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(Received for publication, April 26, 1996, and in revised form, September 5, 1996)
From the Cancer Research Campaign Medical Oncology Unit,
Southampton General Hospital,
Southampton SO16 6YD, United Kingdom
It has been assumed that substitution of
homologous regions of transforming growth factor
Volume 271, Number 48,
Issue of November 29, 1996
pp. 30392-30397
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Tail Chimera with the Human Epidermal Growth Factor Receptor
Reveals Unexpected Complexities
(TGF-) into
epidermal growth factor (EGF) can be used to probe ligand-receptor
recognition without detrimental effects on ligand characteristics for
the human EGF receptor (EGFR). We show that a chimera of murine (m) EGF
in which the carboxyl-terminal tail is substituted for that of TGF-
(mEGF/TGF-44-50) results in complex features that belie
this initial simplistic assumption. Comparison of EGF and mEGF/TGF-44-50 in equilibrium binding assays showed
that although the relative binding affinity of the chimera was reduced 80-200-fold, it was more potent than EGF in mitogenesis assays using
NR6/HER cells. This superagonist activity could not be attributed to
differences in ligand processing or to binding to other members of the
c-erbB family. It appeared to be due, in part, to choice of an
EGFR-overexpressing target cell where high receptor number compensated
for the low affinity of the ligand; it also appeared to be related to
the ability of the chimera to activate the EGFR tyrosine kinase. Thus,
when EGFR autophosphorylation was measured, mEGF/TGF-44-50 was more potent than EGF, despite its
low affinity. When tested using chicken embryo fibroblasts,
substitution of the TGF- carboxyl-terminal tail into mEGF failed to
enhance its binding affinity for chicken EGFRs; however, the
chimera was intermediate in potency between TGF- and mEGF in
mitogenesis assays. Our results suggest a contextual requirement for
EGFR recognition which is ligand-specific. Further, the unpredictable responses to chimeric ligands underline the complex nature of the
processes of ligand recognition, receptor activation, and the ensuing
cellular response.
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