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

整合不同的信号通路可以潜在地解释胚胎身体计划是如何受到调节的，以及人类疾病是如何引起的。涉及的主要信号通路有骨形态发生蛋白(BMP)、Wnt、MAPK和Hedgehog网络。最近发现，在转录因子Smad1的阶段，Wnt信号可以延长建立非洲爪哇早期胚胎中轴的BMP信号的持续时间。宿主实验室未发表的研究结果表明，Wnt信号导致细胞GSK3移位到细胞的蛋白质分解中心--胞体周围区域。此外，培养细胞和果蝇胚胎中规范的Wnt信号增加了总多泛素化蛋白的水平。工作假说是Wnt信号是蛋白质分解代谢的一般抑制因子。我建议：1)利用蛋白质组学分析和His标记的泛素，确定哪些蛋白质被Wnt信号阻断降解；2)研究Wnt信号对非洲爪哇胚胎蛋白酶体系统的调节；3)研究Wnt信号对不对称蛋白质分离和细胞分裂的影响。通过这些研究，我希望对信号级联如何影响它们在人类疾病或胚胎发育中的功能做出贡献。

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 Unpublished findings in the host lab indicate that Wnt signals lead to a translocation of cellular GSK3 to the pericentrosomal region, a proteolytic center of the cell.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