| First Author | Yang W | Year | 2012 |
| Journal | Nat Cell Biol | Volume | 14 |
| Issue | 12 | Pages | 1295-304 |
| PubMed ID | 23178880 | Mgi Jnum | J:195243 |
| Mgi Id | MGI:5476901 | Doi | 10.1038/ncb2629 |
| Citation | Yang W, et al. (2012) ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14(12):1295-304 |
| abstractText | 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 alpha5 and translocating to the nucleus. Nuclear PKM2 acts as a coactivator of beta-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. |
