Abstract
The ErbB family of receptor tyrosine kinases engage in homo- and heterodimerization, permitting signal diversification. ErbB2, the preferred heteroassociation partner of the other ErbB proteins, enhances ligand binding and signaling. ErbB2 overexpression promotes ligand-independent receptor activation and is associated with breast cancer and other malignancies. Nagy et al . investigated the influence of localized ErbB2 and ErbB3 density and lipid microenvironment on ErbB2 dimerization and functional activity in a breast cancer cell line. Analysis of fluorescence resonance energy transfer (FRET) between fluorescently labeled antibodies showed that ErbB2 homodimerization was no higher within high-density clusters of ErbB2 receptors than outside; within clusters, ErbB2 homodimerization was associated with high ErbB2 density and was inversely proportional to ErbB3 density. Clusters colocalized with lipid rafts, membrane domains enriched in cholesterol and sphingolipids, identified by binding of fluorescently labeled cholera toxin subunit B (CTX-B) to G M1 ganglioside. ErbB2 homodimerization was inversely proportional to local G M1 density. Crosslinking lipid rafts through prolonged exposure to CTX-B promoted raft migration into caveolae, decreased association of ErbB2 clusters with rafts, and decreased ErbB2 heteroassociation with ErbB3. Crosslinking also decreased tyrosine phosphorylation of Shc in cells stimulated with the ligands epidermal growth factor and heregulin. Crosslinking inhibited ErbB2 internalization after treatment of cells with a monoclonal antibody to ErbB2 (the murine version of a humanized antibody used in breast cancer immunotherapy), but enhanced the antibody's antiproliferative effect. The authors conclude that composition of the lipid microenvironment, as well as the densities of ErbB2 and ErbB3, influence ErbB2 dimerization and function. P. Nagy, G. Vereb, Z. Sebestyén, G. Horváth, S. J. Lockett, S. Damjanovich, J. W. Park, T. M. Jovin, J. Szöllősi, Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2, J. Cell Sci. 115 , 4251-4262 (2002). [Abstract] [Full Text]
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