title: mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s.
abstract: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that participates in at least two distinct multiprotein complexes, mTORC1 and mTORC2 . These complexes play important roles in the regulation of cell growth, proliferation, survival, and metabolism. mTORC2 is a hydrophobic motif kinase for the cell-survival protein Akt/PKB and, here, we identify mSin1 as a component of mTORC2 but not mTORC1. mSin1 is necessary for the assembly of mTORC2 and for its capacity to phosphorylate Akt/PKB. Alternative splicing generates at least five isoforms of the mSin1 protein , three of which assemble into mTORC2 to generate three distinct mTORC2s. Even though all mTORC2s can phosphorylate Akt/PKB in vitro, insulin regulates the activity of only two of them. Thus, we propose that cells contain several mTORC2 flavors that may phosphorylate Akt/PKB in response to different signals.
authors.affiliation: Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Frias
authors.forename: Carson C
authors.initials: CC
authors.lastname: Thoreen
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Jaffe
authors.forename: Wayne
authors.initials: W
authors.lastname: Schroder
authors.forename: Tom
authors.initials: T
authors.lastname: Sculley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007328:Insulin / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; C493277:MAPKAP1 protein, human; D020033:Protein Isoforms; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus