Cell polarity is critical for the development of multicellular organisms as well as for the function of cell types ranging from the simple yeast to the highly differentiated cells such as epithelial cells and neurons. Our work has established an important role for the yeast IQGAP, Iqg1p, a putative target/effector for Cdc42p, in coordinating cell polarity with cytokinesis. Aberrations in such signal-controlled processes lead to a myriad of diseases among which cancer is most notorious. This proposal, building on our previous work, is designed to address an important goal: How IQGAP functions. The studies will therefore be targeted to three complementary aims. First, identify the domains for Iqg1p that mediate its distinct functions in cell polarization and cytokinesis. How the structure of the yeast Iqg1p correlates with its different functions will be determined by deletion mapping analyses. Particular emphasis will be placed on determining the function of the domains conserved in orthologs from different organisms. Our model that the human IQGAP1 functions similar to the yeast homologue will be tested in Aim Two. The association and co-localization of IQGAP1 with the exocyst and septin will be examined as a function of the mammalian IQGAP1 structure using deletion mapping and site-directed mutagenesis. Third, we will determine how the yeast Iqg1p localization is regulated spatially and temporally during the cell cycle. These studies will include time-lapse video-microscopy and analysis of Iqg1p in mutant cell background. Since the hallmark of cancer cells is the loss of their polarity, we are also investigating the role of IQGAP1-complex in cancers of epithelial origin. By design, these studies will set the stage for future work on the role of IQGAP1 in cytokinesis, early development of embryonic cells and cancer of epithelial origin, such as breast cancer. It is well appreciated that cell polarity is important yet complicated. Thus, the studies on these conserved polarity components will have a broad impact on understanding the mechanisms controlling morphogenesis in more complicated organisms for which there are no convenient genetic approaches. Therefore, this work will complement other studies in development, neurobiology, immunology, and cancer etiology.
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