Members of the ARF family of regulatory GTPases function as nodes in cell signaling to coordinate essential cell processes; including membrane traffic, energy metabolism, ciliogenesis, and the cytoskeleton. I have studied first ARF and later ARF-like (ARL) proteins for over 30 years, using a combination of biochemical, cell and molecular biological, and phylogenetic approaches and propose to continue these studies with a focus on their actions at specific sites; including mitochondria, cytosol, cilia, and centrosomes. We will both study mechanisms by which one GTPase acts in multiple sites in the same cells, to explore the potential for cross-talk or higher level ordering of cell signaling, but also explore novel, single actions for atypical GTPases as a means of determining shared or unique mechanisms within the family. A better understanding of these systems will reveal novel insights into fundamental aspects of cell biology as well as providing potential targets for intervention to alter the course of human diseases; including but not limited to cancer, heart disease, neurodegeneration, ciliopathies, retinal degeneration, and deafness.
Essential cellular processes common to all cells are often controlled by GTPases within the ARF family and dysfunction in these regulatory systems result in human diseases ranging from cancer, heart disease, neurodegeneration, retinal degeneration, and deafness. We propose to determine molecular mechanisms by which these GTPases act and consequences at the cellular level when they dysfunction. As a result, we hope to discover fundamental aspects of cell biology that are relevant to understanding and treating a host of human conditions and also allow us and others to decipher fundamental concepts involved in cell regulation.
