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

Valeria Facchinetti1, Weiming Ouyang, Hua Wei

  • 1Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA. vfacchin@mdanderson.org

The EMBO Journal
|June 21, 2008
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) regulates protein folding and stability. This novel function of the TOR pathway is conserved across species and impacts protein synthesis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The target of rapamycin (TOR) pathway, particularly TOR complex 1 (TORC1), is known to regulate protein synthesis.
  • The role of TOR complex 2 (TORC2) in protein synthesis, specifically in protein folding and stability, remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of mammalian (m)TORC2 in protein folding and stability.
  • To determine if mTORC2 influences the phosphorylation and stability of key kinases like Akt and protein kinase C (PKC).

Main Methods:

  • Investigated the requirement of mTORC2 components (mTOR, SIN1, rictor) for Akt and PKC phosphorylation at the turn motif (TM) site.
  • Assessed the impact of TM site phosphorylation on protein folding, stability, and degradation pathways.
  • Utilized in vivo and in vitro assays to examine mTORC2's control over Akt TM and hydrophobic motif (HM) sites.

Main Results:

  • mTORC2 is essential for the phosphorylation of Akt and PKC at the TM site, a process independent of growth factors and conserved from yeast to mammals.
  • TM site phosphorylation is crucial for the proper folding and stability of newly synthesized Akt and PKC, preventing degradation.
  • mTORC2 directly phosphorylates both the TM and HM sites of Akt in vitro and controls them independently in vivo.

Conclusions:

  • mTORC2 plays a novel role in regulating protein folding and stability through TM site phosphorylation of Akt and PKC.
  • This TORC2-mediated regulation of protein folding and stability is intrinsically linked to the broader functions of the TOR pathway in protein synthesis.
  • The findings reveal a new layer of control exerted by mTORC2 over kinase maturation and cellular proteostasis.

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