Studies on histidine phosphorylation in Wnt/beta-catenin signaling

Wnt/β-catenin 信号传导中组氨酸磷酸化的研究

• 批准号: 399176750
• 负责人: Professor Dr. Jürgen Behrens
• 金额: --
• 依托单位: Lehrstuhl für Experimentelle Medizin II - Molekulare Tumorforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399176750?language=en
• 关键词: Studies; histidine; phosphorylation; Wnt; beta

The amino acid histidine can be modified in proteins by phosphorylation which alters the function of these protein as has been shown for a few examples in the literature. However, until now only a few studies have addressed this modification in mammalian cells. The recent generation of antibodies that specifically detect phospho-histidines in proteins now allows a more general analysis of the function of histidine phosphorylation in cellular processes. In our preliminary work we have found evidence for a role of histidine phosphorylation in the regulation of the Wnt/beta-catenin signaling pathway. This pathway takes part in numerous biological processes, including cell proliferation, stem cell development and differentiation as well as in pathological processes such as cancer. Wnt factors bind to specific cell surface receptors thereby activating cytoplasmic proteins such as Dvl2 to increase the stability of the beta-catenin protein which alters gene transcription. We found that histidine kinases and phosphatases inhibit and stimulate Wnt signaling, respectively, and that the Dvl2 protein is heavily histidine phosphorylated. The aim of our proposal is to decipher the relevance of histidine phosphorylation in Wnt signaling using molecular and cell biological methods. In particular we will focus on the consequences of histidine phosphorylation for Dvl2 activity, on the role of of the kinases and phosphatases that are part of this process, as well as the regulation of histidine phosphorylation by Wnt signaling. Moreover we will extend our analysis to detect and functionally analyze histidine phosphorylation of other key components of the pathway. Histidine phosphorylation is a relatively new research field which has to our knowledge not been applied to Wnt signaling before and hopefully will yield new clues on the function and regulation of this biologically and medically highly relevant pathway.

如文献中的一些实例所示，蛋白质中的氨基酸组氨酸可以通过磷酸化修饰，磷酸化改变这些蛋白质的功能。然而，到目前为止，只有少数研究在哺乳动物细胞中解决了这种修饰。最近一代特异性检测蛋白质中磷酸化组氨酸的抗体现在允许对细胞过程中组氨酸磷酸化的功能进行更全面的分析。在我们的初步工作中，我们发现了组氨酸磷酸化在Wnt/β-连环蛋白信号通路调节中的作用的证据。该途径参与许多生物过程，包括细胞增殖、干细胞发育和分化以及病理过程如癌症。Wnt因子与特异性细胞表面受体结合，从而激活细胞质蛋白如Dvl 2以增加β-连环蛋白的稳定性，这改变了基因转录。我们发现组氨酸激酶和磷酸酶分别抑制和刺激Wnt信号传导，并且Dvl 2蛋白被严重组氨酸磷酸化。我们建议的目的是使用分子和细胞生物学方法来破译Wnt信号中组氨酸磷酸化的相关性。特别是，我们将集中在Dvl 2活性的组氨酸磷酸化的后果，对激酶和磷酸酶的作用，这是这个过程的一部分，以及通过Wnt信号调节组氨酸磷酸化。此外，我们将扩展我们的分析，以检测和功能分析组氨酸磷酸化的其他关键组成部分的途径。组氨酸磷酸化是一个相对较新的研究领域，据我们所知，它以前没有应用于Wnt信号转导，并有望为这一生物学和医学高度相关的途径的功能和调控提供新的线索。