Substrate-specific regulation of mTORC1 activity by G protein-coupled receptors

The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase controls cell growth in response to various external stimuli. mTORC1 has a myriad of substrates, and the activation of distinct downstream pathways has important physiological outcomes. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, differentially regulating individual substrates and downstream biological processes. The nature of signals that determine the signaling selectivity of mTORC1 is not fully understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that muscarinic acetylcholine receptor M5, formyl peptide receptor 2, and beta-2 adrenergic receptor, which are coupled to distinct effector G proteins, all trigger substrate-specific activation of mTORC1. Remarkably, phosphorylation of the TFEB transcription factor, a non-canonical mTORC1 substrate that controls lysosome biogenesis, responded to GPCRs differently, sometimes even oppositely, compared to canonical mTORC1 substrates such as S6K1 and 4EBP1. This study highlights the need to re-evaluate the effects of GPCRs on mTORC1 by parallelly monitoring individual substrates, an important consideration to be made when assessing GPCR ligands as therapeutic tools to manipulate the mTORC1 pathway.