Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor
Open accessAbstract
Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.
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Asparagine functions as an exchange factor needed for uptake of other amino acids required for mTORC1 activation and for enhanced nucleotide biosynthesis under mitochondrial electron transport chain impairment.
“Recently, asparagine has been reported to function as an exchange factor needed for the uptake of other amino acids that are required for mTORC1 activation53 and for enhanced nucleotide biosynthesis under mitochondrial electron chain transport system impairment54.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [53]
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Self-citation
- Authors
- Krall, A. S., Xu, S., Graeber, T. G., Braas, D., & Christofk, H. R.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Christofk, Heather R.
- Venue
- Nature Communications
- Published
- 2016-04-29
- Volume
- 7
- Issue
- 1
- Pages
- 11457-11457
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4855534
- OpenAlex
- W2343975196
- Cited by
- 504
- References
- 34
- Citations by year
- 2026: 39 · 2025: 47 · 2024: 43 · 2023: 56 · 2022: 63 · 2021: 64 · 2020: 66 · 2019: 50 · 2018: 48 · 2017: 24 · 2016: 3
- FWCI
- 27.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Damon Runyon Cancer Research Foundation
- Searle Scholars Program
- Calithera Biosciences (CB839)
- National Institutes of Health (1dp2od008454-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- asparagine, amino acid substitutions, amino acid uptake, mTORC1, tumor cell proliferation, asparagine synthetase, serine metabolism, nucleotide synthesis, protein synthesis, amino acid homeostasis, anabolic metabolism, histidine uptake, arginine uptake
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Arginine, Asparagine, Aspartate-Ammonia Ligase, Biological Transport, Culture Media, Glutamine, HeLa Cells, Histidine, Humans, Nucleotides, Serine, Signal Transduction, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Multiprotein Complexes, Cell Proliferation, Metabolic Networks and Pathways, TOR Serine-Threonine Kinases
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