The process of mass accumulation (cell growth) is an important regulator of cell, organ, and body size and can be deregulated in diverse diseases such as cancer and diabetes. Our lab is studying the mammalian TOR (mTOR) pathway, a signaling network that regulates growth in response to growth factors, stress, nutrients, and metabolism. The mTOR pathway is medically important, as it is the target of the FDA-approved immunosuppressant rapamycin that also prevents vessel restenosis after angioplasty and has potential as an anti-cancer agent. Moreover, recent work suggests that in the cancer-prone genetic syndrome tuberous sclerosis complex the mTOR pathway becomes hyperactive and deregulated. Over the last few years we have been studying the biochemistry of the mTOR pathway in human tissue culture cells and have discovered two distinct mTOR-containing protein complexes. The first contains mTOR and two novel proteins, raptor and GbL, and mediates the rapamycin-sensitive roles of mTOR (like S6K1 phosphorylation). The second complex also contains mTOR and GbetaL but, instead of raptor, another novel protein that we named rictor. Our proposed work focuses on understanding the biochemical, cellular and organismal functions of the rictor protein, the central component of the rapamycin-insensitive mTOR pathway. Although we know little about this pathway compared to the rapamycin-sensitive branch, our preliminary results suggest that rictor plays critical roles in the control of cell survival and proliferation by regulating the activity of known effectors of these processes. Our unexpected discovery that mTOR has rapamycin-insensitive functions suggests that direct inhibitors of the mTOR kinase activity will likely have different pharmacological effects and clinical applications than rapamycin. Therefore, our proposed work will lead to an important advance in our understanding of the molecular mechanisms that regulate cell growth and survival and that may be exploited to tackle diseases in which these processes are deregulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI047389-06
Application #
6924447
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Esch, Thomas R
Project Start
2000-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$449,500
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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Ersching, Jonatan; Efeyan, Alejo; Mesin, Luka et al. (2017) Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity 46:1045-1058.e6
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Wolfson, Rachel L; Chantranupong, Lynne; Saxton, Robert A et al. (2016) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351:43-8
Chen, Walter W; Freinkman, Elizaveta; Wang, Tim et al. (2016) Absolute Quantification of Matrix Metabolites Reveals the Dynamics of Mitochondrial Metabolism. Cell 166:1324-1337.e11
Beyaz, Semir; Mana, Miyeko D; Roper, Jatin et al. (2016) High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531:53-8
Shaul, Yoav D; Yuan, Bingbing; Thiru, Prathapan et al. (2016) MERAV: a tool for comparing gene expression across human tissues and cell types. Nucleic Acids Res 44:D560-6

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