Journal
SCIENCE
Volume 370, Issue 6514, Pages 351-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaz0863
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Funding
- Canadian Cancer Society Research Institute Innovation
- i2I grants (CCSRI) [704301, 705938]
- Canadian Institutes of Health Research Foundation Grant [CIHR FDN 143301]
- Canada Foundation for Innovation funding
- Government of Ontario
- Genome Canada
- Ontario Genomics [OGI-139]
- Parkinson Canada
- Natural Sciences and Engineering Research Council of Canada Undergraduate Student Research Award
- BioTalent Canada
- Glowinsky-Sandler family
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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.
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