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

Nat Cell Biol. 2012 Dec;14(12):1295-304. doi: 10.1038/ncb2629. Epub 2012 Nov 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Female
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Immunoprecipitation
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • 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
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Carrier Proteins
  • Glucose Transporter Type 1
  • Membrane Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Thyroid Hormones
  • beta Catenin
  • thyroid hormone-binding proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse