The mTOR pathway is a signaling network that controls growth (mass accumulation) and metabolism in response to the nutritional state of organisms. The pathway is commonly deregulated in cancer, neurological disorders like epilepsy, and diabetes, and also modulates the aging process. Indeed, pharmacological or genetic inhibition of mTOR is amongst the best validated approaches for increasing the lifespan of animals. 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 stimuli. mTORC1 responds to a variety of signals, including diverse types of growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes, including protein, nucleotide, and lipid synthesis as well as autophagy, respectively. Recently, we discovered that mTORC1 senses nutrients in two compartments, the lysosome and the cytosol, and uncovered many of the molecular components involved. While we have made progress in understanding the functions of many of these components, one in particular, GATOR2, has been frustratingly mysterious. We know this protein complex is very important as it binds several nutrient sensors and its loss inhibits mTORC1 activity. However, we still do not understand its biochemical function or structure or function in vivo. We have recently made progress on all of these fronts and now have assays to detect its activity and approaches to isolate its regulation by the amino acid leucine in vivo. The goals of our proposed work are to understand the function and structure of GATOR2 (Aim 1); the role of the GATOR2-interacting leucine sensor Sestrin2 in the adaptation of mice to a leucine-free diet (Aim 2); and the mechanism through which mTORC1 senses glucose in AMPK-independent fashion (Aim 3). We will accomplish these goals with a multi-disciplinary approach that uses the tools of biochemistry, structural and molecular biology, and mouse engineering and analyses. Our results will substantially increase our understanding of a central growth regulator and reveal the function of a component (GATOR2) that may be of value to target in certain disease states.
Growth is the fundamental process through which cells and organisms accumulate mass and increase in size. In mammals we are studying the major regulator of growth, a network of signaling proteins called the mTOR Complex 1 (mTORC1) pathway. Our overall goals are to understand how nutrients, such as amino acids and glucose, communicate to mTORC1 through the GATOR2 complex and the role of this communication in vivo.
|Shen, Kuang; Huang, Rick K; Brignole, Edward J et al. (2018) Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature 556:64-69|
|Shen, Kuang; Sabatini, David M (2018) Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proc Natl Acad Sci U S A 115:9545-9550|
|Rohde, Jason M; Brimacombe, Kyle R; Liu, Li et al. (2018) Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors. Bioorg Med Chem 26:1727-1739|
|Kory, Nora; Wyant, Gregory A; Prakash, Gyan et al. (2018) SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science 362:|
|Mihaylova, Maria M; Cheng, Chia-Wei; Cao, Amanda Q et al. (2018) Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell 22:769-778.e4|
|Wyant, Gregory A; Abu-Remaileh, Monther; Frenkel, Evgeni M et al. (2018) NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 360:751-758|
|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|
|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|
|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|
|Cantor, Jason R; Abu-Remaileh, Monther; Kanarek, Naama et al. (2017) Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase. Cell 169:258-272.e17|
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