title: A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation.
abstract: The mechanistic target of rapamycin complex 2 (mTORC2) regulates cell survival and cytoskeletal organization by phosphorylating its AGC kinase substrates; however, little is known about the regulation of mTORC2 itself. It was previously reported that Akt phosphorylates the mTORC2 subunit SIN1 at T86, activating mTORC2 through a positive feedback loop, though another study reported that S6K phosphorylates SIN1 at the same site, inhibiting mTORC2 activity. We performed extensive analysis of SIN1 phosphorylation upon inhibition of Akt, S6K, and mTOR under diverse cellular contexts, and we found that, in all cell lines and conditions studied, Akt is the major kinase responsible for SIN1 phosphorylation. These findings refine the activation mechanism of the Akt-mTORC2 signaling branch as follows: PDK1 phosphorylates Akt at T308, increasing Akt kinase activity. Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt.
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; The Charles Perkins Centre, The School of Molecular Bioscience, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Murashige
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried 82152, Germany.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Humphrey
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; The Charles Perkins Centre, The School of Molecular Bioscience, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: david.james@sydney.edu.au.
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C493277:MAPKAP1 protein, human; D046912:Multiprotein Complexes; D010879:Piperazines; D011743:Pyrimidines; C583616:ipatasertib; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1