The GATOR–Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids
Geoffrey G. Hesketh, Fotini Papazotos, Judy Pawling, Dushyandi Rajendran, James D.R. Knight, Sébastien Martinez, Mikko Taipale, Daniel Schramek, James W. Dennis, Anne‐Claude Gingras
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR-Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase-independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.