Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation1. Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine2. Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation.
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The work performed at the Beatson Institute for Cancer Research was supported by Cancer Research UK. We thank D. Sumpton for technical support with two-dimensional gel electrophoresis and N. Thompson, N. Wallis and M. Jones for comments provided during manuscript preparation. We would also like to thank D. M. Sabatini for the Scramble shRNA plasmid used as a control (shCntrla) and the Structural Genomics Consortium for providing us with the PKM2 expression plasmid from their collection. We thank A. King for editorial work and S. Tardito for graphical help.
E.G. is a consultant of Astex Pharmaceuticals.
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Chaneton, B., Hillmann, P., Zheng, L. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462 (2012). https://doi.org/10.1038/nature11540
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