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Mol. Biol. Cell 13 (7): 2547-2557

Copyright © 2002 by The American Society for Cell Biology.

Vol. 13, Issue 7, 2547-2557, July 2002

Ligand-independent Dimer Formation of Epidermal Growth Factor Receptor (EGFR) Is a Step Separable from Ligand-induced EGFR Signaling

Xiaochun Yu,dagger Kailash D. Sharma,dagger Tsuyoshi Takahashi,* Ryo Iwamoto,* and Eisuke Mekada*Dagger

 *Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan, and  dagger Institute of Life Science, Kurume University, Kurume, Fukuoka 839-0861, Japan

Dimerization and phosphorylation of the epidermal growth factor (EGF) receptor (EGFR) are the initial and essential events of EGF-induced signal transduction. However, the mechanism by which EGFR ligands induce dimerization and phosphorylation is not fully understood. Here, we demonstrate that EGFRs can form dimers on the cell surface independent of ligand binding. However, a chimeric receptor, comprising the extracellular and transmembrane domains of EGFR and the cytoplasmic domain of the erythropoietin receptor (EpoR), did not form a dimer in the absence of ligands, suggesting that the cytoplasmic domain of EGFR is important for predimer formation. Analysis of deletion mutants of EGFR showed that the region between 835Ala and 918Asp of the EGFR cytoplasmic domain is required for EGFR predimer formation. In contrast to wild-type EGFR ligands, a mutant form of heparin-binding EGF-like growth factor (HB2) did not induce dimerization of the EGFR-EpoR chimeric receptor and therefore failed to activate the chimeric receptor. However, when the dimerization was induced by a monoclonal antibody to EGFR, HB2 could activate the chimeric receptor. These results indicate that EGFR can form a ligand-independent inactive dimer and that receptor dimerization and activation are mechanistically distinct and separable events.

Dagger Corresponding author. E-mail address: emekada{at}

Molecular Biology of the Cell
Vol. 13, 2547-2557, July 2002
Copyright © 2002 by The American Society for Cell Biology

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