title: 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 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.
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D013963:Thyroid Hormones; D051176:beta Catenin; D000097810:Thyroid Hormone-Binding Proteins; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse