The mTOR pathway is a signaling system that regulates growth and metabolism in response to the nutritional state of the organism. Increasing evidence indicates that the pathway is commonly deregulated in cancer, neurodegeneration, and diabetes, and also plays a major role in the aging process. The large 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 mTOR pathway and respond to different upstream signals. mTORC1 responds to a diverse set of stimuli, such as growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes, including protein and lipid synthesis and autophagy. We propose to study how the mTORC1 pathway senses amino acids. Our current model indicates that amino acid sensing originates within the lysosomal lumen and we have discovered many new components of the pathway that transmit the amino acid signal to mTORC1, including the Rag GTPases, Ragulator, the v-ATPase, GATOR1 and GATOR2 We still know relatively little about the molecular and in vivo functions of these components and so we propose the following aims. First, we will test the hypothesis that the v-ATPase is the amino acid sensor of the lysosomal lumen (Aim 1). Second, we will determine how GATOR2 inhibits GATOR1 and define its molecular function (Aim 2). Third, because GATOR1 components appear to be tumor suppressors in humans, we will define the function of GATOR1 in vivo in mice in regulating normal liver growth and tumor genesis (Aim 3). We will accomplish our goals with a multi-disciplinary approach that uses the tools of biochemistry, molecular biology, and mouse engineering and we will also develop new methods, such as lysosomal metabolite profiling. Our results are likely to have important consequences for our understanding of the clinically important mTORC1 pathway as some of the signaling mechanisms we uncover may serve in the future as targets for drug development.

Public Health Relevance

Growth is the fundamental process through which cells and organisms accumulate mass and increase in size. It is increasingly evident that the pathways that regulate growth become deregulated in common human diseases, including cancer, diabetes, and neurodegeneration and are involved in the aging process. We have been studying in mammalian systems a network within cells called the 'mTOR pathway'that is a major growth regulator. A branch of this pathway called the 'mTORC1 pathway'senses the nutritional state of the organism and regulates many anabolic and catabolic processes. We have identified many of the protein components through which the mTORC1 pathway senses nutrients, particularly amino acids, and we seek to understand the molecular and in vivo functions of these proteins. Our overarching goal is to increase our molecular understanding of the mTOR pathway and its physiological roles, so as to enable the community to exploit the pathway for therapeutic benefit.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01CA103866-11
Application #
8693125
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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