Cell-cell signaling is a primary mechanism by which development is orchestrated. Cells transmit signals that direct the fate of other cells. These signals are usually small polypeptides secreted by the signaling cells or presented on their surfaces. The signals bind and activate receptors on the receiving cells, which results in the initiation of intracellular second messenger cascades. The Wnt signaling pathway is of interest for two major reasons. First, it represents one of the major types of cell-cell signaling that occurs during development. Second, inappropriate activation of the pathway causes oncogenic transformation of cells. Thus from the perspectives of disease and development understanding this signaling pathway is of clear importance. Frizzled (Fz) proteins are a family of serpentine receptors that bind Wnt peptides and transduce the signal across the plasma membrane and activate a second messenger system that transduces the signal to the nucleus to effect transcriptional regulation. Fz proteins also transduce a second distinct class of signal known as the polarity pathway. The ligand(s) for this pathway is unknown and this signal targets the recipient cells' cytoskeletons, leading to the uniform polarization of cells within epithelia, which for example project hairs in the same direction. The mechanism by which the signal is received and interpreted by the cells is seen as equivalent to that which occurs in neutrophil or slime mold amoebae chemotaxis in an extracellular signaling gradient. Thus this signaling pathway is of importance for understanding how cells respond and polarize with respect to gradients and how effectors are able to reorganize the cellular cytoskeleton. In Drosophila there are two well-characterized Wg (the fly Wnt-1) receptors - Fz1 and Fz2. Fz2 only transduces the Wg signal whereas Fzl transduces both the Wg and polaritysignals. This application proposes: 1. A detailed structure/function analysis of the intra-cellular portions of Fz1is proposed to locate the sequences that allow this receptor to engage polarity transduction machinery. 2. We have identified G-alpha-o (part of a trimeric complex that transduce signals from this class of receptors) as a candidate mediator of Fz1 signaling and we have shown that G-alpha-o and Fz1 bind in vitro. Using biochemical techniques we intend to determine which other G-alpha subunits bind Fz1 and which other Fz receptors bind to G-alpha-o. 3. We will use fly genetics to determine whether G-alpha-o also transduces the Wg signal, and also identify its molecular partners in the trimeric complex.
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