The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 2008 Jul 23;27(14):1932-43
Date
06/21/2008Pubmed ID
18566586Pubmed Central ID
PMC2486276DOI
10.1038/emboj.2008.120Scopus ID
2-s2.0-47949125486 (requires institutional sign-in at Scopus site) 440 CitationsAbstract
The target of rapamycin (TOR), as part of the rapamycin-sensitive TOR complex 1 (TORC1), regulates various aspects of protein synthesis. Whether TOR functions in this process as part of TORC2 remains to be elucidated. Here, we demonstrate that mTOR, SIN1 and rictor, components of mammalian (m)TORC2, are required for phosphorylation of Akt and conventional protein kinase C (PKC) at the turn motif (TM) site. This TORC2 function is growth factor independent and conserved from yeast to mammals. TM site phosphorylation facilitates carboxyl-terminal folding and stabilizes newly synthesized Akt and PKC by interacting with conserved basic residues in the kinase domain. Without TM site phosphorylation, Akt becomes protected by the molecular chaperone Hsp90 from ubiquitination-mediated proteasome degradation. Finally, we demonstrate that mTORC2 independently controls the Akt TM and HM sites in vivo and can directly phosphorylate both sites in vitro. Our studies uncover a novel function of the TOR pathway in regulating protein folding and stability, processes that are most likely linked to the functions of TOR in protein synthesis.
Author List
Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C, Lowry C, Newton AC, Mao Y, Miao RQ, Sessa WC, Qin J, Zhang P, Su B, Jacinto EMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAmino Acid Motifs
Animals
Carrier Proteins
Cell Line
Embryo, Mammalian
Fibroblasts
Humans
Mice
Models, Molecular
Multiprotein Complexes
Protein Folding
Protein Kinase C
Protein Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
