Differential Regulation of mTORC1 by Amino Acids

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Organisms sense nutrient fluctuations and respond accordingly to control cell growth. When this process goes awry, the result can be detrimental, often leading to cancer. Central to this process is the mechanistic target of rapamycin (mTOR), a conserved kinase that is the main component of a protein complex termed mTOR complex 1 (mTORC1). mTORC1 activation is frequently observed in human cancers, and therapeutics that target mTORC1 have proven efficacious in clinical trials. Amino acids are the most potent stimuli for mTORC1 activation; however, the detailed molecular mechanisms are obscure, and importantly, the specific amino acids that regulate mTORC1 are unclear. Recently, we discovered that the amino acids, leucine and glutamine activate mTORC1 through two distinct signaling pathways involving the small G‐proteins RagA/B and the adenosine diphosphate ribosylation factor‐1 (Arf1), respectively. Importantly, we identified Arf1 as an essential component that specifically couples glutamine signaling to mTORC1 activation at the lysosome and independent of RagA/B. This is important because cancer cells have a high dependence on glutamine for growth and proliferation. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.Support or Funding InformationCancer Prevention & Research Institute of Texas (CPRIT)