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EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

Oncogene volume 25, pages 6497–6509 (2006)Cite this article

Abstract

The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2–7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The overexpression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFRvIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

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Acknowledgements

We thank Marion M Nau for helpful discussion and critical review of the manuscript. We thank Jeremy Karlin for helpful discussion and for help with quantitation of the immunoblots. Also, we thank Valarie A Barr for help with the confocal microscopy. Philip E Ryan is a graduate student in the Genetics Program of the George Washington University Institute of Biomedical Sciences. The work presented here is in partial fulfillment for the degree of PhD. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    G C Davies, P E Ryan & S Lipkowitz

  2. George Washington University Institute of Biomedical Sciences, Washington, DC, USA

    P E Ryan

  3. Molecular Therapeutics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    L Rahman & M Zajac-Kaye

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  1. G C Davies
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Correspondence to S Lipkowitz.

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Davies, G., Ryan, P., Rahman, L. et al. EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins. Oncogene 25, 6497–6509 (2006). https://doi.org/10.1038/sj.onc.1209662

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