Pyruvate kinase M2 is a phosphotyrosine-binding protein
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.
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As glucose uptake and usage are under growth factor control, this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.
“As glucose uptake and usage are under growth factor control (58, 59, 60), this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [58]
Growth-factor-stimulated tyrosine phosphorylation of PKM2 decreases its activity.
“Moreover, growth-factor–stimulated tyrosine phosphorylation of PKM2 further decreases its activity (58, 59).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [58]
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- Authors
- Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Cantley, Lewis C.
- Venue
- Nature
- Published
- 2008-03
- Volume
- 452
- Issue
- 7184
- Pages
- 181-186
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1995444593
- Cited by
- 995
- References
- 18
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 34 · 2023: 46 · 2022: 47 · 2021: 56 · 2020: 47 · 2019: 56 · 2018: 67 · 2017: 55 · 2016: 55 · 2015: 68 · 2014: 88 · 2013: 60 · 2012: 88
- FWCI
- 21.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute (T32CA009172)
- National Institute of General Medical Sciences (R01GM056203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PKM2, tyrosine phosphorylation, fructose-1,6-bisphosphate, allosteric regulation, glycolysis, cancer metabolism, Warburg effect, growth factor signaling, anabolic metabolism, tumor cell proliferation
- MeSH terms
- Allosteric Site, Animals, Catalysis, Cell Line, Cells, HeLa Cells, Humans, Lysine, Models, Molecular, Protein Binding, Pyruvate Kinase, Substrate Specificity, Phosphotyrosine, Peptide Library, Proteomics, Cell Proliferation
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