title: EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis.
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.
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.forename: Wen
authors.initials: W
authors.lastname: Bu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.forename: Mei Yee
authors.initials: MY
authors.lastname: Koh
authors.forename: Gilbert
authors.initials: G
authors.lastname: Cote
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D057809:HEK293 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D054875:Ubiquitination; D015854:Up-Regulation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005947:Glucose; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051550:I-kappa B Kinase; D019344:Lactic Acid; D008565:Membrane Proteins; D016328:NF-kappa B; D051966:Phospholipase C gamma; D038941:Polypyrimidine Tract-Binding Protein; D051744:Protein Kinase C-epsilon; D012694:Serine; D013963:Thyroid Hormones; D051996:Transcription Factor RelA; D000097810:Thyroid Hormone-Binding Proteins; C497442:HIF1A protein, human; C491731:IKBKG protein, human; C450006:PTBP1 protein, human; C498143:RELA protein, human; C512478:EGFR protein, human; C496560:IKBKB protein, human; C497255:PRKCE protein, human; C522157:PLCG1 protein, human