Research

Research

Cartoon of biochemical interactions
Glutamine signaling to mTORC1
The cycling of Arf1 between GTP-and GDP-bound states promotes the action of glutamine, which activates mTORC1 and localizes it to the lysosome. mTORC1 activators are indicated in teal. Currently, the Jewell lab is identifying new components involved in the pathway

The Jewell Lab investigates how organisms sense nutrient fluctuations and respond accordingly to control cell growth, cell proliferation, metabolism, and autophagy. Dysregulation of nutrient sensing often leads to human disease. Central to these processes is the mammalian target of rapamycin (mTOR), a conserved kinase that is the key component of a protein complex termed mTOR complex 1 (mTORC1). mTOR, often referred to as a “master regulator,” controls cellular and organismal homeostasis by coordinating anabolic and catabolic processes with nutrient availability. mTORC1 activation is frequently observed in cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Therapeutics that target and inhibit mTORC1 are currently used in the clinic with limited success. Thus, understanding the molecular mechanisms by which mTORC1 is regulated is of great interest in order to combat mTORC1-driven diseases.

Amino acids are the most potent stimuli and are essential for mTORC1 activation. However, the detailed mechanisms are only beginning to be unraveled. In 2008 the Rag GTPases were identified to link amino acid signaling to mTORC1. And later, the Rag GTPases were shown to be required for leucine and arginine signaling to mTORC1 at the lysosome.

Recently, we discovered a novel-signaling pathway where glutamine (Gln) activates mTORC1 independently of the Rag GTPases; this signaling cascade requires the small G-protein ADP ribosylation factor-1 (Arf1). Gln promotes mTORC1 lysosomal localization and activation. The importance of this discovery is underscored by the fact that cancer cells are often “addicted” to Gln to fuel cell growth and proliferation.

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.