Metabolism. Differential regulation of mTORC1 by leucine and glutamine.
Bottom Line: Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase).Furthermore, we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine.Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.
Affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.Show MeSH
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Mentions: Amino acid transporters (5, 12) and the Ragulator complex (11, 13) have been implicated in mTORC1 activation. We analyzed mTORC1 activity in cells depleted of several amino acid transporters and in MEFs lacking p14 (p14 KO MEFs), an essential subunit of the Ragulator complex. Gln activated mTORC1 in cells depleted of some amino acid transporters and in p14 KO MEFs, which indicated that these transporters and the Ragulator are not required for Gln-induced activation of mTORC1 (fig. S12 and Fig. 3A).
Affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.