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Vol. 15, Issue 12, 5268-5282, December 2004
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* Genentech, Inc., South San Francisco, CA 94080;
Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands
Submitted July 14, 2004;
Revised September 7, 2004;
Accepted September 8, 2004
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, whereas 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 down-regulates 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.
Abbreviations used: 488-, Alexa-488–conjugated; 547-, Alexa-594–conjugated; 647-, Alexa-647–conjugated; ErbB2-ECD, recombinant ErbB2 extracellular domain; GA, geldanamycin; MVB, multivesicular endosomal bodies; NG, 1-nm Nanogold; Tf, transferrin; TfR, transferrin receptor; TR-EGF, Texas Red–conjugated EGF.
Note Added in Proof. While this manuscript was under review, an article by Nagata et al. (2004. Cancer Cell 6, 117–127) was published suggesting that rapid activation of the lipid phosphatase PTEN may underlie the mechanism of action of trastuzumab. Their findings are consistent with our conclusions and provide an alternative explanation for the mechanism of action of trastuuzumab.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Corresponding author. E-mail address: scheller{at}gene.com.
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