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 Hormone-Binding Proteins
-
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
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
PIN1 protein, human
-
Peptidylprolyl Isomerase
-
Pin1 protein, mouse