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ERBB2 is a target for USP8-mediated deubiquitination

Inez M J Meijer1, Jeroen E M van Leeuwen

  • 1Department of Cell & Applied Biology, Faculty of Science, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Cellular Signalling
|November 4, 2010
PubMed

Insights

The study reveals that Usp8 deubiquitinase is involved in the endosomal trafficking of the ErbB2 receptor. This finding clarifies the regulation of ErbB2 signaling pathways in cancer.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • ErbB receptor tyrosine kinases, including EGFR and ErbB2, are crucial in cell signaling and implicated in tumorigenesis when dysregulated.
  • EGFR signaling attenuation involves endocytosis and ubiquitination by the E3-ligase Cbl, followed by deubiquitination by Usp8 en route to lysosomes.
  • ErbB2 exhibits enhanced recycling, leading to the hypothesis that Usp8 might not be involved in its trafficking pathway.

Purpose of the Study:

  • To investigate the role of Usp8 in the endosomal trafficking pathway of the ErbB2 receptor.
  • To elucidate the mechanisms of Usp8 interaction with EGFR-ErbB2 chimeric receptors.

Main Methods:

  • Utilized a chimeric EGFR-ErbB2 receptor system to study receptor trafficking and ubiquitination.
  • Employed techniques to assess EGF-induced polyubiquitination, tyrosine phosphorylation of Cbl and Usp8, and the impact of Usp8 mutants on EGFR-ErbB2 ubiquitination.

Main Results:

  • EGF stimulation induced K63-polyubiquitination of the EGFR-ErbB2 chimeric receptor, dependent on the Cbl binding site.
  • EGF stimulation also led to tyrosine phosphorylation of Usp8, which was dependent on Src and EGFR-ErbB2 kinase activity.
  • Coexpression of catalytically inactive Usp8 enhanced EGFR-ErbB2 ubiquitination, indicating Usp8's role in deubiquitination within the ErbB2 pathway.

Conclusions:

  • Usp8 is demonstrated to be part of the ErbB2 endosomal trafficking pathway.
  • Usp8 deubiquitinates EGFR-ErbB2, influencing its trafficking and signaling.
  • These findings contribute to understanding the regulation of ErbB receptor signaling in cancer.

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