The mammalian target of rapamycin, mTOR (also known as mechanistic target of rapamycin) controls cell growth. Dysregulation of mTOR has been implicated in many human diseases and drugs inhibiting mTOR have been approved for cancer treatment. mTOR forms two distinct structural and functional complexes, mTORC1 and mTORC2. mTORC1 is the rapamycin sensitive target and plays a major role in cell growth by promoting protein synthesis and anabolism, and inhibiting autophagy. The precise regulation of mTORC1 is critically important for cell growth and organism development. mTORC1 activity is controlled by cellular energy levels, nutrients, and growth factors. Amino acids have emerged as a major signal for mTORC1. The Rag family GTPases has been identified as key mediators relaying amino acid signals to mTORC1 activation. However, the physiological function of Rag GTPases and their role in mTORC1 regulation in vivo are largely unknown. The major goal of this proposal is to determine the in vivo function of Rag GTPases in mTORC1 regulation and physiology using genetically altered mouse models. In addition, we have discovered that amino acids can still activate mTORC1 even when the RagA and RagB genes are deleted. We will investigate the Rag-independent amino acid signaling to mTORC1 activation.

Public Health Relevance

mTORC1 is a central cell growth controller that integrates a wide range of signals, including amino acids, to regulate metabolism, protein synthesis, and autophagy, therefore promoting cell growth. The Rag GTPases have been implicated to play a key role in mTORC1 regulation in response to amino acids. The major goals of this project are to understand the physiological function of Rag GTPases in mTORC1 regulation and metabolism in vivo and to investigate the mechanism of Rag-independent amino acid signaling to mTORC1 activation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA108941-11A1
Application #
8760071
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
2004-09-03
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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