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Spatial Compartmentalization of Akt/mTOR Signaling: What Happens in the Nucleus

The Akt/mTOR pathway is a central player in regulating distinct and diverse cellular processes, such as cell growth, survival, and metabolism. We hypothesize that spatial compartmentalization is a critical mechanism for achieving signaling specificity of Akt/mTOR signaling. To examine this spatial regulation of Akt/mTOR signaling within subcellular compartments, we developed a series of genetically encoded fluorescent protein‐based molecular tools, including Akt activity reporter (AktAR2) and mTORC1 activity reporter (TORCAR), to directly visualize the kinase activities dynamics of Akt and mTORC1 in single living cell. We found that cellular mTORC1 activity is intricately regulated in a signal‐ and location‐specific manner. Surprisingly, both growth factor and amino acid surrogate induce mTORC1 activity in the nucleus, in contrast to the current thinking that mTORC1 is not active in nucleus. To further dissect the regulatory mechanisms of nuclear mTORC1 activity, we developed Akt‐STOPS (Akt Substrate‐based Tandem Occupancy Peptide Sponge), which allows perturbation of Akt signaling at distinct subcellular compartments. Expression of Akt‐STOPS in the nucleus suppressed the growth factor stimulated nuclear Akt activity without significant inhibition of Akt activity in the cytosol. Strikingly, expression of Akt‐STOPS in the nucleus largely diminished the growth factor‐induced nuclear mTORC1 activity, and down‐regulated the transcription by mTORC1‐dependent RNA pol III, suggesting that growth factor induced nuclear mTORC1 activity is dependent on nuclear Akt activity. These results have led to a new model of regulation of mTORC1 in nucleus. Taken together, we developed new molecular tools to interrogate the spatial control of Akt/mTOR signaling and uncovered new insights into the spatial compartmentalization of Akt/mTOR signaling.