title: Phosphorylation of the TOR ATP binding domain by AGC kinase constitutes a novel mode of TOR inhibition.
abstract: TOR (target of rapamycin) signaling coordinates cell growth, metabolism, and cell division through tight control of signaling via two complexes, TORC1 and TORC2. Here, we show that fission yeast TOR kinases and mTOR are phosphorylated on an evolutionarily conserved residue of their ATP-binding domain. The Gad8 kinase (AKT homologue) phosphorylates fission yeast Tor1 at this threonine (T1972) to reduce activity. A T1972A mutation that blocked phosphorylation increased Tor1 activity and stress resistance. Nitrogen starvation of fission yeast inhibited TOR signaling to arrest cell cycle progression in G1 phase and promoted sexual differentiation. Starvation and a Gad8/T1972-dependent decrease in Tor1 (TORC2) activity was essential for efficient cell cycle arrest and differentiation. Experiments in human cell lines recapitulated these yeast observations, as mTOR was phosphorylated on T2173 in an AKT-dependent manner. In addition, a T2173A mutation increased mTOR activity. Thus, TOR kinase activity can be reduced through AGC kinase-controlled phosphorylation to generate physiologically significant changes in TOR signaling.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK.
authors.forename: Lenka
authors.initials: L
authors.lastname: Hálová
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Sara
authors.initials: S
authors.lastname: Kirkham
authors.forename: Duncan L
authors.initials: DL
authors.lastname: Smith
authors.forename: Janni
authors.initials: J
authors.lastname: Petersen
mesh_terms: D000255:Adenosine Triphosphate; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011494:Protein Kinases / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000201:enzymology*; D029702:Schizosaccharomyces pombe Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D029702:Schizosaccharomyces pombe Proteins; D010769:Phosphothreonine; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C523461:Tor1 protein, S pombe; C476401:Gad8 protein, S pombe; D017346:Protein Serine-Threonine Kinases