As a major regulator of cellular growth, mTORC1 activates a diverse set of anabolic processes within the cell, including translation and nucleotide biogenesis, and inhibits catabolic processes, such as autophagy. Multiple inputs converge on mTORC1, including, importantly, information about nutrient availability and growth factor levels. This pathway is deregulated in a variety of human diseases, and therapeutics that target mTORC1 are FDA-approved treatments for certain types of cancer. Growth factors activate mTORC1 through a well-characterized pathway that includes many known oncogenes and tumor suppressor genes (TSGs). In comparison, the pathway which signals the presence of amino acids is less well understood, and, until recently, no oncogenes or TSGs had been identified in this pathway. Recent work for our lab identified GATOR1, a trimeric complex that consists of DEPDC5, Nprl2, and Nprl3 which acts as a GTPase activating protein (GAP) for the RagA/B GTPases, which indirectly activate mTORC1 in the presence of amino acids. While it is clear that GATOR1 is an important negative regulator of this pathway, little is known about its regulation. In addition, preliminary data suggest that GATOR1 may act as a tumor suppressor complex. Further work needs to be performed to understand the potential role of GATOR1 as a tumor suppressor. Preliminary data now suggest that GATOR1 null cancer cell lines have constitutive mTORC1 signaling in the absence of both amino acids and growth factors, and that GATOR1 is necessary for proper TSC localization to the lysosome in the absence of amino acids. This exciting result indicates that GATOR1 may have a novel role in both the growth factor and amino acid sensing arms of the mTORC1 signaling pathway. Moreover, while it seems that GATOR1 loss may drive tumorigenesis, further work needs to be performed to investigate the function of this putative tumor suppressor complex in vivo. In addition, because this is one of the first examples of an oncogene or TSG in the amino acid sensing pathway upstream of mTORC1, we propose to explore the advantage that deregulation of this pathway confers on cancer cells. The goal of this project is to further characterize the regulation of GATOR1 and investigate the importance of regulation of the amino acid sensing pathway upstream of mTORC1 in vivo. To reach this goal, we propose the following aims: 1. Investigate the mechanism by which GATOR1 influences growth factor signaling to mTORC1. 2. Determine the tumorigenic potential of loss of GATOR1 in vivo. 3. Identify contexts in which deregulation of the nutrient sensing pathway is beneficial to tumor cells.
This project will help elucidate the regulation of a protein complex that is a negative regulator of mTORC1, a major regulator of cell growth. In addition, we will work to understand the role of this complex in promoting tumorigenesis in vivo, with the possibility of helping to better define patient populations which may respond to therapeutics which target mTORC1 and inspiring therapeutic design that targets the differential sensitivities of these tumors.
|Wyant, Gregory A; Abu-Remaileh, Monther; Wolfson, Rachel L et al. (2017) mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell 171:642-654.e12|
|Wolfson, Rachel L; Chantranupong, Lynne; Wyant, Gregory A et al. (2017) KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543:438-442|
|Wolfson, Rachel L; Sabatini, David M (2017) The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway. Cell Metab 26:301-309|
|Okosun, Jessica; Wolfson, Rachel L; Wang, Jun et al. (2016) Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet 48:183-8|
|Saxton, Robert A; Knockenhauer, Kevin E; Wolfson, Rachel L et al. (2016) Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351:53-8|
|Wolfson, Rachel L; Chantranupong, Lynne; Saxton, Robert A et al. (2016) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351:43-8|