Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce a variety of signals (e.g. hormones, neurotransmitters, and light) across the plasma membrane by coupling transmembrane receptors with intracellular effectors. G proteins are composed of three distinct subunits: alpha (which defines the heterotrimer, beta, and gamma. Alpha subunits can be divided into four classes based on sequence similarities. Members of the G12 class are potential oncogenes because activating mutants have highly potent transforming activities. Signal transduction pathways mediated by members of the G12 class are poorly understood. I propose to study the G12 pathway in Drosophila melanogaster, a powerful genetic system that is ideal for dissection of novel signaling pathways. The Drosophila gene concertina encodes a G protein alpha subunit of the G12 class (CTA) that is required for coordinated cell shape changes during gastrulation. Another Drosophila gene required during gastrulation, fog, encodes a secreted protein (FOG) that potentially activates the CTA pathway. To elucidate the G12 signaling pathway, I plan to examine the effects of ectopic activation of the CTA pathway in Drosophila, identify new components of the pathway by performing a dominant modifier screen and a two-hybrid assay, and demonstrate that FOG is a ligand for a CTA-coupled receptor. Numerous examples of conservation of signaling networks between invertebrates and vertebrates have been described, so identification of new components of the G12 pathway in Drosophila will likely have relevance for our understanding of this important pathway in humans.
