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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA103866-16
Application #
9737172
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
2004-03-23
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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
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
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
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

Showing the most recent 10 out of 105 publications