EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis

Mol Cell. 2012 Dec 14;48(5):771-84. doi: 10.1016/j.molcel.2012.09.028. Epub 2012 Nov 1.

Abstract

Many types of human tumor cells have overexpressed pyruvate kinase M2 (PKM2). However, the mechanism underlying this increased PKM2 expression remains to be defined. We demonstrate here that EGFR activation induces PLCγ1-dependent PKCε monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKCε interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCε phosphorylates IKKβ at Ser177 and activates IKKβ. Activated RelA interacts with HIF1α, which is required for RelA to bind the PKM promoter. PKCε- and NF-κB-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKKβ activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-κB by EGF, in contrast to TNF-α, and the importance of the metabolic cooperation between the EGFR and NF-κB pathways in PKM2 upregulation and tumorigenesis.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Glucose / metabolism
  • Glycolysis
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • I-kappa B Kinase / metabolism
  • Lactic Acid / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Mutagenesis, Site-Directed
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Grading
  • Neoplasm Transplantation
  • Phospholipase C gamma / metabolism
  • Phosphorylation
  • Polypyrimidine Tract-Binding Protein / metabolism
  • Prognosis
  • Promoter Regions, Genetic
  • Protein Kinase C-epsilon / genetics
  • Protein Kinase C-epsilon / metabolism*
  • RNA Interference
  • Serine
  • Signal Transduction
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Transcription Factor RelA / metabolism
  • Transfection
  • Ubiquitination
  • Up-Regulation

Substances

  • Carrier Proteins
  • HIF1A protein, human
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IKBKG protein, human
  • Membrane Proteins
  • NF-kappa B
  • PTBP1 protein, human
  • RELA protein, human
  • Thyroid Hormones
  • Transcription Factor RelA
  • Polypyrimidine Tract-Binding Protein
  • Lactic Acid
  • Serine
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • I-kappa B Kinase
  • IKBKB protein, human
  • PRKCE protein, human
  • Protein Kinase C-epsilon
  • PLCG1 protein, human
  • Phospholipase C gamma
  • Glucose