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.

蛋白质中的氨基酸组氨酸可以通过磷酸化进行修饰，从而改变这些蛋白质的功能，如文献中的一些例子所示。然而，到目前为止，只有少数研究解决了哺乳动物细胞中的这种修饰。最近一代专门检测蛋白质中磷酸化组氨酸的抗体现在可以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-catenin 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癌症等病理过程。 Wnt 因子与特定的细胞表面受体结合，从而激活 Dvl2 等细胞质蛋白，从而增加改变基因转录的 β-连环蛋白的稳定性。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 Dvl2 蛋白被严重组氨酸磷酸化。我们提案的目的是利用分子和细胞生物学方法破译组氨酸磷酸化在 Wnt 信号传导中的相关性。我们将特别关注组氨酸磷酸化对 Dvl2 活性的影响、作为该过程一部分的激酶和磷酸酶的作用，以及 Wnt 信号传导对组氨酸磷酸化的调节。此外，我们将扩展我们的分析，以检测和功能分析该途径其他关键成分的组氨酸磷酸化。组氨酸磷酸化是一个相对较新的研究领域，据我们所知，之前尚未应用于 Wnt 信号转导，希望能够为这一生物学和医学高度相关途径的功能和调节提供新线索。