Fig. 7. Model for the association of ErbB proteins inside and outside clusters. The extent of ErbB2-ErbB2 and ErbB2-ErbB3 associations depend on the relative expression levels of the proteins: high local ErbB3 density decreases ErbB2 homoassociation. Lipid rafts, which were identified as GM1-enriched domains labeled by CTX-B in our studies, colocalize with ErbB protein clusters. Although the high local concentration of ErbB proteins inside clusters favors their spontaneous activation (e.g. the formation of highly active ErbB2 homodimers), lipid rafts keep the activation of ErbB2 under control by limiting the homodimerization of ErbB2. By contrast, ErbB proteins are maintained in a signaling competent form inside rafts (i.e. heregulin-responsive ErbB2-ErbB3 heterodimers are present), which are disassembled if ErbB proteins are removed from them. CTX-B treatment induces migration of GM1-enriched domains into caveolae and disrupts ErbB2-ErbB3, but not ErbB2-ErbB2 or ErbB2-ErbB1 dimers.