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 cis-trans 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.
Original language | English (US) |
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Pages (from-to) | 1295-1304 |
Number of pages | 10 |
Journal | Nature cell biology |
Volume | 14 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2012 |
ASJC Scopus subject areas
- Cell Biology
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