mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s.
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.
Frias
Maria A
MA
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
Thoreen
Carson C
CC
Jaffe
Jacob D
JD
Schroder
Wayne
W
Sculley
Tom
T
Carr
Steven A
SA
Sabatini
David M
DM
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
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