UC San Diego

The ability of cells to sense and respond to changes in cellular nutrient or energy availability is crucial for their survival. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy levels, and is responsible for shutting down energy-costly processes, and turning on processes that will help restore cellular energy levels. The ability of AMPK to inhibit mTORC1 signaling allows it not only to shut down costly processes like protein synthesis and ribosome biogenesis, but also to allow the energy-restoring process, autophagy to proceed. Additionally, action of AMPK in specialized metabolic tissues like muscle and liver allow it to regulate blood glucose levels, and glucose uptake in the whole organism. Using a bioinformatic and proteomic approach, we have identified the mTORC1 component, raptor, as a novel substrate of AMPK that contributes to its role in downregulation of mTORC1, which is required for engagement of an energy-stress checkpoint. Loss of the ability of AMPK to phosphorylate raptor sensitizes cells to apoptosis during energy poor conditions. We have also investigated the regulation of mTORC1 signaling during mitosis, and its role in altering translation during the cell cycle. Finally, we have identified AMPK phosphorylation sites in the RalGAP complex that may contribute to AMPK regulation of the Ral small GTPases, and the exocyst complex, which has been shown to be important for glucose uptake, insulin secretion and cellular migration. These findings contribute to our under-standing of how AMPK functions both in a cell-autonomous fashion in the restoration of cellular energy levels, and cell-non-autonomously in regulation of organismal metabolism