Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

A Corrigendum to this article was published on 05 October 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: EGF induces the PKM2–β-catenin interaction in the nucleus.
Figure 2: c-Src phosphorylates β-catenin at Y333 upon EGFR activation.
Figure 3: The PKM2–β-catenin interaction is required for β-catenin-induced cyclin D1 expression.
Figure 4: The PKM2–β-catenin interaction is required for tumour development.

Similar content being viewed by others

Change history

  • 01 December 2011

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

References

  1. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009)

    Article  ADS  CAS  Google Scholar 

  2. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85–95 (2011)

    Article  CAS  Google Scholar 

  3. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011)

    Article  CAS  Google Scholar 

  4. Lu, Z. & Hunter, T. Wnt-independent β-catenin transactivation in tumor development. Cell Cycle 3, 569–571 (2004)

    Article  Google Scholar 

  5. Lu, Z., Jiang, G., Blume-Jensen, P. & Hunter, T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol. Cell. Biol. 21, 4016–4031 (2001)

    Article  CAS  Google Scholar 

  6. Wykosky, J., Fenton, T., Furnari, F. & Cavenee, W. K. Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations. Chin. J. Cancer 30, 5–12 (2011)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  8. Yochum, G. S. et al. Serial analysis of chromatin occupancy identifies β-catenin target genes in colorectal carcinoma cells. Proc. Natl Acad. Sci. USA 104, 3324–3329 (2007)

    Article  ADS  CAS  Google Scholar 

  9. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008)

    Article  ADS  CAS  Google Scholar 

  10. Le Mellay, V. et al. Regulation of glycolysis by Raf protein serine/threonine kinases. Adv. Enzyme Regul. 42, 317–332 (2002)

    Article  CAS  Google Scholar 

  11. Mazurek, S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol. 43, 969–980 (2011)

    Article  CAS  Google Scholar 

  12. Coluccia, A. M. et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 26, 1456–1466 (2007)

    Article  CAS  Google Scholar 

  13. Miravet, S. et al. Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates β-catenin-mediated transcription. Mol. Cell. Biol. 23, 7391–7402 (2003)

    Article  CAS  Google Scholar 

  14. Xia, Y. et al. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol. Cell 25, 219–232 (2007)

    Article  CAS  Google Scholar 

  15. Tetsu, O. & McCormick, F. β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999)

    Article  ADS  CAS  Google Scholar 

  16. Freije, W. A. et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res. 64, 6503–6510 (2004)

    Article  CAS  Google Scholar 

  17. Gravendeel, L. A. et al. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res. 69, 9065–9072 (2009)

    Article  CAS  Google Scholar 

  18. Petalidis, L. P. et al. Improved grading and survival prediction of human astrocytic brain tumors by artificial neural network analysis of gene expression microarray data. Mol. Cancer Ther. 7, 1013–1024 (2008)

    Article  CAS  Google Scholar 

  19. Phillips, H. S. et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006)

    Article  CAS  Google Scholar 

  20. Furnari, F. B. et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21, 2683–2710 (2007)

    Article  CAS  Google Scholar 

  21. Ji, H. et al. EGF-induced ERK activation promotes CK2-mediated disassociation of α-catenin from β-catenin and transactivation of β-catenin. Mol. Cell 36, 547–559 (2009)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Lu, Z., Ghosh, S., Wang, Z. & Hunter, T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion. Cancer Cell 4, 499–515 (2003)

    Article  CAS  Google Scholar 

  24. Luo, W. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Gomez-Manzano, C. et al. Delta-24 increases the expression and activity of topoisomerase I and enhances the antiglioma effect of irinotecan. Clin. Cancer Res. 12, 556–562 (2006)

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Zhimin Lu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-21 with legends, a Supplementary Discussion and Supplementary References. (PDF 8004 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, W., Xia, Y., Ji, H. et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480, 118–122 (2011). https://doi.org/10.1038/nature10598

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10598

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer