Mechanism of Wnt and Planar Cell Polarity Signal Transduction by Frizzled Receptors through Trimeric G-proteins (N01)

卷曲家族的受体转导两种不同类型的信号。一个是典型的Wnt信号，在发育过程中调节细胞命运规范，并在许多癌症中失活。另一种是平面细胞极性（PCP）类型的信号，需要细胞骨架极化，类似于白细胞趋化性或轴突锥寻路。我们已经证明，在果蝇中，这两种信号都是由卷曲受体通过相关的三聚体G蛋白Go转导的（Katanaev等人）。2005细胞)。基于这些信息，三年前我在Nachwuchsgruppe的原始申请中制定了三个解决细胞、发育和医学重要性问题的项目。第一个目的是通过结合遗传学和生化/蛋白质组学手段鉴定三聚体氧化石墨烯蛋白gas亚基的分子靶点。第二个目标是建立一个强大的体外实验来监测Frizzled受体的激活，并使用该实验来识别Frizzled受体的新的天然和人工激动剂和拮抗剂。第三项研究旨在了解三聚体氧化石墨烯蛋白的ßy亚基的作用，特别是在卷曲的PCP信号传导中。在我的Nachwuchsgruppe的三年研究中，在这三个方向上都取得了重大进展，这促使我申请了1年的续期，以完成我们令人兴奋的研究。

Receptors of the Frizzled family transduce two distinct types of signals. One is the canonical Wnt signal regulating cell fate specification during development and misactivated in many cancers. The other is the'planar cell polarity (PCP) type of signal requiring cytoskeletal polarizations similar to leukocyte Chemotaxis or axon cone pathfinding. We have shown that in Drosophila both signals are transduced by Frizzled receptors through an associated trimeric G protein Go (Katanaev et al. Cell 2005). Based on this information, three projects addressing issues of cell, developmental, and medical importance were formulated three years ago in my original application for the Nachwuchsgruppe. The first aimed at identification of molecular targets of the Gasubunit of the trimeric Go protein through a combination of genetics and biochemical/proteomics means. The second aimed at establishment of a robust in vitro assay for monitoring Frizzled receptor activation and usage ofthis assay to identify new natural and artificial agonists and antagonists of Frizzled receptors. The third aimed at understanding of the role of the ßy subunits of the trimeric Go protein, especially in the Frizzled PCP signaling. During the three years of research of my Nachwuchsgruppe, significant advances in these three directions have been made,- prompting me to apply for a 1-year continuation of my current grant in order to complete our exciting investigations.