Crucial aspects of cellular organization and function are determined by interactions between membranes and the cytoskeleton. In many cases, these interactions are initiated by extracellular signals and transduced by families of proteins also responsible for controlling transcriptional activity and the cell cycle. Although incompletely understood, the polarized budding of daughter cells in yeast provides a striking example of how rho family of GTPases and related proteins lead to alterations of known and novel cytoskeletal elements to control cellular morphogenesis. Given the fundamental natures of these responses, it is highly likely that a similar cascade of events is responsible for controlling morphogenesis and polarity in mammalian cells. Recent evidence provides provocative hints that this may indeed be the case. We propose to apply novel assays to characterize the mechanisms responsible for initiating and maintaining polarity in mammalian cells, and to directly test the possibility that polarity in yeast and mammalian cells is mediated by fundamentally similar strategies. In addition, we will examine the relationship between polarity and tumorigenesis, since proteins which are strong candidates in controlling cell polarity are encoded by known or suspected oncogenes.
Our Specific Aims are: i) to understand the events leading to the initial development of polarity in epithelial cells, neurons and lymphocytes; ii) To characterize the mechanisms responsible for the maintenance of distinct plasma membrane domains in the absence of cell-cell contact; iii) To determine the intracellular localization of mammalian homologs of genes that control polarized budding in yeast, and evaluate alterations in metastatic cells from epithelial tumors where polarity appears to have been lost; and iv) To characterize the function of rho family proteins and related molecules in the generation or maintenance of polarity in epithelia, neurons, and lymphocytes.
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