ERK1/2-dependent Phosphorylation and Nuclear Translocation of PKM2 Promotes the Warburg Effect

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2012 Nov 27

PMID 23178880

Citations 452

Authors

Weiwei Yang

Yanhua Zheng

Yan Xia

Haitao Ji

Xiaomin Chen

Fang Guo

Costas A Lyssiotis

Kenneth Aldape

Lewis C Cantley

Zhimin Lu

Affiliations

Soon will be listed here.

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.

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