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Endocytic down-regulation of ErbB2 is stimulated by cleavage of its C-terminus

Mads Lerdrup1, Silas Bruun, Michael V Grandal

  • 1Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, DK-2200 Copenhagen N, Denmark.

Molecular Biology of the Cell
|July 13, 2007
PubMed

Insights

High ErbB2 levels in cancer may stem from impaired endocytosis. This study reveals geldanamycin induces ErbB2 C-terminal cleavage, promoting its endocytosis and lysosomal degradation, offering insights into ErbB2 down-regulation.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Protein Trafficking

Background:

  • Elevated ErbB2 levels are linked to various cancers.
  • Impaired endocytosis of ErbB2 may contribute to its overexpression.
  • Understanding ErbB2 endocytic regulation is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the link between ErbB2 C-terminal cleavage and its endocytosis.
  • To elucidate the mechanisms of ErbB2 down-regulation.

Main Methods:

  • Utilized Förster Resonance Energy Transfer (FRET) by fusing yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) to ErbB2 (YFP-ErbB2-CFP).
  • Stimulated cells with geldanamycin to inhibit HSP90.
  • Analyzed ErbB2 cleavage, localization, and degradation pathways using proteasome and lysosome inhibitors.

Main Results:

  • Geldanamycin induced proteasome-dependent cleavage of YFP-ErbB2-CFP in nonapoptotic cells.
  • Cleavage occurred at the plasma membrane, with cleaved ErbB2 rapidly internalized to early endosomes.
  • Cleaved ErbB2 and C-terminally truncated ErbB2 were more efficiently endocytosed and degraded than full-length ErbB2.

Conclusions:

  • Geldanamycin treatment triggers ErbB2 C-terminal cleavage.
  • This cleavage releases ErbB2 from a retention mechanism, promoting its endocytosis and subsequent lysosomal degradation.
  • The findings provide a novel mechanism for ErbB2 down-regulation relevant to cancer biology.

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