Cited by 457PI3K/AKT/mTOR signaling in cancerAutophagy in Disease and TherapyCellular transport and secretion

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The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1

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Palm, Wilhelm, Park, Youngkyu, Wright, Kevin, Pavlova, Natalya N., Tuveson, David A., Thompson, Craig B.·2015·Cell

DOI 10.1016/j.cell.2015.06.017PMC PMC4506698

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Abstract

Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.

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Authors: Palm, W., Park, Y., Wright, K., Pavlova, N. N., Tuveson, D. A., & Thompson, C. B.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Cold Spring Harbor Laboratory (US)
Corresponding author: Thompson, Craig B.
ORCID: Palm, Wilhelm
Park, Youngkyu
Pavlova, Natalya N.
Tuveson, David A.
Thompson, Craig B.
Venue: Cell
Publisher: Elsevier BV
Published: 2015-07
Volume: 162
Issue: 2
Pages: 259-270
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2015.06.017
PMC: PMC4506698
OpenAlex: W1829589101
Cited by: 457
References: 30
Citations by year: 2026: 22 · 2025: 31 · 2024: 34 · 2023: 29 · 2022: 51 · 2021: 50 · 2020: 64 · 2019: 30 · 2018: 48 · 2017: 45 · 2016: 44 · 2015: 9
FWCI: 21.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders: Genentech Foundation
Memorial Sloan-Kettering Cancer Center
Cold Spring Harbor Laboratory
Hope Funds for Cancer Research
Foundation of Hope for Research and Treatment of Mental Illness
National Institutes of Health (5p30ca045508-35)
National Cancer Institute (5U01CA168409-3, P50CA101955, U10CA180944, P01CA104838, 5P30CA045508, U01CA168409, R01CA201318, P30-CA045508, 5P30CA45508-26, P30CA008748, R01CA190092)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: mTORC1, extracellular proteins, macropinocytosis, amino acid metabolism, essential amino acids, lysosomal degradation, cell proliferation, nutrient deprivation, tumor vascularization, mTOR inhibitors, Ras signaling, glutamine addiction
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Albumins, Amino Acids, Animals, Cell Survival, Embryo, Mammalian, Fibroblasts, Lysosomes, Pinocytosis, Proteins, ras Proteins, Multiprotein Complexes, Cell Proliferation, Mice, Eukaryota, TOR Serine-Threonine Kinases

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The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1

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