mTORC2 targets AGC kinases through Sin1-dependent recruitment

作者：Cameron Angus J M; Linch Mark D; Saurin Adrian T; Escribano Cristina; Parker Peter J^*

来源：Biochemical Journal, 2011, 439(2): 287-297.

DOI：10.1042/BJ20110678

• cancer
• mammalian target of rapamycin (mTOR)
• nucleotide pocket
• protein kinase B (PKB)
• protein kinase C (PKC)
• Sin 1

The protein kinase TOR (target of rapamycin) is a key regulator of cell growth and metabolism with significant clinical relevance. In mammals, TOR signals through two distinct multi-protein complexes, mTORC1 and mTORC2 (mammalian TOR complex 1 and 2 respectively), the subunits of which appear to define the operational pathways. Rapamycin selectively targets mTORC1 function, and the emergence of specific ATP-competitive kinase inhibitors has enabled assessment of dual mTORC1 and mTORC2 blockade. Little is known, however, of the molecular action of mTORC2 components or the relative importance of targeting this pathway. In the present study, we have identified the mTORC2 subunit Sin 1 as a direct binding partner of the PKC (protein kinase C) epsilon kinase domain and map the interaction to the central highly conserved region of Sin 1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC. Inducible expression of Sin 1 mutants, lacking the PKC-interaction domain, displaces endogenous Sin 1 from mTORC2 and disrupts PKC phosphorylation. PKB (protein kinase B)/Akt phosphorylation is also suppressed by these Sin 1 mutants, but not the mTORC1 substrate p70(s6k) (S6 kinase), providing evidence that Sin 1 serves as a selectivity adaptor for the recruitment of mTORC2 targets. This inducible selective mTORC2 intervention is used to demonstrate a key role for mTORC2 in cell proliferation in three-dimensional culture.

• 出版日期2011-10-15