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Volume 271, Number 48, Issue of November 29, 1996 pp. 30392-30397
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Interaction of an Epidermal Growth Factor/Transforming Growth Factor  Tail Chimera with the Human Epidermal Growth Factor Receptor Reveals Unexpected Complexities

(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  (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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