The tumor-specific de2-7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR.
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.
Luwor
Rodney B
RB
Tumour Targeting Program, Ludwig Institute for Cancer Research, Melbourne Branch, Austin Hospital, Heidelberg 3084, Australia.
Zhu
Hong-Jian
HJ
Walker
Francesca
F
Vitali
Angela A
AA
Perera
Rushika M
RM
Burgess
Antony W
AW
Scott
Andrew M
AM
Johns
Terrance G
TG
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D018815:Genes, erbB; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction
D007377:Interleukin-3; D066246:ErbB Receptors