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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Tennant, D. A., Duran, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267–277 (2010)
Chaneton, B. & Gottlieb, E. Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem. Sci. 37, 309–316 (2012)
Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008)
Altenberg, B. & Greulich, K. O. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84, 1014–1020 (2004)
Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005)
Yamada, K. & Noguchi, T. Nutrient and hormonal regulation of pyruvate kinase gene expression. Biochem. J. 337, 1–11 (1999)
Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011)
Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869–874 (2011)
Pollari, S. et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res. Treat. 125, 421–430 (2011)
Vander Heiden, M. G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010)
Dombrauckas, J. D., Santarsiero, B. D. & Mesecar, A. D. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 44, 9417–9429 (2005)
Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009)
Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008)
Ashizawa, K., Willingham, M. C., Liang, C. M. & Cheng, S. Y. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J. Biol. Chem. 266, 16842–16846 (1991)
Spellman, C. M. & Fottrell, P. F. Similarities between pyruvate kinase from human placenta and tumours. FEBS Lett. 37, 281–284 (1973)
Eigenbrodt, E., Leib, S., Kramer, W., Friis, R. R. & Schoner, W. Structural and kinetic differences between the M2 type pyruvate kinases from lung and various tumors. Biomed. Biochim. Acta 42, S278–S282 (1983)
Ye, J. et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc. Natl Acad. Sci. USA 109, 6904–6909 (2012)
Davies, T. G. & Tickle, I. J. Fragment screening using X-ray crystallography. Top. Curr. Chem. 317, 33–59 (2012)
Allali-Hassani, A. et al. A survey of proteins encoded by non-synonymous single nucleotide polymorphisms reveals a significant fraction with altered stability and activity. Biochem. J. 424, 15–26 (2009)
Medina, M. A., Marquez, J. & Nunez de Castro, I. Interchange of amino acids between tumor and host. Biochem. Med. Metab. Biol. 48, 1–7 (1992)
Márquez, J., Sanchez-Jimenez, F., Medina, M. A., Quesada, A. R. & Nunez de Castro, I. Nitrogen metabolism in tumor bearing mice. Arch. Biochem. Biophys. 268, 667–675 (1989)
Mattevi, A., Bolognesi, M. & Valentini, G. The allosteric regulation of pyruvate kinase. FEBS Lett. 389, 15–19 (1996)
Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011)
de Koning, T. J. et al. l-serine in disease and development. Biochem. J. 371, 653–661 (2003)
Luo, B., Groenke, K., Takors, R., Wandrey, C. & Oldiges, M. Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J. Chromatogr. A 1147, 153–164 (2007)
Salituro, F. G. & Saunders, J. O. Therapeutic compositions and related methods of use. PTC patent application WO/2010/118063. (2010)
Boxer, M. B. et al. Evaluation of substituted N,N′-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. J. Med. Chem. 53, 1048–1055 (2010)
Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)
Mooij, W. T. et al. Automated protein-ligand crystallography for structure-based drug design. Chem Med Chem 1, 827–838 (2006)
Brünger, A. T. Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 355, 472–475 (1992)
Diederichs, K. & Karplus, P. A. Improved R factors for diffraction data analysis in macromolecular crystallography. Nature Struct. Biol. 4, 269–275 (1997)
Weiss, M. S. & Hilgenfeld, R. On the use of the merging R factor as a quality indicator for X-ray data. J. Appl. Crystallogr. 30, 203–205 (1997)
Weiss, M. S. Global indicators of X-ray data quality. J. Appl. Crystallogr. 34, 130–135 (2001)
Pedrioli, P. G. et al. A common open representation of mass spectrometry data and its application to proteomics research. Nature Biotechnol. 22, 1459–1466 (2004)
Kessner, D., Chambers, M., Burke, R., Agus, D. & Mallick, P. ProteoWizard: open source software for rapid proteomics tools development. Bioinformatics 24, 2534–2536 (2008)
Tautenhahn, R., Bottcher, C. & Neumann, S. Highly sensitive feature detection for high resolution LC/MS. BMC Bioinformatics 9, 504 (2008)
Smith, C. A., Want, E. J., O’Maille, G., Abagyan, R. & Siuzdak, G. XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Anal. Chem. 78, 779–787 (2006)
Fernandez, C. A., Des Rosiers, C., Previs, S. F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass Spectrom. 31, 255–262 (1996)
Scheltema, R. A., Jankevics, A., Jansen, R. C., Swertz, M. A. & Breitling, R. PeakML/mzMatch: a file format, Java library, R library, and tool-chain for mass spectrometry data analysis. Anal. Chem. 83, 2786–2793 (2011)
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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