? Signal transduction research today encompasses all aspects of cell regulation and metabolism. While dissecting the complexities inherent in the detailed mechanisms of each cellular pathway there is a growing appreciation for the need to understand how different pathways are connected within each cell. Such connections are required for cells to respond in a coordinated fashion to changes in environment, cell cycle or developmental stage. At the heart of these integrated circuits are the regulatory GTPases in the Ras superfamily. While most families within the Ras superfamily have fairly well defined functions (e.g., Ras as regulator of proliferation, Rho as regulators of cytoskeleton) the Arf family is more divergent in both structures and functions. Though Arfs regulate vesicle traffic in all eukaryotes, they also regulate aspects of lipid metabolism. Models that integrate these two principal functions into a general view of cell regulation by Arfs remain controversial but correctly identify what is needed in modeling Arf functions - a vision of a higher order integration of cell regulation. In this proposal we focus on mammalian Arl2, and its novel locations and functions in cells. Evidence from a number of organisms reveals that Arl2 orthologs regulate microtubule dynamics. Studies in my laboratory have revealed a unique assortment of cellular locations for mammalian Arl2 (including mitochondria, cytosol, and plasma membrane) that argue for cellular roles distinct from microtubule Idynamics. Understanding the role of Arl2 in each of these locations is predicted to add to our understanding of the integration of tubulin dynamics with other cellular processes. Insight into why and how these activities are linked by a common regulatory protein will provide a higher level of understanding of cell regulation and the interplay between these essential processes. Because Arl2 and Arl3 share a number of structural, biochemical, and biological similarities I also propose to study aspects of Arl3 function, originally in comparison to Arl2 but also in its own right as a putative regulator of actin dynamics. And finally, relating these functions and mechanisms to those of the Arfs should also reveal important similarities and differences within the Arf family. ? ?
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| Cunningham, Leslie A; Kahn, Richard A (2008) Cofactor D functions as a centrosomal protein and is required for the recruitment of the gamma-tubulin ring complex at centrosomes and organization of the mitotic spindle. J Biol Chem 283:7155-65 |
| Zhou, Chengjing; Cunningham, Leslie; Marcus, Adam I et al. (2006) Arl2 and Arl3 regulate different microtubule-dependent processes. Mol Biol Cell 17:2476-87 |
| Kahn, Richard A; Cherfils, Jacqueline; Elias, Marek et al. (2006) Nomenclature for the human Arf family of GTP-binding proteins: ARF, ARL, and SAR proteins. J Cell Biol 172:645-50 |
| Bowzard, J Bradford; Sharer, J Daniel; Kahn, Richard A (2005) Assays used in the analysis of Arl2 and its binding partners. Methods Enzymol 404:453-67 |
