PI(3,4,5)P3 Regulates Cell Polarity During Chemotaxis and Cytokinesis

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DESCRIPTION (provided by applicant): Cellular polarization is essential in morphogenesis, the immune response, neuronal development, chemotaxis (the sensing of chemical gradients by cells) and cell division. The proposed studies on the model system D. discoideum relate to the basic problems of directional sensing and polarization. We have found that a number of signaling and cytoskeletal proteins that are important for polarity during chemotaxis are also critical for the bipolar shape changes that a cell undergoes during cell division. The signaling enzymes PI3K and the tumor suppressor PTEN are reciprocally localized during both chemotaxis and cell division. Understanding their regulation may have important implications for investigators trying to determine why these two genes are mutated or lost in many cancers. We are also actively trying to determine the molecular steps that lead to the redistribution of other signaling and cytoskeletal proteins that occur during cell migration and cell division. Lastly, we have developed a powerful fluorescence assay to monitor the state of a class of proteins called G proteins. These G proteins are extremely important signal transducers and the receptors that couple to them are major targets for drugs by pharmaceutical companies. Our goals are to: 1) Model the sensing mechanism, challenge cells with stimulus inputs and measure their responses to gain insight into how the mechanism works. 2) Investigate the localization of important signaling proteins during cell polarity and find new components with novel genetic screens. 3) Understand the fundamental properties of the G protein cycle. These projects will provide significant training opportunities for researchers at various stages of their career. I currently have a visiting scholar developing new assays for chemotaxis and a graduate student and a postdoctoral fellow work on several aspects of the research. I also have a number of talented undergraduates who are working on various aspects of the project. I intend on actively recruiting more graduates students (I have had 3 rotations students this year) and another postdoctoral fellow. Work in my lab will help uncover the intricate signaling mechanisms that lead to changes in the cells architecture in a variety of dynamic cellular processes. PUBLIC HEALTH REVELANCE: Cells take on a polarized morphology when they divide and move. We are using the amoeba Dictyostelium as a model system to understand the basic mechanisms that control these changes in cell shape. Many of the homologous components we are studying are mutated or lost in many human diseases.