EGFR-Induced and PKCε Monoubiquitylation-Dependent NF-κB Activation Upregulates PKM2 Expression and Promotes Tumorigenesis

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 PLC gamma 1-dependent PKC epsilon monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKC epsilon interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKC epsilon phosphorylates IKK beta at Ser177 and activates IKK beta. Activated RelA interacts with HIF1 alpha, which is required for RelA to bind the PKM promoter. PKC epsilon- and NF-kappa B-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKK beta activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-kappa B by EGF, in contrast to TNF-alpha, and the importance of the metabolic cooperation between the EGFR and NF-kappa B pathways in PKM2 upregulation and tumorigenesis.