1与Wnt信号通路中β -连环蛋白之间的直接联系。
The ubiquitous transcription factor specificity protein 1 (SP1) is heavily modified posttranslationally. These modifications are critical for switching its functions and modulation of its transcriptional activity and DNA binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidence that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In the absence of Wnt signaling, glycogen synthase kinase 3 beta (GSK3 beta)-mediated phosphorylation and beta-TrCP E3 ubiquitin ligase-mediated ubiquitination are required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in a beta-catenin-dependent manner. SP1 directly interacts with beta-catenin, and Wnt signaling induces the stabilization of SP1 by impeding its interaction with beta-TrCP and axin1, components of the destruction complex. Wnt signaling suppresses ubiquitination and subsequent proteosomal degradation of SP1. Furthermore, SP1 regulates Wnt-dependent stability of beta-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization, SP1 and beta-catenin cooccupy the promoters of TCFL2/beta-catenin target genes. Collectively, this study uncovers a direct link between SP1 and beta-catenin in the Wnt signaling pathway.