The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C

Valeria Facchinetti, Weiming Ouyang, Hua Wei, Nelyn Soto, Adam Lazorchak, Christine Gould, Carolyn Lowry, Alexandra C. Newton, Yuxin Mao, Robert Q. Miao, William C. Sessa, Jun Qin, Pumin Zhang, Bing Su, Estela Jacinto

Research output: Contribution to journalArticlepeer-review

375 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1932-1943
Number of pages12
JournalEMBO Journal
Volume27
Issue number14
DOIs
StatePublished - Jul 23 2008

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Keywords

  • Akt
  • PKC
  • Protein folding
  • Turn motif
  • mTOR

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