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  Ligand-independent activation of the EGFRvIII: A naturally occurring mutation of the EGFR commonly expressed in glioma [Abstract]

Johns, T. G., Vitali, A. A., Perera, R. M., Vernes, S. C., & Scott, A. M. (2005). Ligand-independent activation of the EGFRvIII: A naturally occurring mutation of the EGFR commonly expressed in glioma [Abstract]. Neuro-Oncology, 7, 299.

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 Creators:
Johns, Terrance G.1, Author
Vitali, Angela A.1, Author
Perera, Rushika M.1, Author
Vernes, Sonja C.1, Author           
Scott, Andrew M.1, Author
Affiliations:
1Institute for Cancer Research, Oncogenic Signalling, Heidelberg, Australia, ou_persistent22              

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 Abstract: 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 at a low level. Transfection of human glioma cells with the de2-7 EGFR has little effect in vitro, but when grown as tumor xenografts this mutated receptor imparts a dramatic growth advantage. We have now mapped the phosphorylation pattern of de2-7 EGFR, both in vivo and in vitro, using a panel of antibodies unique to the different phosphorylated tyrosine residues. Phosphorylation of de2-7 EGFR was detected constitutively at all tyrosine sites surveyed both in vitro and in vivo, including tyrosine 845, a known target in the wild-type EGFR for src kinase. There was a substantial upregulation of phosphorylation at every tyrosine residue of the de2-7 EGFR when cells were grown in vivo compared to the receptor isolated from cells cultured in vitro. Upregulation of phosphorylation could be mimicked in vitro by the addition of specifi c components of the ECM such as collagen via an integrin-dependent mechanism. Since this increase in in vivo phosphorylation enhances de2-7 EGFR signaling, this observation explains why the growth enhancement mediated by de2-7 EGFR is largely restricted to the in vivo environment. In a second set of experiments we analyzed the interaction between EGFRvIII and ErbB2. Co-expression of these proteins in NR6 cells, a mouse fi broblast line devoid of ErbB family members, dramatically enhanced in vivo tumorigenicity of these cells compared to cells expressing either protein alone. Detailed analysis of these xenografts demonstrated that EGFRvIII could heterodimerize and transphosphorylate the ErbB2. Since both EGFRvIII and ErbB2 are commonly expressed at gliomas, this data suggests that the co-expression of these two proteins may enhance glioma tumorigenicity.

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Language(s): eng - English
 Dates: 2005
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1215/S1152851705200388
 Degree: -

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Title: The World Federation of Neuro-Oncology Second Quadrennial Meeting and the Sixth Meeting of the European Association for Neuro-Oncology
Place of Event: Edinburgh, SCOTLAND
Start-/End Date: 2005-05-05 - 2005-05-08

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Title: Neuro-Oncology
Source Genre: Journal
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Publ. Info: Oxford UP
Pages: - Volume / Issue: 7 Sequence Number: - Start / End Page: 299 Identifier: ISSN: 1522-8517
CoNE: https://pure.mpg.de/cone/journals/resource/110985821000943