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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


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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  • 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.


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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


  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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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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