The mTOR pathway is a signaling system that regulates growth and metabolism in response to the nutritional state of organisms. Increasing evidence shows that the pathway is commonly deregulated in cancer, neurological disorders, and diabetes, and also modulates the aging process. The mTOR protein kinase is the target of the drug rapamycin and the catalytic subunit of two multi-protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2), that nucleate distinct branches of the pathway and respond to different upstream signals. mTORC1 responds to a variety of stimuli, including diverse types of growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes, including protein, nucleotide, and lipid synthesis and autophagy, respectively. Recently, we discovered that mTORC1 senses nutrients in part through the lysosome and identified a multi-pass lysosomal membrane protein, SLC38A9, that is key for sensing the amino acid arginine. SLC38A9 turns out to be much more interesting than we originally anticipated as not only does it signal to mTORC1 it also has a major role in effluxing an essential amino acid out of the lysosome so it can be used in cytosolic processes. In addition, using a new method we developed to profile the metabolite contents of lysosomes, we made the surprising discovering that mTORC1 itself is a major regulator of the efflux of most non-polar essential amino acids from lysosomes. Thus, mTORC1 is both downstream and upstream of lysosomal function, indicating that it is part of a circuit that modulates and senses lysosome function in response to growth signals. The broad goals of our work are to arrive at a mechanistic understanding of how the lysosome signals to mTORC1 and in turn how mTORC1 regulates lysosome function. In addition, we have found that the mechanisms we are studying are particularly important for the proliferation of pancreatic cancer cells and so we intend to test their roles in the development of pancreatic tumors in mice.
The specific aims of our proposed work are to: understand how the lysosomal membrane protein SLC38A9 controls mTORC1 signaling (Aim 1); test the importance of SLC38A9 in the development of pancreatic tumors (Aim 2); and understand how mTORC1 controls the efflux of lysosomal amino acids (Aim 3). We will accomplish these goals with a multi-disciplinary approach that uses the tools of biochemistry, molecular biology, and mouse engineering. Our results will substantially increase our understanding of the clinically important mTORC1 pathway and test if SLC38A9 is a potential drug target in pancreatic cancer.
Growth is the fundamental process through which cells and organisms accumulate mass and increase in size. In mammals we are studying a major regulator of growth, a network of signaling proteins called the mTOR Complex 1 (mTORC1) pathway. Our overarching goals are to increase our understanding of how lysosomes communicate to mTORC1 and how mTORC1 signals to lysosomes and to enable the development of new drugs that target in novel ways the mTORC1 pathway for clinical benefit.
|Abu-Remaileh, Monther; Wyant, Gregory A; Kim, Choah et al. (2017) Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358:807-813|
|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|
|Shen, Kuang; Choe, Abigail; Sabatini, David M (2017) Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability. Mol Cell 68:552-565.e8|
|Alvarez, Samantha W; Sviderskiy, Vladislav O; Terzi, Erdem M et al. (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551:639-643|
|Shen, Kuang; Choe, Abigail; Sabatini, David M (2017) Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability. Mol Cell 68:821|
|Kalaitzidis, Demetrios; Lee, Dongjun; Efeyan, Alejo et al. (2017) Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Invest 127:1405-1413|
|Saxton, Robert A; Sabatini, David M (2017) mTOR Signaling in Growth, Metabolism, and Disease. Cell 168:960-976|
|Caron, Alexandre; Labbé, Sébastien M; Lanfray, Damien et al. (2016) Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity. Mol Metab 5:102-12|
|Dominguez-Brauer, Carmen; Hao, Zhenyue; Elia, Andrew J et al. (2016) Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation. Cell Stem Cell 19:205-216|
|Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an ?-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84|
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