mTORC2 can integrate multiple activating influences to positively influence anabolism, survival and cytoskeletal remodelling. We have characterised a positive feedback loop between mTORC2 and AKT and have shown that mTORC2 has a great potential for activation that has been overlooked in previous work. We have structurally characterized the mechanism for the mTORC2 activation, and we are elucidating the roles of positive feedback loops involving other AGC kinases. These mechanisms are central to activation of mTORC2 upstream of mTORC1, in endocytic pathways and macropinocytosis.
A variety of approaches are being harnessed to understand how mTORC2 is activated. The structural component of the programme involves single particle and tomographic cryo-EM in solution and on membranes. To characterise kinetic control of signalling loops, we have reconstituted mTORC1 and mTORC2 signalling in vitro. To understand activation dynamics of these enzyme complexes, we are also carrying out molecular dynamics and using AI-generated ensembles with HDX‑MS.
In collaboration with AstraZeneca, we have developed small molecule mTORC2 activators that might be useful chemical-genetic probes, with exquisite specificity. The core of the student project will be elucidating the natural mechanisms of mTORC2 activation, but the small-molecule activators can act as mimics of the natural ones or point toward alternative mechanisms. Eventually, these activators might have therapeutic applications in tissue healing and regeneration.