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MBC in Press, published online ahead of print September 22, 2004
Mol. Biol. Cell 10.1091/mbc.E04-07-0591

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Submitted on July 14, 2004
Revised on September 7, 2004
Accepted on September 8, 2004

Endocytosis and Sorting of ErbB2 and the Site of Action of Cancer Therapeutics Trastuzumab and Geldanamycin

Cary D. Austin,* Ann M. De Mazière,{dagger} Paul I. Pisacane,* Suzanne M. van Dijk,{dagger} Charles Eigenbrot,* Mark X. Sliwkowski,* Judith Klumperman,{dagger} and Richard H. Scheller*{ddagger}

*Genentech, Inc., South San Francisco, CA 94080; {dagger}Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584CX Utrecht, Netherlands

Monitoring Editor: Suzanne Pfeffer

ErbB2 is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. Two models have emerged that account for the high surface distribution of ErbB2. In one model, the surface pool is dynamic and governed by a balance between endocytosis and recycling, while in the other it is retained, static, and excluded from endocytosis. These models have contrasting implications for how ErbB2 exerts its biological function and how cancer therapies might down-regulate surface ErbB2, such as the antibody trastuzumab (Herceptin) or the Hsp90 inhibitor geldanamycin. Little is known however, about how these treatments affect ErbB2 endocytic trafficking. To investigate this issue, we examined breast carcinoma cells by immunofluorescence and quantitative immunoelectron microscopy, and developed imaging and trafficking kinetics assays using cell surface fluorescence quenching. Surprisingly, trastuzumab does not influence ErbB2 distribution but instead recycles passively with internalized ErbB2. By contrast, geldanamycin downregulates surface ErbB2 through improved degradative sorting in endosomes exclusively rather than through increased endocytosis. These results reveal substantial dynamism in the surface ErbB2 pool and clearly demonstrate the significance of endosomal sorting in the maintenance of ErbB2 surface distribution, a critical feature of its biological function.

{ddagger}Corresponding author. E-mail: scheller{at}gene.com






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