BEG4/MIM FUNCTION IN EPITHELIAL NEOPLASIA

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DESCRIPTION (provided by applicant): While guided cell migration plays a critical role in normal skin development and wound healing, the cell biological mechanisms that guide wound closure or the developing skin remain poorly understood. We and others have previously shown that Missing in Metastasis (MIM) is a defining member of a novel class of membrane associated BAR (I-BAR) domain protein that regulates the actin cytoskeleton. We have used Drosophila border cell migration to provide the first genetic evidence that I-BAR proteins regulate directed cell migration through a novel epidermal growth factor-- dependent steering mechanism. Our working hypothesis is that pro-endocytic endophilin/CD2AP/cortactin enhance endocytosis and migration, while the anti-endocytic protein MIM spatially inhibits endocytosis to provide a directional signal during skin development and wound healing. The studies proposed in the BIRT revision extend the parent grant studies to migratory systems in skin and focuses on identifying additional proteins that work with MIM to direct cell migration. We will team with Professor Tobias Meyer, a prominent systems biologist at Stanford and an expert on high-throughput cell imaging analysis. The Oro-Meyer research team will be uniquely suited to carry out this innovative approach. The collaboration is built on our expertise in the genetics of development, and the Meyer lab's expertise in live cell imaging and siRNA screening. We will first identify which well characterized migratory system uses MIM-dependent steering. Next, using high throughput migration assays and cell tracking algorithms, we will perform a genome wide siRNA screen for genes like MIM that complement loss of cortactin. Our milestones are to identify vertebrate cell types that use MIM to steer toward their migratory cues and to identify 10 genes in the siRNA screen for further validation with our in vivo assays. Identification of novel components of the MIM-dependent steering mechanisms will provide key insights into understanding of how cells normally move to their desired locations during development and how tumor cells may use similar mechanisms during cancer metastasis.