Elucidating the mechanisms that allow cells to survive under adverse growth conditions is crucial for understanding how cancer cells arise and persist. The mammalian target of rapamycin (mTOR) is a protein kinase that is inhibited by the potential anti-cancer drug, rapamycin, and plays a central role in growth and proliferation. Recently, we discovered that mTOR is part of two distinct protein complexes and that mTORC2 (mTOR Complex 2) performs a novel function in cell survival that is not inhibited by rapamycin. This novel function of mTORC2 involves phosphorylation of Akt/PKB and is critical only under stress conditions. We have identified SIN1 as an integral component of mTORC2. We found that SIN1 is required for phosphorylation of Akt. Using SIN1 knockout cells, our initial studies indicate that when Akt phosphorylation is abolished at the mTORC2-mediated site, phosphorylation of the pro- apoptotic targets of Akt is defective and cells become susceptible to stress-induced apoptosis. We will now elucidate the mechanism of how Akt regulation by mTORC2 can promote cell survival. We have preliminary findings that in the absence of SIN1, Akt is destabilized more readily upon stress induction. We now hypothesize that mTORC2 regulates protein stability and that this novel function of mTORC2 is required specifically for cell survival under stress conditions. First, we will examine Akt turnover and degradation in the absence of SIN1. Second, we will investigate if mTORC2 can regulate Akt by phosphorylation or if SIN1 serves as a scaffold to allow Akt phosphorylation. Third, we will elucidate how Akt stabilization by mTORC2-mediated phosphorylation can promote cell survival. These studies will advance our knowledge on how mTOR can regulate cell growth and survival pathways and will provide clues as to how mTORC2 can be exploited as a drug target to specifically inhibit the survival of cancer cells.

Public Health Relevance

Cancer is characterized by uncontrolled growth and proliferation and the increased viability of these abnormal cells despite hostile conditions. Our studies will examine the mechanisms of how the mammalian target of rapamycin (mTOR) can enhance survival capacity of cancer cells via upregulation of Akt, a protein that is found mutated in a number of tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM079176-06S1
Application #
8732106
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2008-04-01
Project End
2014-08-31
Budget Start
2013-07-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$92,499
Indirect Cost
$33,693
Name
Rbhs-Robert Wood Johnson Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Moloughney, Joseph G; Vega-Cotto, Nicole M; Liu, Sharon et al. (2018) mTORC2 modulates the amplitude and duration of GFAT1 Ser-243 phosphorylation to maintain flux through the hexosamine pathway during starvation. J Biol Chem 293:16464-16478
Weiss, Harvey R; Chi, Oak Z; Kiss, Geza K et al. (2018) Akt activation improves microregional oxygen supply/consumption balance after cerebral ischemia-reperfusion. Brain Res 1683:48-54
Moloughney, Joseph G; Kim, Peter K; Vega-Cotto, Nicole M et al. (2016) mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1. Mol Cell 63:811-26
Chi, Oak Z; Wu, Chang-Chih; Liu, Xia et al. (2015) Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis. Neuromolecular Med 17:305-13
Chou, Po-Chien; Oh, Won Jun; Wu, Chang-Chih et al. (2014) Mammalian target of rapamycin complex 2 modulates ??TCR processing and surface expression during thymocyte development. J Immunol 193:1162-70
Destefano, Michael A; Jacinto, Estela (2013) Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2). Biochem Soc Trans 41:896-901
Kim, Sung Jin; DeStefano, Michael A; Oh, Won Jun et al. (2012) mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol Cell 48:875-87
Su, Bing; Jacinto, Estela (2011) Mammalian TOR signaling to the AGC kinases. Crit Rev Biochem Mol Biol 46:527-47
Jacinto, Estela (2011) TFEBulous control of traffic by mTOR. EMBO J 30:3215-6
Oh, Won Jun; Jacinto, Estela (2011) mTOR complex 2 signaling and functions. Cell Cycle 10:2305-16

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