title: The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling.
abstract: Two structurally and functionally distinct mammalian TOR complexes control cell growth and metabolism in physiological and pathological contexts including cancer. Upregulated glutaminolysis is part of the metabolic reprogramming occurring in cancer, providing fuels for growth but also liberating ammonium, a potent neurotoxic waste product. Here, we identify ammonium as a novel dose-dependent signal mediating rapid mTORC2 activation and further regulating mTORC1. We show that ammonium induces rapid RICTOR-dependent phosphorylation of AKT-S473, a process requiring the PI3K pathway and further involving the Src-family kinase YES1, the FAK kinase and the ITGβ1 integrin. Release of calcium from the endoplasmic reticulum store triggers rapid mTORC2 activation, similar to ammonium-induced activation, the latter being conversely prevented by calcium chelation.Moreover, in analogy to growth factors, ammonium triggers the AKT-dependent phosphoinhibition of the TSC complex and of PRAS40, two negative regulators of mTORC1. Consistent with mTORC1 stimulation, ammonium induces the inhibitory phosphorylation of 4EBP1, a negative regulator of protein biogenesis. Ammonium however dually impacts on the phosphorylation of p70S6K1 triggering a transient AKT-independent decrease in the phosphorylation of this second mTORC1 readout. Finally, we reveal ammonium as a dose-dependent stimulator of proliferation. This study underscores an mTORC2 and mTORC1 response to the so-called ammonium waste.
authors.affiliation: Biology of Membrane Transport, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.|Institute of Pathology and Genetics, Avenue Georges Lemaître 25, 6041 Gosselies, Belgium.|Tumour Bank, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, 6041 Gosselies, Belgium.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Merhi
authors.affiliation: Institute of Pathology and Genetics, Avenue Georges Lemaître 25, 6041 Gosselies, Belgium.|Tumour Bank, Institute of Pathology and Genetics, Avenue Georges Lemaître 25, 6041 Gosselies, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Delrée
authors.affiliation: Biology of Membrane Transport, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
mesh_terms: D064751:Ammonium Compounds / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D064751:Ammonium Compounds; D019012:Integrin beta1; D010768:Phosphoserine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium