The tumor-specific de2-7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR

• Published in: Oncogene Vol. 23; no. 36; pp. 6095 - 6104
• Main Authors: LUWOR, Rodney B, ZHU, Hong-Jian, WALKER, Francesca, VITALI, Angela A, PERERA, Rushika M, BURGESS, Antony W, SCOTT, Andrew M, JOHNS, Terrance G
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 12.08.2004; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Amino acids; Animals; Apoptosis; Biological and medical sciences; Brain tumors; Cancer research; Cell Cycle; Cell Division; Cell Line; Cell physiology; Cell proliferation; Cell receptors; Cell structures and functions; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Dimerization; Epidermal growth factor; Epidermal growth factor receptors; Exons; Fundamental and applied biological sciences. Psychology; Gene deletion; Genes, erbB; Glioma; Glioma cells; Interleukin 3; Interleukin-3 - pharmacology; Kinases; Ligands; Lymphocytes B; Medical prognosis; Medical research; Mice; Miscellaneous; Molecular and cellular biology; Mutation; Neoplasms - genetics; Phosphorylation; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Sequence Deletion; Signal Transduction; Tumors; Australia; Nervous system diseases; Enzyme; Transferases; epidermal growth factor receptor; Carcinogenesis; Survival; cell survial; 1-Phosphatidylinositol 3-kinase; Epidermal growth factor; Glioma; Central nervous system disease; Tumor; Mutation; Dimerization; Biological receptor; phosphatidylinositol 3-kinase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207870

Mutations of the epidermal growth factor receptor (EGFR) gene are found at a relatively high frequency in glioma, with the most common being the de2-7 EGFR (or EGFRvIII). This mutation arises from an in-frame deletion of exons 2-7, which removes 267 amino acids from the extracellular domain of the receptor. Despite being unable to bind ligand, the de2-7 EGFR is constitutively active and imparts a significant in vivo growth advantage to glioma cells. In order to examine the signalling pathways activated by the de2-7 EGFR and its biological effects in an in vitro system, the de2-7 EGFR gene was transfected into the murine IL-3-dependent pro-B-cell line BaF/3. Expression of the de2-7 EGFR enhanced the survival of BaF/3 cells in the absence of IL-3 by reducing apoptosis in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. Interestingly, while de2-7 EGFR also enhanced proliferation of BaF/3 cells in low levels of IL-3, this effect was independent of PI3-K. Survival and proliferation were further enhanced when BaF/3 cells were cotransfected with the de2-7 and wt EGFR. This was due to heterodimerization between the de2-7 and wt EGFR leading to trans-phosphorylation of the wt EGFR. This observation is directly relevant to glioma where de2-7 and wt EGFR appear to be coexpressed. Thus, expression of de2-7 EGFR in BaF/3 cells provides an in vitro model for evaluating the signalling pathways activated by this receptor.