title: Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism.
abstract: A common mutation of the epidermal growth factor receptor in glioma is the de2-7EGFR (or EGFRvIII). Glioma cells expressing de2-7EGFR contain an intracellular pool of receptor with high levels of mannose glycosylation, which is consistent with delayed processing. We now show that this delay occurs in the Golgi complex. Low levels of de2-7EGFR were also seen within the mitochondria. Src activation dramatically increased the amount of mitochondrial de2-7EGFR, whereas its pharmacological inhibition caused a significant reduction. Because de2-7EGFR is phosphorylated by Src at Y845, we generated glioma cells expressing a Y845F-modified de2-7EGFR. The de2-7EGFR(845F) mutant failed to show mitochondrial localisation, even when co-expressed with constitutive active Src. Low levels of glucose enhanced mitochondrial localisation of de2-7EGFR, and glioma cells expressing the receptor showed increased survival and proliferation under these conditions. Consistent with this, de2-7EGFR reduced glucose dependency by stimulating mitochondrial oxidative metabolism. Thus, the mitochondrial localisation of de2-7EGFR contributes to its tumorigenicity and might help to explain its resistance to some EGFR-targeted therapeutics.
authors: Tumour Targeting Program, Ludwig Institute for Cancer Research, Heidelberg, Victoria 3084, Australia.
authors: Anna N
authors: AN
authors: Cvrljevic
authors: David
authors: D
authors: Akhavan
authors: Min
authors: M
authors: Wu
authors: Paul
authors: P
authors: Martinello
authors: Frank B
authors: FB
authors: Furnari
authors: Amelia J
authors: AJ
authors: Johnston
authors: Deliang
authors: D
authors: Guo
authors: Lisa
authors: L
authors: Pike
authors: Webster K
authors: WK
authors: Cavenee
authors: Andrew M
authors: AM
authors: Scott
authors: Paul S
authors: PS
authors: Mischel
authors: Nick J
authors: NJ
authors: Hoogenraad
authors: Terrance G
authors: TG
authors: Johns
mesh_terms: D045744:Cell Line, Tumor; D000069439:Dasatinib; D004721:Endoplasmic Reticulum / Q000201:enzymology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010101:Oxygen Consumption; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D019061:src-Family Kinases; D005947:Glucose; D000069439:Dasatinib