Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target?
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a multicomponent, nutrient-sensitive protein that is implicated in a wide range of major human diseases. mTORC1 responds to both growth factors and changes in local amino acid levels. Until recently, the intracellular amino acid-sensing mechanism that regulates mTORC1 had remained unexplored. However, studies in human cells in culture have demonstrated that in response to amino acid stimulation, mTOR (a conserved member of the PI3K superfamily) is shuttled to late endosomal and lysosomal compartments, where it binds the Ragulator-Rag complex and is assembled into active mTORC1. Members of the proton-assisted amino acid transporter (PAT/SLC36) family have been identified as critical components of the amino acid-sensing system that regulates mTORC1 present in endosomal and lysosomal membranes. These discoveries not only highlight several new potential drug targets that could impact selectively on mTORC1 activity in cancer cells, but also provide novel insights into the strategies used by such cells to outcompete their neighbors in growth factor- and nutrient-depleted conditions. In this review, recent mechanistic insights into how mTORC1 activity is controlled by amino acids and the potential for the selective targeting this regulatory input are discussed.