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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 ?5 and translocating to the nucleus. Nuclear PKM2 acts as a coactivator of ?-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.

SUBMITTER: Yang W 

PROVIDER: S-EPMC3511602 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Yang Weiwei W   Zheng Yanhua Y   Xia Yan Y   Ji Haitao H   Chen Xiaomin X   Guo Fang F   Lyssiotis Costas A CA   Aldape Kenneth K   Cantley Lewis C LC   Lu Zhimin Z  

Nature cell biology 20121125 12


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  ...[more]

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