Jewell Lab

The Jewell Lab investigates how organisms sense environmental nutrient fluctuations and respond appropriately, fine tuning anabolic and catabolic processes to control cell growth, metabolism, and autophagy. Nutrient sufficiency fuels anabolism such as protein synthesis, whereas nutrient deficiency results in catabolism like autophagy. Defects in these sensing mechanisms can be detrimental, often resulting in human disease. Orchestrating these events is the mammalian target of rapamycin (mTOR), an evolutionarily conserved Ser/Thr kinase, and a key component of a complex referred to as mTOR complex 1 (mTORC1). Increased mTORC1 activity is typically seen in in many human diseases such as cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Because of the significance of mTORC1 in human disease, small molecules that target and inhibit mTORC1, are currently used in the clinic. For example, rapamycin or rapalogs (analogs of rapamycin) are used to inhibit mTORC1. However, there are many limitations of rapamycin and rapalogs, like being cytostatic instead of cytotoxic, and they fail to inhibit all mTORC1-mediated processes. Thus, by understanding how mTORC1 is regulated, we can begin to develop more efficient therapeutics that may be used alone or in combination with existing mTORC1 inhibitors. 

Amino acids are the most potent stimuli and are essential for mTORC1 activation. However, the detailed mechanisms are only beginning to be unraveled. We discovered a novel-signaling pathway where glutamine and asparagine activate mTORC1. Deciphering the molecular underpinnings of this new pathway will undoubtedly have important implications in understanding mTORC1 and human disease. We also anticipate that our results will lead to a greater understanding of how eukaryotes sense nutrients in their environment, in both normal and disease states.

In addition, to understanding how amino acids regulate mTORC1 we are also interested in understanding the molecular mechanisms by which mTORC1 is inhibited. Through a G-protein coupled receptor (GPCR) screen, we found that GPCRs paired to Galphas proteins potently inhibited the activity of mTORC1. Activation of GPCR-Galphas signaling elevates cyclic adenosine 3’5’ monophosphate (cAMP) levels, resulting in the activation of a well characterized Ser/Thr kinase called Protein Kinase A (PKA). Interestingly, elevated cAMP levels have been shown to have anti-proliferative effects on cancer cells. We discovered that PKA phosphorylates the mTORC1 component Raptor at Ser791 and potently inhibits mTORC1. The activation of Galphas-coupled GPCRs in vivo with hormones or agonists leads to mTORC1 inhibition in multiple human cell lines and in mice. GPCRs are the largest group of cell surface receptors comprising >1% of the human genome, and are the main family of drug targets with many approved FDA compounds.