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  • The EMBO Journal (2008) 27, 1932 - 1943
  • doi:10.1038/emboj.2008.120

Published online: 19 June 2008

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

Valeria Facchinetti1, Weiming Ouyang2, Hua Wei3, Nelyn Soto3, Adam Lazorchak2, Christine Gould4, Carolyn Lowry3, Alexandra C Newton4, Yuxin Mao5, Robert Q Miao6, William C Sessa6, Jun Qin7, Pumin Zhang8, Bing Su1,2 and Estela Jacinto3

  1. Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
  2. Department of Immunobiology and Vascular Biology and Transplantation Program, New Haven, CT, USA
  3. Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA
  4. Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA
  5. Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA
  6. Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
  7. Verna and Mars McLean Department of Biochemistry and Molecular Biology, Houston, TX, USA
  8. Department of Physiology, Baylor College of Medicine, Houston, TX, USA

Correspondence to:

Estela Jacinto, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 8854, USA. Tel.: +1 732 235 4476; Fax: +1 732 235 5038; E-mail: jacintes@umdnj.edu

Bing Su, Department of Immunobiology, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA. Tel.: +1 203 737 2463; Fax: +1 203 737 2293; E-mail: bing.su@yale.edu

Valeria Facchinetti, Department of Immunology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel.: +1 713 794 3069; Fax: +1 713 563 3276; E-mail: vfacchin@mdanderson.org

Received 30 January 2008; Accepted 28 May 2008

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.

  • Keywords:

    • Akt,
    • mTOR,
    • PKC,
    • protein folding,
    • turn motif