LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

M. A. Stutz, D. L. Shattuck, M. B. Laederich, Kermit L Carraway, Colleen A Sweeney

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5741-5752
Number of pages12
JournalOncogene
Volume27
Issue number43
DOIs
StatePublished - Sep 25 2008

Fingerprint

Epidermal Growth Factor Receptor
Glioblastoma
epidermal growth factor receptor VIII
Neoplasms
Ligases
Ubiquitin
RNA Interference
Lysosomes
Brain Neoplasms
Exons
Cell Survival
Carcinogenesis
Down-Regulation
Cell Proliferation

Keywords

  • EGFRvIII
  • Glioblastoma
  • LRIG1
  • Negative regulator

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. / Stutz, M. A.; Shattuck, D. L.; Laederich, M. B.; Carraway, Kermit L; Sweeney, Colleen A.

In: Oncogene, Vol. 27, No. 43, 25.09.2008, p. 5741-5752.

Research output: Contribution to journalArticle

Stutz, M. A. ; Shattuck, D. L. ; Laederich, M. B. ; Carraway, Kermit L ; Sweeney, Colleen A. / LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. In: Oncogene. 2008 ; Vol. 27, No. 43. pp. 5741-5752.
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