The overall objective of the four projects in this program of research is to develop and exploit biosensors and image analysis techniques to delineate the mechanisms that control the spatial and temporal activity of Rho GTPases in different biological contexts. In particular, guanine nucleotide exchange factors (GEFs), the upstream activators of Rho GTPases, are thought to promote highly polarized signaling that is capable of generating changes in the shape, movement and organization of cells.
The aim of this project (project 3) is to study GEFs in the context of epithelial morphogenesis and migration. Epithelial morphogenesis and migration drive development in the embryo and regeneration and repair in the adult, while defects underlie a wide spectrum of human diseases and syndromes, notably cancer. Depsite representing very different aspects of cell behavior, morphogenesis and migration share many signaling pathway components, in particular Rho GTPases, but the key feature that distinguishes their respective contributions is their distinct spatial localization. The underlying hypothesis is that the spatial localization and molecular specificity of Rho GTPase signaling pathways are determined by specific GEFs (of which there are 82 in the human genome). The key aims are to: (i) identify and molecularly characterize GEFs involved in the establishment (morphogenesis) and dynamic reorganization (collective migration) of apically localized cell-cell junctions and basally localized cell- matrix adhesions in the human bronchial epithelial cell line, 16HBE, and (ii) use GEF biosensors developed by Hahn and Sondek together with image analysis techniques developed by Danuser to visualize their activity and relationship to GTPase signaling in space and time. It is expected that the project will generate significant new insights into the molecular mechanisms regulating fundamental aspects of epithelial cell behavior.
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