title: Phospholipase D mediates nutrient input to mammalian target of rapamycin complex 1 (mTORC1).
abstract: The mammalian target of rapamycin (mTOR) is a critical sensor of nutritional sufficiency. Although much is known about the regulation of mTOR in response to growth factors, much less is known about the regulation of mTOR in response to nutrients. Amino acids have no impact on the signals that regulate Rheb, a GTPase required for the activation of mTOR complex 1 (mTORC1). Phospholipase D (PLD) generates a metabolite, phosphatidic acid, that facilitates association between mTOR and the mTORC1 co-factor Raptor. We report here that elevated PLD activity in human cancer cells is dependent on both amino acids and glucose and that amino acid- and glucose-induced increases in mTORC1 activity are dependent on PLD. Amino acid- and glucose-induced PLD and mTORC1 activity were also dependent on the GTPases RalA and ARF6 and the type III phosphatidylinositol-3-kinase hVps34. Thus, a key stimulatory event for mTORC1 activation in response to nutrients is the generation of phosphatidic acid by PLD.
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, USA.
authors.forename: Limei
authors.initials: L
authors.lastname: Xu
authors.forename: Darin
authors.initials: D
authors.lastname: Salloum
authors.forename: Phil S
authors.initials: PS
authors.lastname: Medlin
authors.forename: Mahesh
authors.initials: M
authors.lastname: Saqcena
authors.forename: Paige
authors.initials: P
authors.lastname: Yellen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Perrella
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D005502:Food; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D020725:ral GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D000596:Amino Acids; D046912:Multiprotein Complexes; D009479:Neuropeptides; D010712:Phosphatidic Acids; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D058546:Class III Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; C492198:RALA protein, human; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020559:Monomeric GTP-Binding Proteins; D020725:ral GTP-Binding Proteins; D005947:Glucose