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EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

G C Davies1, P E Ryan, L Rahman

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.

Oncogene
|May 17, 2006
PubMed

Insights

Cbl proteins ubiquitinate and degrade the cancer-driving EGFRvIII mutant. This EGFRvIII downregulation by Cbl proteins is crucial for the effectiveness of anti-EGFRvIII immunotoxins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tyrosine kinases (TKs), like EGFR, are implicated in cancer development when overexpressed or mutated.
  • EGFRvIII, a common EGFR mutation in glioblastomas, is constitutively active and drives cancer.
  • Cbl ubiquitin ligases target activated EGFR for degradation.

Purpose of the Study:

  • To investigate the role of Cbl proteins in downregulating the transforming EGFRvIII.
  • To determine if EGFRvIII transforms by evading Cbl-mediated regulation.

Main Methods:

  • Overexpression of Cbl proteins (Cbl, Cbl-b, Cbl-c) in cells expressing EGFRvIII.
  • Analysis of EGFRvIII ubiquitination and degradation.
  • Assessing the effect of Cbl-b domains and EGFRvIII mutations on EGFRvIII activity.
  • Treatment with EGFR TK inhibitor AG 1478 and anti-EGFRvIII immunotoxins.

Main Results:

  • All three Cbl proteins induced EGFRvIII ubiquitination and degradation.
  • Cbl-b's TK-binding domain and RING finger were sufficient for EGFRvIII downregulation.
  • EGFRvIII transformation was inhibited by Cbl-b, but a Y1045F mutation abolished this effect.
  • EGFR TK inhibitor AG 1478 blocked Cbl-mediated EGFRvIII downregulation and immunotoxin efficacy.

Conclusions:

  • EGFRvIII transformation is not due to escape from Cbl regulation.
  • Activation-induced downregulation of EGFRvIII by Cbl proteins is essential for anti-EGFRvIII immunotoxin activity.

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