The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments

Cortese, Katia, Howes, Mark T., Lundmark, Richard, Tagliatti, Erica, Bagnato, Paola, Petrelli, Annalisa, Bono, Maria, McMahon, Harvey T., Parton, Robert G. and Tacchetti, Carlo (2013) The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments. Molecular Biology of the Cell, 24 2: 129-144. doi:10.1091/mbc.E12-04-0282

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Author Cortese, Katia
Howes, Mark T.
Lundmark, Richard
Tagliatti, Erica
Bagnato, Paola
Petrelli, Annalisa
Bono, Maria
McMahon, Harvey T.
Parton, Robert G.
Tacchetti, Carlo
Title The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartments
Journal name Molecular Biology of the Cell   Check publisher's open access policy
ISSN 1059-1524
1939-4586
Publication date 2013-01-15
Year available 2012
Sub-type Article (original research)
DOI 10.1091/mbc.E12-04-0282
Open Access Status File (Publisher version)
Volume 24
Issue 2
Start page 129
End page 144
Total pages 16
Place of publication Bethesda, MD, United States
Publisher American Society for Cell Biology
Collection year 2013
Language eng
Formatted abstract
The ErbB2 receptor is a clinically validated cancer target whose internalization and trafficking mechanisms remain poorly understood. HSP90 inhibitors, such as geldanamycin (GA), have been developed to target the receptor to degradation or to modulate downstream signaling. Despite intense investigations, the entry route and postendocytic sorting of ErbB2 upon GA stimulation have remained controversial. We report that ErbB2 levels inversely impact cell clathrin-mediated endocytosis (CME) capacity. Indeed, the high levels of the receptor are responsible for its own low internalization rate. GA treatment does not directly modulate ErbB2 CME rate but it affects ErbB2 recycling fate, routing the receptor to modified multivesicular endosomes (MVBs) and lysosomal compartments, by perturbing early/recycling endosome structure and sorting capacity. This activity occurs irrespective of the cargo interaction with HSP90, as both ErbB2 and the constitutively recycled, HSP90-independent, transferrin receptor are found within modified endosomes, and within aberrant, elongated recycling tubules, leading to modified MVBs/lysosomes. We propose that GA, as part of its anticancer activity, perturbs early/recycling endosome sorting, routing recycling cargoes toward mixed endosomal compartments.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print 14 November 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
Centre for Microscopy and Microanalysis Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 21 Jan 2013, 14:23:38 EST by Susan Allen on behalf of Institute for Molecular Bioscience