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Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase

Zhongwei Cao1, Xiuli Wu, Lily Yen

  • 1UC Davis Cancer Center, Sacramento, CA 95817, USA.

Molecular and Cellular Biology
|January 11, 2007
PubMed

Insights

Neuregulin-1 (NRG1) stabilizes ErbB3 receptor levels by stabilizing USP8 and Nrdp1, which mediate ErbB3 ubiquitination and degradation. This study reveals a novel protein stability cascade in receptor tyrosine kinase regulation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Epidermal Growth Factor (EGF) receptor tyrosine kinase down-regulation involves cbl-mediated ubiquitination and lysosomal degradation.
  • Mechanisms for ligand-stimulated degradation of related ErbB family receptor tyrosine kinases, excluding cbl, remain largely unexplored.
  • The E3 ubiquitin ligase Nrdp1 mediates growth factor-independent degradation, maintaining steady-state ErbB3 levels.

Purpose of the Study:

  • To elucidate the mechanisms of ErbB3 receptor tyrosine kinase down-regulation following neuregulin-1 (NRG1) stimulation.
  • To investigate the role of USP8 and Nrdp1 in NRG1-induced ErbB3 degradation.
  • To identify upstream regulators of Nrdp1 stability in response to NRG1.

Main Methods:

  • Cellular treatments with NRG1.
  • Analysis of protein stability and ubiquitination.
  • Knockdown experiments using Nrdp1 or USP8.
  • Phosphorylation site analysis of USP8.

Main Results:

  • NRG1 treatment stabilizes the deubiquitinating enzyme USP8, which in turn stabilizes Nrdp1.
  • USP8 catalytic activity is essential for NRG1-induced Nrdp1 stabilization.
  • Akt-mediated phosphorylation of USP8 at T907 enhances USP8 stability.
  • Nrdp1 or USP8 knockdown inhibits NRG1-induced ErbB3 ubiquitination and degradation in MCF7 cells.

Conclusions:

  • A novel NRG1-induced protein stability cascade involving USP8 and Nrdp1 mediates ErbB3 down-regulation.
  • Ligand-induced stabilization of pathways maintaining basal receptor tyrosine kinase levels can contribute to ligand-stimulated down-regulation.
  • This pathway offers potential therapeutic targets for diseases involving ErbB3 signaling.

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