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

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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Yang W,Zheng Y,Xia Y,Ji H,Chen X,Guo F,Lyssiotis CA,Aldape K,Cantley LC,Lu Z

doi

10.1038/ncb2629

subject

Has Abstract

pub_date

2012-12-01 00:00:00

pages

1295-304

issue

12

eissn

1465-7392

issn

1476-4679

pii

ncb2629

journal_volume

14

pub_type

杂志文章

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