Applying a chemical genetic approach to inositol polyphosphate signaling (1013.10)

Signal transduction is a key area of study as we try to understand habitual cell physiology, and also discover new targets for amelioration of disease symptoms. Inositol polyphosphates, IPs, are small molecule messengers that play a critical role in cellular signal transduction pathways. Several highly phosphorylated IPs, such as 5‐diphosphoinositol pentakisphosphate, (5‐PP‐IP5) have been linked to insulin signaling in mammalian cells and maintaining overall energy balance in yeast. While these phenotypes are exciting, the field has been limited by traditional genetic techniques, and the exact mechanism of action by IPs has remained elusive. Through the development of a chemical genetic technique largely applied to protein kinases, we have engineered analog sensitive kinases responsible for the metabolism of IPs in yeast. We have exhibited the functionality of these enzymes, while simultaneously displaying the ability to specifically and temporally inhibit their kinase activity in both in‐vitro and in‐vivo assays. We plan to use this system in conjunction with metabolomics to further elucidate the role that these intriguing small molecules play in signal transduction pathways. Grant Funding Source : NIH