Letter | Published:

Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

Nature volume 480, pages 118122 (01 December 2011) | Download Citation

  • A Corrigendum to this article was published on 20 September 2017

This article has been updated

Abstract

The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. In contrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect1,2,3, its non-metabolic functions remain elusive. Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited to the CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation and cyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, β-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces β-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless4 and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.

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Change history

  • 01 December 2011

    A minor text correction was made in paragraph beginning, 'PCR-amplified human PKM1 was cloned into...'.

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Acknowledgements

We thank T. Hunter (The Salk Institute for Biological Studies) for Abl and Src knockout cells, H. Clevers (Netherlands Institute for Developmental Biology) for the pTOP-FLASH and the pFOP-FLASH, and Y. Li (Baylor College of Medicine) for a WNT1 lenti-vector. This work was supported by National Cancer Institute grants 5R01CA109035 (Z.L.), 5 P50 CA127001-03 and CA16672 (Cancer Center Support Grant); a research grant (RP110252; Z.L.) from the Cancer Prevention and Research Institute of Texas (CPRIT), an American Cancer Society Research Scholar Award RSG-09-277-01-CSM (Z.L.), and a Sister Institution Network Fund from The University of Texas MD Anderson Cancer Center (Z.L.).

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
    • , Yan Xia
    • , Haitao Ji
    • , Yanhua Zheng
    • , Ji Liang
    •  & Zhimin Lu
  2. Jiaxing Xinda Biotechnology Company, 1369 Cheng Nan Road, Science and Technology Building, STE 112, Jiaxing, Zhejiang Province 314000, China

    • Wenhua Huang
  3. Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210061, China

    • Xiang Gao
  4. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

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

    • Zhimin Lu
  6. 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.X., H.J., Y.Z. and J.L. performed experiments; K.A. provided pathology assistance; W.H. and X.G. 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/nature10598

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