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ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect
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ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect
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Journal Article
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect
2012
Overview
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.
Lu and colleagues delineate a pathway through which the PKM2 enzyme promotes aerobic glycolysis, known as the Warburg effect, in cancer cells. They show that EGFR-activated ERK phosphorylates PKM2, leading to its accumulation in the nucleus. Nuclear PKM2 subsequently promotes the c-Myc-dependent upregulation of genes involved in the Warburg effect, resulting in tumour growth.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Biology
/ Carrier Proteins - metabolism
/ Female
/ Glucose
/ Glucose Transporter Type 1 - genetics
/ Glucose Transporter Type 1 - metabolism
/ Humans
/ Kinases
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Mitogen-Activated Protein Kinase 1 - genetics
/ Mitogen-Activated Protein Kinase 1 - metabolism
/ Mitogen-Activated Protein Kinase 3 - genetics
/ Mitogen-Activated Protein Kinase 3 - metabolism
/ NIMA-Interacting Peptidylprolyl Isomerase
/ Oncology
/ Peptidylprolyl Isomerase - genetics
/ Peptidylprolyl Isomerase - metabolism
/ Protein Transport - genetics
/ Protein Transport - physiology
/ Proteins
/ Thyroid Hormone-Binding Proteins
