title: Lipid sensing by mTOR complexes viade novosynthesis of phosphatidic acid.
abstract: mTOR, the mammalian target of rapamycin, integrates growth factor and nutrient signals to promote a transformation from catabolic to anabolic metabolism, cell growth, and cell cycle progression. Phosphatidic acid (PA) interacts with the FK506-binding protein-12-rapamycin-binding (FRB) domain of mTOR, which stabilizes both mTOR complexes: mTORC1 and mTORC2. We report here that mTORC1 and mTORC2 are activated in response to exogenously supplied fatty acids via thede novosynthesis of PA, a central metabolite for membrane phospholipid biosynthesis. We examined the impact of exogenously supplied fatty acids on mTOR in KRas-driven cancer cells, which are programmed to utilize exogenous lipids. The induction of mTOR by oleic acid was dependent upon the enzymes responsible forde novosynthesis of PA. Suppression of thede novosynthesis of PA resulted in G1cell cycle arrest. Although it has long been appreciated that mTOR is a sensor of amino acids and glucose, this study reveals that mTOR also senses the presence of lipids via production of PA.
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.|the Biochemistry Program and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Menon
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.|the Biology Program, Graduate Center of the City University of New York, New York, New York 10016.
authors.forename: Darin
authors.initials: D
authors.lastname: Salloum
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.|the Biochemistry Program and.
authors.forename: Elyssa
authors.initials: E
authors.lastname: Bernfeld
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gorodetsky
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors.forename: Alla
authors.initials: A
authors.lastname: Akselrod
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Frias
authors.affiliation: the Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: the Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chen
authors.affiliation: the Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and.
authors.forename: Ralph
authors.initials: R
authors.lastname: DeBerardinis
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, foster@genectr.hunter.cuny.edu.|the Biochemistry Program and.|the Biology Program, Graduate Center of the City University of New York, New York, New York 10016.|the Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021.
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000096:biosynthesis* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D046912:Multiprotein Complexes; D010712:Phosphatidic Acids; D019301:Oleic Acid; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Ras protein; glycolysis; lipid; mammalian target of rapamycin (mTOR); phosphatidic acid; phospholipase D