Regulation of the mTOR Pathway by Nutrients

Whitehead Institute For Biomedical Res, Cambridge MA

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Abstract

DESCRIPTION (provided by applicant): 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.