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Vol. 13, Issue 7, 2547-2557, July 2002
*Department of Cell Biology, Research Institute for Microbial
Diseases, Osaka University, Suita, Osaka 565-0871, Japan, and
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.
Institute of Life Science, Kurume University, Kurume,
Fukuoka 839-0861, Japan
Corresponding author. E-mail address:
emekada{at}biken.osaka-u.ac.jp.
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