Cell‐surface and nuclear localization of preformed ErbB receptor homo‐ and heterodimers in living cells

Abstract

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, also known as ErbB or HER, plays crucial roles in the development of organisms. It is widely recognized that ErbB receptors function in the cell membrane, and that ligand binding to the monomeric form of the receptors induces its dimeric form for activation. By using the receptor molecules labeled with fluorescent proteins, however, we have found that ErbB3 was localized in the nucleus when expressed alone or together with ErbB4. Furthermore, ErbB3 was relocated to the plasma membrane by co-expressing with EGFR or ErbB2. These results indicate that in the absence of bound ligand, the EGFR family members can form homodimers and heterodimers. Furthermore, ErbB3 could form homodimers by itself or heterodimers with ErbB4 in the nucleus. Binding of ligands such as EGF and HRGbeta1 had no effect on the efficiency of the dimmer formation. In summary, ErbB receptors exist as preformed homo- and heterodimers prior to ligand binding, and the nuclear localization of ErbB3 homodimers and heterodimers with ErbB4 suggests that these receptors may also play roles in the nucleus. These provide new insights into an understanding of transmembrane signal transduction mediated by the EGFR family, and are relevant to the development of anti-cancer drugs.