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First published online 2 September 2008
doi: 10.1242/jcs.020404


Journal of Cell Science 121, 3155-3166 (2008)
Published by The Company of Biologists 2008
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Research Article

Clathrin-independent endocytosis of ErbB2 in geldanamycin-treated human breast cancer cells

Daniel J. Barr, Anne G. Ostermeyer-Fay, Rachel A. Matundan and Deborah A. Brown*

Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA

* Author for correspondence (e-mail: deborah.brown{at}sunysb.edu)

Accepted 25 June 2008

The epidermal growth factor (EGF)-receptor family member ErbB2 is commonly overexpressed in human breast cancer cells and correlates with poor prognosis. Geldanamycin (GA) induces the ubiquitylation, intracellular accumulation and degradation of ErbB2. Whether GA stimulates ErbB2 internalization is controversial. We found that ErbB2 was internalized constitutively at a rate that was not affected by GA in SK-BR-3 breast cancer cells. Instead, GA treatment altered endosomal sorting, causing the transport of ErbB2 to lysosomes for degradation. In contrast to earlier work, we found that ErbB2 internalization occurred by a clathrin- and tyrosine-kinase-independent pathway that was not caveolar, because SK-BR-3 cells lack caveolae. Similar to cargo of the glycosylphosphatidylinositol (GPI)-anchored protein-enriched early endosomal compartment (GEEC) pathway, internalized ErbB2 colocalized with cholera toxin B subunit, GPI-anchored proteins and fluid, and was often seen in short tubules or large vesicles. However, in contrast to the GEEC pathway in other cells, internalization of ErbB2 and fluid in SK-BR-3 cells did not require Rho-family GTPase activity. Accumulation of ErbB2 in vesicles containing constitutively active Arf6-Q67L occurred only without GA treatment; Arf6-Q67L did not slow transport to lysosomes in GA-treated cells. Further characterization of this novel clathrin-, caveolae- and Rho-family-independent endocytic pathway might reveal new strategies for the downregulation of ErbB2 in breast cancer.

Key words: Non-clathrin endocytosis, Membrane traffic, Receptor tyrosine kinase, Receptor downregulation, Arf6, Rho-family GTPase, HER2


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P. Bhagatji, R. Leventis, J. Comeau, M. Refaei, and J. R. Silvius
Steric and not structure-specific factors dictate the endocytic mechanism of glycosylphosphatidylinositol-anchored proteins
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[Abstract] [Full Text] [PDF]




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