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

卷曲受体通过三聚体 G 蛋白进行 Wnt 和平面细胞极性信号转导的机制 (N01)

• 批准号: 51913270
• 金额: --
• 依托单位: Department of Cell Physiology and Metabolism
• 依托单位国家: 德国
• 项目类别: CRC/Transregios
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/51913270?language=en
• 关键词: Mechanism; Wnt; Planar; Cell; Polarity

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.

卷曲家族的受体包含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特化，并在许多癌症中被错误激活。另一种是“平面细胞极性”（PCP）类型的信号，需要类似于白细胞趋化性或轴突锥寻路的细胞骨架极化。我们已经证明，在果蝇中，两种信号都是通过相关的三聚体G蛋白Go由Frizzled受体转导的（Katanaev等人，Cell 2005）。基于这些信息，三年前，在我为Nachwuchsgruppe提出的最初申请中，制定了三个解决细胞、发育和医学重要性问题的项目。第一个目的是通过遗传学和生物化学/蛋白质组学手段的组合来鉴定三聚体Go蛋白的Gas亚基的分子靶标。第二个目的是建立一个强大的在体外检测监测卷曲受体的激活和使用ofthis检测，以确定新的天然和人工激动剂和拮抗剂卷曲受体。第三个目的是了解三聚体Go蛋白的β y亚基的作用，特别是在卷曲PCP信号传导中。在我的Nachwuchsgruppe的三年研究期间，在这三个方向上取得了重大进展，促使我申请继续我目前的资助一年，以完成我们令人兴奋的研究。