Article | Published:

ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect

Nature Cell Biology volume 14, pages 12951304 (2012) | Download Citation

  • A Corrigendum to this article was published on 24 December 2012

This article has been updated

Abstract

Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and contributes to the Warburg effect by unclear mechanisms. Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 Ile 429/Leu 431 through the ERK2 docking groove and phosphorylates PKM2 at Ser 37, but does not phosphorylate PKM1. Phosphorylated PKM2 Ser 37 recruits PIN1 for cistrans isomerization of PKM2, which promotes PKM2 binding to importin α5 and translocating to the nucleus. Nuclear PKM2 acts as a coactivator of β-catenin to induce c-Myc expression, resulting in the upregulation of GLUT1, LDHA and, in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of wild-type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the EGFR-promoted Warburg effect and brain tumour development in mice. In addition, levels of PKM2 Ser 37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens. Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis.

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Change history

  • 27 June 2014

    In the online version of this Article originally published, the company name 'Signalway Biotechnology' should have read 'Signalway Antibody'. This has now been corrected in all online versions of the Article.

References

  1. 1.

    , & Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science324, 1029–1033 (2009).

  2. 2.

    , & Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer11, 325–337.

  3. 3.

    , & Regulation of cancer cell metabolism. Nat. Rev. Cancer11, 85–95.

  4. 4.

    & Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics84, 1014–1020 (2004).

  5. 5.

    et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med.10, 594–601 (2004).

  6. 6.

    , , , & HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature463, 364–368.

  7. 7.

    et al. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc. Natl Acad. Sci. USA107, 1894–1899.

  8. 8.

    et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

  9. 9.

    et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499.

  10. 10.

    et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature480, 118–122 (2011).

  11. 11.

    et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell145, 732–744 (2011).

  12. 12.

    , , , & Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol. Cell45, 598–609 (2012).

  13. 13.

    Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis. Chin. J. Cancer31, 5–7 (2012).

  14. 14.

    et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell150, 685–696 (2012).

  15. 15.

    & ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life58, 621–631 (2006).

  16. 16.

    & The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat. Rev. Mol. Cell Biol.8, 904–916 (2007).

  17. 17.

    et al. FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol. Cell35, 11–25 (2009).

  18. 18.

    & Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain. FEBS Lett.583, 271–276 (2009).

  19. 19.

    , & Nuclear targeting signal recognition: a key control point in nuclear transport?Bioessays22, 532–544 (2000).

  20. 20.

    , & Evolution of the metazoan-specific importin alpha gene family. J. Mol. Evol.68, 351–365 (2009).

  21. 21.

    , , & Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4, 499–515 (2003).

  22. 22.

    , , & The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab.7, 11–20 (2008).

  23. 23.

    , , & The interplay between MYC and HIF in cancer. Nat. Rev. Cancer 8, 51–56 (2008).

  24. 24.

    On the origin of cancer cells. Science123, 309–314 (1956).

  25. 25.

    & Cancer cell metabolism: Warburg and beyond. Cell134, 703–707 (2008).

  26. 26.

    et al. Activation of protein kinase C triggers its ubiquitination and degradation. Mol. Cell Biol.18, 839–845 (1998).

  27. 27.

    et al. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol. Cell25, 219–232 (2007).

  28. 28.

    et al. Phosphorylation of β-catenin by AKT promotes beta-catenin transcriptional activity. J. Biol. Chem.282, 11221–11229 (2007).

Download references

Acknowledgements

This work was supported by National Institute of Health grants 2R01CA109035 (Z.L.), R01GM068566 (X.C.), R01GM56302 (L.C.C.) and CA16672 (Cancer Center Support Grant) and a research grant (RP110252; Z.L.) from the Cancer Prevention and Research Institute of Texas (CPRIT).

Author information

Affiliations

  1. Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Weiwei Yang
    • , Yanhua Zheng
    • , Yan Xia
    • , Haitao Ji
    •  & Zhimin Lu
  2. Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Xiaomin Chen
  3. Nanomedicine Center, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China

    • Fang Guo
  4. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Costas A. Lyssiotis
    •  & Lewis C. Cantley
  5. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Costas A. Lyssiotis
    •  & Lewis C. Cantley
  6. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Kenneth Aldape
  7. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Zhimin Lu
  8. The Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    • Zhimin Lu

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Contributions

This study was conceived by Z.L.; Z.L. and W.Y. designed the study; W.Y., Y.Z., Y.X., H.J. and C.A.L. carried out experiments; K.A. provided pathology assistance; X.C., F.G. and L.C.C. provided reagents and conceptual advice; Z.L. wrote the paper with comments from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Zhimin Lu.

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DOI

https://doi.org/10.1038/ncb2629

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