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

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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.