Ligand‐induced activation of preformed inactive EGF/ErbB receptor homo‐ and heterodimers: a model for EGF/ErbB receptors

Abstract

The epidermal growth factor receptor (EGFR) family, also known as ErbB or HER, mediates a variety of cellular responses in normal biological processes and in pathological states. It is widely considered that ErbB receptors are located on the cell membrane, and that ligand binding to the monomeric form of the receptors induces its dimeric form for activation. However, using bimolecular fluorescence complementation assay in the present study, we demonstrate that in the absence of bound ligand, the four ErbB family members have preformed homo‐ and heterodimers on living cell surface, while ErbB3 homodimers and heterodimers with ErbB4 exist primarily in the nuclei. Binding of ligands such as EGF and HRGbeta1 had no effect on the amount of preformed dimers, but activated the preformed inactive dimers and their downstream molecules, and also induced the preformed dimers endocytosis. These ligand‐independent dimerizations of ErbB receptors occurred via interactions between their intracellular domains. Together, the results indicate that ErbB family receptors may preform inactive dimers before ligand binding. These findings provide new insights into an understanding of a molecular mechanism by which the inactive receptors switch into active form, and can explain at the molecular level for the activated EGFR mutants found in lung and breast cancers, and hence are relevant to the development of anti‐cancer drugs.