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LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

Abstract

Epidermal growth factor receptor (EGFR) mutation is frequently observed in human cancer and contributes to the growth, survival and therapeutic resistance of tumors. EGFRvIII is an oncogenic EGFR mutant resulting from the deletion of exons 2–7 and is the most common EGFR mutant observed in glioblastoma multiforme, an aggressive brain tumor. EGFRvIII is constitutively active but poorly ubiquitinated, leading to inefficient receptor trafficking to lysosomes and unattenuated oncogenic signaling. The mechanism by which EGFRvIII evades downregulation is not fully understood although recent studies suggest that its interaction with the ubiquitin ligase Cbl may be compromised. In this study, we examine the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain. Here, we determine whether the extracellular domain deletion in EGFRvIII renders it refractory to LRIG1 regulation. We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. We demonstrate that LRIG1 regulation of EGFRvIII is distinct from the only other known mechanism of EGFR regulation, Cbl-mediated degradation. Ectopic expression of LRIG1 in EGFRvIII(+) glioblastoma cells opposes EGFRvIII-driven tumor cell proliferation, survival, motility and invasion. Finally, RNAi-mediated silencing of LRIG1 alters EGFRvIII intracellular trafficking and leads to enhanced EGFRvIII expression, suggesting that loss of LRIG1 in tumors may contribute to a permissive environment for EGFRvIII overexpression, contributing to EGFRvIII oncogenesis.

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Acknowledgements

We thank Dr Webster Cavenee from the Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California for the U87MG parental and EGFRvIII expressing glioblastoma cells. We thank Dr Laurel Beckett, Chief of the Division of Biostatistics at UC Davis School of Medicine, for statistical consultation. We thank Carol Oxford, Manager of the UC Davis Optical Biology Core, for her assistance in the flow cytometry experiments. This work was supported by NIH grants CA118384 (CS) and GM068994 (KLC). DLS is a recipient of a DOD BCRP predoctoral fellowship Award no. W81XWH-06-1-0772.

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Correspondence to C Sweeney.

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Stutz, M., Shattuck, D., Laederich, M. et al. LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene 27, 5741–5752 (2008). https://doi.org/10.1038/onc.2008.185

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  • DOI: https://doi.org/10.1038/onc.2008.185

Keywords

  • EGFRvIII
  • LRIG1
  • negative regulator
  • glioblastoma

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