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

TitlemTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein.
Publication TypeJournal Article
Year of Publication2017
AuthorsNofal, M, Zhang, K, Han, S, Rabinowitz, JD
JournalMol Cell
Volume67
Issue6
Pagination936-946.e5
Date Published2017 Sep 21
ISSN1097-4164
KeywordsAmino Acids, Animals, Cell Line, Cell Proliferation, Computer Simulation, Energy Metabolism, Fibroblasts, Mechanistic Target of Rapamycin Complex 1, Mice, Models, Biological, Multiprotein Complexes, Mutation, Naphthyridines, Pinocytosis, Protein Kinase Inhibitors, Proteins, Proteolysis, Proto-Oncogene Proteins p21(ras), RNA Interference, Signal Transduction, Time Factors, TOR Serine-Threonine Kinases, Transfection
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.

DOI10.1016/j.molcel.2017.08.011
Alternate JournalMol. Cell
PubMed ID28918901
PubMed Central IDPMC5612669
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
F31 CA186513 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States