Extracellular and intracellular nutrient availability is sensed by organisms in order to control metabolic processes and maintain proper cell growth. Disruption in nutrient sensing can be disastrous, often leading to human disease. Perhaps the most notable player in this process is the mammalian target of rapamycin (mTOR) protein kinase, a key component in the multi-subunit protein complex called mTOR complex 1 (mTORC1). Increased mTORC1 activation is common in many human diseases including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules such as rapamycin and rapamycin analogs (rapalogs) that inhibit mTORC1, are currently used in the clinic to treat disease with limited success. Therefore, elucidating the molecular mechanisms of mTORC1 regulation is of great interest in order to treat mTORC1 driven disease. Amino acids are the most powerful activator of mTORC1 and for several years were thought to activate mTORC1 exclusively through the Rag GTPases. We recently discovered a novel signaling pathway whereby glutamine signals to mTORC1 independent of the Rag GTPases, and requires another small GTPase, ADP ribosylation factor-1 (Arf1). Arf1 guanine nucleotide cycling is required for glutamine to promote mTORC1 lysosomal localization and activation. The potential significance of this discovery is underscored by the fact that cancer cells are often ?addicted? to glutamine, in part through mTORC1, to fuel cell growth and proliferation. We have identified two new components involved in this pathway, a known Arf1 GAP (Specific Aim 1) and a poorly characterized solute carrier (SLC) glutamine transporter (Specific Aim 2). We propose to investigate the role of these two new components in glutamine-induced mTORC1 activation. Furthermore, we will determine the significance of these components in mTORC1-mediated biology and disease (Specific Aim 3). Thus, the overall objective of this proposal is to decipher the molecular mechanisms by which glutamine signals to mTORC1. We anticipate that the proposed studies will yield new insights into mTORC1 regulation by glutamine and will uncover therapeutic targets to perturb mTORC1-mediated disease. !
The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is frequently elevated in human disease, including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. We recently discovered a novel pathway where the amino acid, glutamine, activates mTORC1. The goal of this R01 proposal is to decipher the molecular mechanisms by which glutamine activates mTORC1, in order to develop more effective therapeutics to inhibit mTORC1. !
