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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA129105-11
Application #
9445643
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
2008-04-08
Project End
2022-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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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
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