TORC2 Structure and Function. Issue 6 (June 2016) - Gaubitz, Christl
Abstract : The target of rapamycin (TOR) kinase functions in two multiprotein complexes, TORC1 and TORC2. Although both complexes are evolutionarily conserved, only TORC1 is acutely inhibited by rapamycin. Consequently, only TORC1 signaling is relatively well understood; and, at present, only mammalian TORC1 is a validated drug target, pursued in immunosuppression and oncology. However, the knowledge void surrounding TORC2 is dissipating. Acute inhibition of TORC2 with small molecules is now possible and structural studies of both TORC1 and TORC2 have recently been reported. Here we review these recent advances as well as observations made from tissue-specific mTORC2 knockout mice. Together these studies help define TORC2 structure–function relationships and suggest that mammalian TORC2 may one day also become a bona fide clinical target. Trends: The target of rapamycin (TOR) kinase assembles into two, evolutionarily conserved multiprotein complexes, TORC1 and TORC2. Unlike TORC1, TORC2 is not acutely inhibited by rapamycin and, consequently, the signaling pathways in which this complex operates are relatively less understood. Recent electron microscopy structures provide a framework for understanding how TORC2 is regulated as well as the specific functions of individual subunits. Tissue-specific ablation of mammalian TORC2 demonstrates a role for this complex in the regulation of growth, proliferation, and metabolism and suggests that, like mTORC1, mTORC2 inhibition may also bring clinical gain.