This application represents the third competitive renewal for this research program. Orginating from our interesting in the zinc finger tumor suppressor protein WT1, we identified the Sproutyl gene as a WT1 target gene relevant to kidney differentiation and the regulation of cellular growth. Over the past four years we confirmed this idea through the creation of a Spryl knockout mouse that exhibited a severe renal phenotype. We also showed that Sproutyl and other Sprouty proteins interefered with signaling through RTKs at the level of ras activation. Nevertheless many questions remain in the field including the role of the other sprouty proteins in animal devlopment; the exact point of action and mechanism of the sprouty proteins in inhibting signal transduction and the critical partner proteins for sprouty action. We believe that the four sprouty genes in higher eukaryotes play distinct roles in development and work through some common and some distinct mechamisms. Lastly emerging data suggest that the Sprouty genes may be bonafide tumor suppressors. Hence in the next funding period we propose a number of biochemical as well as animal model approaches towards the fuller understanding of the sprouty family of proteins. Specifically we will 1. Determine the point of action of the sprouty proteins in signal transduction through the Ras/MAP kinase and other pathways through the use of knockout cells and repeletion with wild-type and mutant forms of Sprouty proteins 2. Determine the identity of the critical partner proteins of Sprouty which interact in a phosphorylation dependent and independent manner to modulate signal transduction 3. Determine the role of Sproutyl as a tumor suppressor protein in an animal model of breast cancer 4. Characterize the biochemical function of the Sprouty 3 protein and target the Spn/3 gene in mice to determine the role of this protein in signal transduction and animal development.
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