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

Autor: Carlo Tacchetti, Annalisa Petrelli, Richard Lundmark, Erica Tagliatti, Robert G. Parton, Maria Bono, Paola Bagnato, Mark T. Howes, Harvey T. McMahon, Katia Cortese
Přispěvatelé: K., Cortese, M. T., Howe, R., Lundmark, E., Tagliatti, P., Bagnato, A., Petrelli, M., Bono, H. T., Mcmahon, R. G., Parton, Tacchetti, Carlo
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Electron Microscope Tomography
Receptor
ErbB-2
Cell- och molekylärbiologi
CLATHRIN-INDEPENDENT ENDOCYTOSIS
RECEPTOR TYROSINE KINASES
INDUCED DOWN-REGULATION
MEMBRANE MICRODOMAINS
MEDIATED ENDOCYTOSIS
PLASMA-MEMBRANE
PROTEIN GRAF1
CELL MOTILITY
CANCER
DEGRADATION
Hsp90 inhibitor
Cancro
chemistry.chemical_compound
Mice
Chlorocebus aethiops
Benzoquinones
Internalization
media_common
biology
Multivesicular Bodies
Transferrin
Clathrin-Coated Vesicles
Articles
Geldanamycin
Hsp90
Endocytosis
Cell biology
Protein Transport
COS Cells
Single-Cell Analysis
Dynamins
Endosome
media_common.quotation_subject
Lactams
Macrocyclic
education
Transferrin receptor
Antineoplastic Agents
Clathrin
Cell Line
Tumor
Animals
Humans
HSP90 Heat-Shock Proteins
Molecular Biology
Cell Biology
chemistry
Microscopy
Fluorescence
Membrane Trafficking
biology.protein
Lysosomes
Cell and Molecular Biology
Zdroj: Molecular Biology of the Cell
Popis: The ErbB2 receptor is a validated cancer target whose internalization and trafficking remain poorly understood. The authors propose that ErbB2 internalization upon geldanamycin (GA) occurs predominantly via clathrin-mediated endocytosis and that GA affects endosomal structure and sorting, forcing recycling cargoes toward mixed endo/lysosomal compartments, irrespective of their HSP90 interaction.
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.
Databáze: OpenAIRE
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