UC San Diego

The mechanistic target of rapamycin complex 1 (mTORC1) is a signaling hub that senses numerous upstream signals including growth factors and regulates a broad range of cellular functions. Dysregulation of mTORC1 signaling pathway has been implicated in various pathological conditions such as cancers and diabetes. To achieve precise regulation and functions, mTORC1 signaling is compartmentalized. Canonical mTORC1 activation on the lysosome has been well established, but mTORC1signaling at other subcellular compartments is undefined. In these studies, using synthetic biology approaches, we developed and applied molecular tools for monitoring and perturbing mTORC1 signaling at subcellular compartments to dissect the mechanisms that regulate subcellular mTORC1 activity and to examine the functions of subcellular mTORC1. Specifically, growth factor-stimulated mTORC1 activity was observed in the nucleus and nuclear mTORC1 was regulated by nuclear Akt and Rheb, two essential positive regulators of mTORC1, through a noncanonical mechanism. By specifically perturbing mTORC1 activity in the nucleus, we found that compared with canonical mTORC1 activity, nuclear mTORC1 played a distinct role in regulating gene transcription in glycolysis, a critical process involved in cancer cell survival. Thus, these studies suggest that precisely tuning subcellular mTORC1 activity rather than targeting it with a sledgehammer approach may provide therapeutic benefits.