Regulation of the mTOR Pathway By Nutrients

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Growth is the process through which cells accumulate mass and increase in size. mTORC1 is a protein kinase composed of the mTOR catalytic subunit and the associated proteins raptor, mLST8/G¿L, and PRAS40, and the central component of a signaling network that regulates growth in response to growth factors, energy levels, amino acids, and stress. Many cancer-promoting lesions activate the mTORC1 pathway. Most notably, the TSC1-TSC2 tumor suppressor complex--whose inactivation causes Tuberous Sclerosis Complex (TSC) and the related disease Lymphangioleiomyomatosis (LAM)--is a major negative regulator of mTORC1. The TSC1-TSC2 heterodimer is a GTPase activating protein (GAP) that inhibits Rheb, a GTP-binding protein that directly binds and activates mTORC1. mTORC1 deregulation also occurs in cancer cells that have lost the PTEN, NF1, LKB1, or p53 tumor suppressors. The TSC1/TSC2/Rheb axis signals insulin and energy levels but not amino acids to mTORC1, suggesting that an amino acid-induced pathway upstream of mTORC1 remains unknown. We propose to understand how the mTORC1 pathway senses amino acids. First, we will determine the molecular mechanisms through which novel regulators of mTORC1 that we have identified in our preliminary studies signal amino acids to mTORC1. Second, by exploiting the results of RNAi and proteomics screens as well as candidate-molecule approaches, we will identify and understand the regulatory steps upstream of these novel regulators. Third, using conditional null alleles of the genes encoding the novel regulators we will understand their roles in vivo in controlling mTORC1 activity and organ growth. We will accomplish our goals with a multi-disciplinary approach that exploits the tools of biochemistry, molecular biology, proteomics, high-throughput RNAi screening, and mouse models. Our results are likely to have important consequences for our understanding of the clinically important mTORC1 pathway. Knowledge of how amino acids signal to mTORC1 is necessary to test if these mechanisms are deranged in human cancers, as are known upstream components of the mTORC1 pathway. Furthermore, some of the signaling mechanisms we uncover may serve in the future as targets for drug development.