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ID: 16908.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2
Authors:Nagy, P.; Vereb, G.; Sebestyen, Z.; Horvath, G.; Lockett, S. J.; Damjanovich, S.; Park, J. W.; Jovin, T. M.; Szoelloesi, J.
Date of Publication (YYYY-MM-DD):2002-11-15
Title of Journal:Journal of Cell Science
Issue / Number:22
Start Page:4251
End Page:4262
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:The ErbB family of transmembrane receptor tyrosine kinases plays an important role in the pathogenesis of many cancers. The four members of the family, ErbB1-4, form various homo- and heterodimers during the course of signal transduction. A second hierarchical level of molecular associations involving 10(2)- 10(3) molecules, termed large-scale clustering, has also been identified, but the regulatory factors and biological consequences of such structures have not been systematically evaluated. In this report, we describe the states of association of ErbB2 and their relationship to local ErbB3 density and lipid rafts based on quantitative fluorescence microscopy of SKBR-3 breast cancer cells. Clusters of ErbB2 colocalized with lipid rafts identified by the GM1-binding B subunit of cholera toxin. Pixel-by-pixel analysis of fluorescence resonance energy transfer between labeled antibodies indicated that the homoassociation (homodimerization) of ErbB2 was proportional to the local density of ErbB2 and inversely proportional to that of ErbB3 and of the raft-specific lipid GM1. Crosslinking lipid rafts with the B subunit of cholera toxin caused dissociation of the rafts and ErbB2 clusters, an effect that was independent of the cytoskeletal anchoring of ErbB2. Crosslinking also decreased ErbB2-ErbB3 heteroassociation and the EGF- and heregulin- induced tyrosine phosphorylation of Shc. When cells were treated with the anti-ErbB2 monoclonal antibody 4D5 (parent murine version of Trastuzumab used in the immunotherapy of breast cancer), internalization of the antibody was inhibited by crosslinking of lipid rafts, but the antiproliferative activity of 4D5 was retained and even enhanced. We conclude that local densities of ErbB2 and ErbB3, as well as the lipid environment profoundly influence the association properties and biological function of ErbB2.
Free Keywords:ErbB proteins; lipid rafts; breast cancer; fluorescence resonance energy transfer
Comment of the Author/Creator:Date: 2002, NOV 15
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
External Affiliations:Debrecen Univ Med, Med & Hlth Sci Ctr, Dept Biophys & Cell; Biol, POB 39, H-4012 Debrecen, Hungary; Debrecen Univ Med, Med & Hlth Sci Ctr, Dept Biophys & Cell Biol, H-4012 Debrecen, Hungary; Debrecen Univ Med, Hungarian Acad Sci, Cell Biophys Workgrp, H-4012 Debrecen, Hungary; Lawrence Berkeley Lab, Div Life Sci, Bioimaging Grp, Berkeley, CA 94720 USA; Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94143 USA
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