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Regulation of mTORC2 by Glutamine Catabolites

by
Nicole M. Vega-Cotto
B.S., University of Puerto Rico, Arecibo - 2010

Thesis Advisor: Estela Jacinto, Ph.D.
Graduate Program in Physiology & Integrative Biology

RWJMS-School of Public Health Building
2nd Floor, Room C-258
Piscataway

Thursday, June 23, 2016
9:00 a.m.


Abstract

Highly proliferating cells require nutrients and growth factors to promote growth and proliferation, and the imbalance of these could result in tumorigenesis and insulin resistance. mTOR is a serine/threonine kinase that forms two distinct protein complexes, mTORC1 and mTORC2. It is well established that mTORC1 responds to nutrients, growth factors, and energy to regulate cell growth and proliferation, cell survival, and metabolism. However, while it is known that mTORC2 responds to growth factors to activate Akt, the complex`s response to other upstream signals remains poorly understood. Our lab identified mTORC2 as a regulator of the hexosamine biosynthesis pathway (HBP), via the regulation of the expression of the rate-limiting enzyme of this pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT1). We discovered that mTORC2 regulates GFAT1 expression in response to levels of glutamine or glutamine catabolites. Our studies aimed to elucidate if mTORC2 could respond to the presence of different metabolites in response to glutamine depletion, where mTORC2 activation is enhanced, revealing a link between mTORC2 and cell metabolism and metabolic adaptation. We show that the mTORC2-mediated Akt activation becomes downregulated with re-addition of glutamine-related metabolites, under different glutamine depletion conditions. Under severe glutamine depletion conditions, supplementation with glutamine catabolites also resulted in decreased cell death. Our findings show that nutrient and metabolite availability can regulate mTORC2 activity in order to control cellular metabolism homeostasis.


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