This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A common structural feature of all eukaryotic cells is an elaborate network of membranes that form internal compartments as well as define the boundary of the cell. The formation and proper functioning of these membrane organelles requires the creation and maintenance of their unique protein and lipid compositions. This process, as well as the surface expansion required for cell growth and division, involves highly regulated membrane trafficking pathways. Delivery of cell surface components is often a polarized process, enabling cells to form specialized surface domains. Polarized membrane transport is also essential for directed cell growth and cell motility. Furthermore, by exporting soluble factors such as hormones and neurotransmitters, and by regulating the delivery and maintenance of cell surface receptors and transporters, membrane traffic pathways offer a means by which cells interact with the extracellular environment, and thereby influence processes such as cell division, morphogenesis and motility. The failure to properly regulate these processes can lead to uncontrolled cell proliferation and tumor formation. Therefore, understanding the mechanisms that control polarized membrane transport is critical for understanding cancer development. We are using a well-established yeast model to conduct classical and chemical genetic screens for identifying novel structural and regulatory components of the membrane transport machinery. The classical genetic screen has identified a novel conserved protein, Avl9, which interacts with Rho3, a known regulator of polarized secretion. Depleting Avl9 results in a block of secretory exit from the Golgi. The chemical genetic strategy has identified a group of related compounds that cause a rapid accumulation of secretory cargo and Golgi membranes. Mutants with partial secretory blocks are hypersensitive to the compounds. We are now identifying compound targets. These results establish the effectiveness of our screening strategies.
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