Highlighted Paper: mTORC2 targets AGC kinases through Sin1-dependent recruitment.

The Protein Phosphorylation Lab headed by Peter Parker published this paper in the Biochemical Journal.

Cameron AJ, Linch MD, Saurin AT, Escribano C, Parker PJ. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem J. 2011 Aug 1. [Epub ahead of print]

The protein kinase mammalian Target Of Rapamycin (mTOR) has emerged as a key nexus for the integration of growth factor signalling with the availability of energy and nutrients. Targeting this kinase has consequently become of increasing interest in the treatment of many forms of cancer. In eukaryotes there are two conserved TOR complexes (TORC1 and TORC2) that phosphorylate distinct downstream targets relevant to cell growth and metabolism. Intriguingly, the immunosuppressant Rapamycin and its analogues specifically target TORC1 and have a history of limited efficacy in cancer therapy. A new class of drugs directed against the mTOR catalytic subunit are capable of inhibiting both TORC1 and TORC2 and this more global inhibition appears to be more effective. It remains unclear however as to the relative importance of targeting TORC1 and/or TORC2. Here we have exploited a mechanism of selectivity to develop a novel system for interfering specifically with the TORC2 arm of mTOR signalling.

Among the targets of mTORC2 are the AGC families of PKB and PKC protein kinases. We have demonstrated that PKC members can interact directly with a conserved domain within the adapter protein, Sin1, which is a subunit specific to TORC2. By making mutations within this Sin1-PKC interaction domain we can uncouple the TORC2 complex from its downstream targets PKC and also PKB without interfering with TORC1 action. By inducible expression of these dominant mutants of Sin1 we are able to selectively block TORC2 signalling in vivo and in doing so have revealed a key role for TORC2 in transformed cell growth.

Figure 1. Sin1 mutants lacking the PKC interaction domain prevent TORC2 from phosphorylating AGC Kinases and block growth (We thank J. Claus for artwork).

By Angus Cameron (Protein Phosphorylation Labortaory)