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

不同信号通路的整合可以潜在地解释胚胎体计划是如何调节的以及人类疾病是如何引起的。主要涉及的信号通路是骨形态发生蛋白（Bmp）、Wnt、MAPK和Hedgehog网络。最近发现，在转录因子Smad 1的阶段，Wnt信号增加了Bmp信号建立早期爪蟾胚胎轴的持续时间。宿主实验室中未发表的发现表明，Wnt信号导致细胞GSK 3易位到细胞的蛋白水解中心--核粒周围区域。此外，典型的Wnt信号在培养的细胞和果蝇胚胎中增加总聚泛素化蛋白的水平。工作假设是Wnt信号传导是蛋白催化剂的一般抑制剂。我提议：I）使用蛋白质组学分析和His标记的泛素来鉴定哪些蛋白质被Wnt信号传导阻断降解，II）研究爪蟾胚胎中Wnt信号传导对蛋白酶体系统的调节，III）研究Wnt信号传导对不对称蛋白质分离和细胞分裂的影响。从这些研究中，我希望有助于信号级联如何影响它们在人类疾病或胚胎发生中的功能。

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 Unpublished findings in the host lab indicate that Wnt signals lead to a translocation of cellular GSK3 to the pericentrosomal region, a proteolytic center of the cell.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.