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

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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Figure 1: ERK is required for PKM2 nucleus translocation.
Figure 2: ERK2 phosphorylates PKM2 Ser 37.
Figure 3: PKM2 Ser 37 phosphorylation recruits PIN1.
Figure 4: PIN1 regulates binding of PKM2 to importin α5.
Figure 5: Nuclear PKM2 regulates glycolytic gene expression.
Figure 6: Nuclear PKM2 is required for the Warburg effect.
Figure 7: Levels of PKM2 Ser 37 phosphorylation correlate with EGFR and ERK1/2 activity in human GBM specimens.

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.

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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).

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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.

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Correspondence to Zhimin Lu.

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Yang, W., Zheng, Y., Xia, Y. et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14, 1295–1304 (2012). https://doi.org/10.1038/ncb2629

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