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Geldanamycin stimulates internalization of ErbB2 in a proteasome-dependent way

Mads Lerdrup1, Anette M Hommelgaard, Michael Grandal

  • 1Structural Cell Biology Unit, Department of Medical Anatomy, The Panum Institute, Blegdamsvej 3C, University of Copenhagen, 2200 Copenhagen, Denmark.

Journal of Cell Science
|December 15, 2005
PubMed

Insights

Geldanamycin, an HSP-90 inhibitor, triggers the internalization and lysosomal degradation of the oncoprotein ErbB2. This process involves proteasomal activity and increases ErbB2 mobility in the cell membrane.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • The oncoprotein and receptor tyrosine kinase ErbB2 is known for its resistance to downregulation.
  • HSP-90 inhibitor geldanamycin can downregulate ErbB2, but the precise cellular mechanisms remain unclear.
  • Previous hypotheses suggested lysosomal delivery, ErbB2 kinase domain cleavage, and proteasomal activity are involved.

Purpose of the Study:

  • To elucidate the cellular mechanisms by which geldanamycin induces ErbB2 downregulation.
  • To investigate the role of proteasomal activity and ErbB2 internalization in geldanamycin-mediated degradation.
  • To determine if ErbB2 kinase domain cleavage is necessary for internalization.

Main Methods:

  • Utilized a non-invasive confocal microscopy assay for quantitative analysis of ErbB2 internalization.
  • Employed fluorescence recovery after photobleaching (FRAP) and electron microscopy.
  • Quantified ErbB2 internalization, mobility, and plasma membrane redistribution.

Main Results:

  • Geldanamycin treatment stimulates ErbB2 internalization and subsequent lysosomal degradation in SK-BR-3 cells.
  • Proteasomal activity is essential for ErbB2 internalization, acting as a regulatory upstream event.
  • ErbB2 is internalized as a full-length protein, indicating kinase domain cleavage is not required.
  • Geldanamycin increases ErbB2 mobility and redistributes it in the plasma membrane, enhancing endocytosis accessibility.

Conclusions:

  • Geldanamycin promotes the internalization of full-length ErbB2 in a proteasome-dependent manner.
  • Internalized ErbB2 is subsequently degraded in lysosomes.
  • Geldanamycin enhances ErbB2 endocytosis by increasing its plasma membrane mobility and accessibility.

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