Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor

Abigail S. Krall, Shili Xu, Thomas G. Graeber, Daniel Braas and Heather R. Christofk ()
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Abigail S. Krall: David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
Shili Xu: David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
Thomas G. Graeber: David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
Daniel Braas: David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA
Heather R. Christofk: David Geffen School of Medicine, University of California, 650 Charles East Young Drive South, Los Angeles, California 90095, USA

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11457

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