Metabolic and biosynthetic pathways drive cell growth and proliferation in response to nutrients and growth factors. Highly proliferating cells utilize glucose and glutamine to fuel biosynthetic processes. These two nutrients serve as substrates for the glutamine:fructose-6-phosphate amidotransferase (GFAT1), the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), which ultimately produces UDP-GlcNAc that is necessary for protein glycosylation. Despite a role for the HBP in insulin resistance and lifespan extension, the mechanisms underlying GFAT1 regulation in vivo has remained elusive. We found mTOR complex 2 (mTORC2) controls flux through the HBP via regulation of GFAT1 expression levels in response to glucose. In the absence of mTORC2, GFAT1 expression is reduced and highly sensitive to glucose starvation. Furthermore, UDP-GlcNAc is highly diminished and glycosylation of specific transmembrane proteins such as CD147 is defective upon mTORC2 disruption. However, mTORC2 is also required for glycolysis and other biosynthetic pathways whose metabolites feed into the HBP. Thus, although exogenous UDP-GlcNAc can partially rescue glycosylation defects, it does not rescue the metabolic deficiencies in the absence of mTORC2. Like GFAT1, key enzymes of biosynthetic pathways have decreased expression in mTORC2-disrupted cells. Thus, by regulating levels of metabolic enzymes, mTORC2 coordinates flux through biosynthetic pathways in response to glucose availability. Our findings have implications for therapeutic targeting of mTORC2 in insulin resistance and cancer metabolism.

Citation Format: Estela Jacinto, Joseph Moloughney, Thomas Lynch, Chang-Chih Wu, Olufunmilola Ibironke, Aixa Navia, Po-Chien Chou, Sisi Zhang, Joshua Rabinowitz, Guy Werlen. mTORC2 enhances flux through the hexosamine biosynthetic pathway by regulation of GFAT1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1150. doi:10.1158/1538-7445.AM2015-1150

©2015 American Association for Cancer Research.
2015