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Mol Cell. 2017 Sep 21;67(6):936-946.e5. doi: 10.1016/j.molcel.2017.08.011. Epub 2017 Sep 14.

mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein.

Author information

1
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
2
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. Electronic address: joshr@princeton.edu.

Abstract

Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth.

PMID:
28918901
PMCID:
PMC5612669
DOI:
10.1016/j.molcel.2017.08.011
[Indexed for MEDLINE]
Free PMC Article

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