Regulation der Proteindegradation durch kanonische Wnt Signalgebung; Erforschung von Kreuzungspunkten verschiedener Signalkaskaden und ihre Auswirkung auf die Embryonalentwicklung und Pathogenese im Menschen durch Nutzung des Modellorganismus Xenopus laev

通过经典 Wnt 信号传导调节蛋白质降解；

• 批准号: 125541588
• 负责人: Dr. Radoslaw Dobrowolski
• 金额: --
• 依托单位: Department of Biological Sciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/125541588?language=en
• 关键词: Regulation; der; Proteindegradation; durch; kanonische

Integration of diverse signaling pathways can potentially explain how the embryonic body plan is regulated and how human diseases are caused. The major signaling pathways involved are the bone morphogenic protein (Bmp), the Wnt, the MAPK and the Hedgehog networks. The duration of Bmp signals establishing the axis of early Xenopus embryos have been recently discovered to be increased by Wnt signaling at the stage of the transcription factor Smad1. Unpublished findings in the host lab indicate that Wnt signals lead to a translocation of cellular GSK3 to the pericentrosomal region, a proteolytic center of the cell. Furthermore, canonical Wnt signals in cultured cells and Drosophila embryos increase the level of total polyubiquitinylated proteins. The working hypothesis is that Wnt signaling is a general inhibitor of protein catabolism. I propose: I) to identify which proteins are blocked for degradation by Wnt signaling using proteomic analyses and His-tagged ubiquitin, II) to study the modulation of the proteasome system by Wnt signals in Xenopus embryo, III) to investigate the impact of Wnt signaling on asymmetrical protein segregation and cell division. From these studies I hope to contribute to how signaling cascades influence their functions in human disease or embryogenesis.

不同信号通路的整合可以潜在地解释胚胎身体计划是如何调节的以及人类疾病是如何引起的。涉及的主要信号通路是骨形态发生蛋白（Bmp）、Wnt、MAPK 和 Hedgehog 网络。最近发现，建立早期非洲爪蟾胚胎轴的 Bmp 信号的持续时间可以通过转录因子 Smad1 阶段的 Wnt 信号延长。宿主实验室未发表的研究结果表明，Wnt 信号导致细胞 GSK3 易位至中心体周围区域，即细胞的蛋白水解中心。此外，培养细胞和果蝇胚胎中的经典 Wnt 信号会增加总多泛素化蛋白的水平。目前的假设是 Wnt 信号传导是蛋白质分解代谢的一般抑制剂。我建议：I) 使用蛋白质组分析和 His 标记的泛素来确定 Wnt 信号传导阻断哪些蛋白质降解，II) 研究非洲爪蟾胚胎中 Wnt 信号对蛋白酶体系统的调节，III) 研究 Wnt 的影响不对称蛋白质分离和细胞分裂的信号传导。我希望通过这些研究为信号级联如何影响其在人类疾病或胚胎发生中的功能做出贡献。