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Pyruvate kinase M2 is a phosphotyrosine-binding protein

Author

Listed:
  • Heather R. Christofk

    (Department of Systems Biology,)

  • Matthew G. Vander Heiden

    (Department of Systems Biology,
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Ning Wu

    (Department of Systems Biology,)

  • John M. Asara

    (Harvard Medical School, Boston, Massachusetts 02115, USA
    Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA)

  • Lewis C. Cantley

    (Department of Systems Biology,
    Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA)

Abstract

Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.

Suggested Citation

  • Heather R. Christofk & Matthew G. Vander Heiden & Ning Wu & John M. Asara & Lewis C. Cantley, 2008. "Pyruvate kinase M2 is a phosphotyrosine-binding protein," Nature, Nature, vol. 452(7184), pages 181-186, March.
    • Handle: RePEc:nat:nature:v:452:y:2008:i:7184:d:10.1038_nature06667
    DOI: 10.1038/nature06667
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    Cited by:

    1. Hanna Kjellin & Henrik Johansson & Anders Höög & Janne Lehtiö & Per-Johan Jakobsson & Magnus Kjellman, 2014. "Differentially Expressed Proteins in Malignant and Benign Adrenocortical Tumors," PLOS ONE, Public Library of Science, vol. 9(2), pages 1-10, February.
    2. Yu-Ju Lai & Yu-Ching Chou & Yi-Jia Lin & Mu-Hsien Yu & Yu-Che Ou & Po-Wei Chu & Chia-Chun Wu & Yu-Chi Wang & Tai-Kuang Chao, 2019. "Pyruvate Kinase M2 Expression: A Potential Metabolic Biomarker to Differentiate Endometrial Precancer and Cancer that is Associated with Poor Outcomes in Endometrial Carcinoma," IJERPH, MDPI, vol. 16(23), pages 1-10, November.

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