Protein Interactions That Regulate Cell Polarity

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DESCRIPTION (provided by applicant): The long-term goal of this work is to understand the structural and biochemical basis of cell polarity. Polarity is a fundamental property of cells that is required for proper development as well as adult physiology. For example, during development, cell fate determinants are polarized in dividing cells as a mechanism for generating cell type diversity. For spatially and temporally precise establishment of cell polarity to occur, cellular signals must be interpreted and ultimately coupled to the segregation of relevant cellular components. We have chosen to focus on a protein complex that plays a central role in controlling cell polarity. This complex, which includes the PAR proteins Par-3 and Par-6, and the atypical protein kinase C (aPKC), localizes to specific cellular sites and subsequently is thought to recruit downstream components of the cell polarization machinery. We have chosen to focus on the proteins in this evolutionarily conserved complex in order to understand their interactions, how they are localized, and how they act as switches to transmit the information that controls cell polarity. Much of our effort will be directed towards understanding how the Rho GTPase family of signaling molecules, which have recently been shown to interact with Par-6, regulates localization, assembly, and/or activity of these adapter proteins. We are also focusing on elucidating how the PDZ protein-interaction domain mediates assembly of the complex and interactions with downstream components. The remainder of our effort will be directed at understanding how these proteins subsequently activate components of the cell polarity machinery. We will use a combined biochemical, biophysical and cell biological approach to investigate Par complex function. Using biochemical and biophysical methods, we will examine the physical basis by which the Par complex assembles and interacts with signaling molecules and downstream components of the cell polarity machinery. Finally, we will test the in vivo importance of these interactions in Drosophila epithelial and neuroblast cells, two models for cell polarity.