title: Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor.
abstract: Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Krall
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|UCLA Metabolomics Center, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
mesh_terms: D001120:Arginine / Q000378:metabolism; D001216:Asparagine / Q000378:metabolism*; D001217:Aspartate-Ammonia Ligase / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism*; D006367:HeLa Cells; D006639:Histidine / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009711:Nucleotides / Q000096:biosynthesis; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D003470:Culture Media; D046912:Multiprotein Complexes; D009711:Nucleotides; D005973:Glutamine; D012694:Serine; D006639:Histidine; D001216:Asparagine; D001120:Arginine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D001217:Aspartate-Ammonia Ligase