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mTORC2 targets AGC kinases through Sin1-dependent recruitment

Angus J M Cameron1, Mark D Linch, Adrian T Saurin

  • 1Protein Phosphorylation Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

The Biochemical Journal
|August 3, 2011
PubMed

Insights

The target of rapamycin complex 2 (mTORC2) subunit Sin1 acts as a scaffold, enabling mTORC2 to phosphorylate protein kinase C (PKC) and protein kinase B (PKB)/Akt, crucial for cell growth and proliferation.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Biochemistry

Background:

  • The target of rapamycin (TOR) pathway regulates cell growth and metabolism.
  • Mammalian TOR exists as two complexes, mTORC1 and mTORC2, with distinct functions.
  • The molecular mechanisms and therapeutic importance of mTORC2 are not fully understood.

Purpose of the Study:

  • To elucidate the molecular role of mTORC2 components.
  • To investigate the interaction between mTORC2 and protein kinase C (PKC).
  • To determine the function of mTORC2 in cell proliferation.

Main Methods:

  • Identified Sin1 as a direct binding partner of the PKCε kinase domain.
  • Mapped the Sin1-PKC interaction site.
  • Utilized inducible expression of Sin1 mutants to disrupt mTORC2 function.
  • Assessed phosphorylation of PKC, PKB/Akt, and p70S6K.

Main Results:

  • Sin1 directly binds to PKCε, facilitating PKC phosphorylation by mTORC2.
  • Disruption of Sin1-PKC interaction impairs mTORC2-mediated phosphorylation of PKC and PKB/Akt.
  • mTORC1 substrate p70S6K phosphorylation remains unaffected.
  • Selective mTORC2 inhibition demonstrates its critical role in 3D cell proliferation.

Conclusions:

  • Sin1 acts as a selectivity adaptor, recruiting substrates like PKC to mTORC2.
  • mTORC2 is essential for PKC and PKB/Akt phosphorylation.
  • Targeting mTORC2, particularly via Sin1, is a promising strategy for controlling cell proliferation.

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