The interaction of an epidermal growth factor/transforming growth factor alpha tail chimera with the human epidermal growth factor receptor reveals unexpected complexities.

The Journal of Biological Chemistry
S M PuddicombeD E Davies

Abstract

It has been assumed that substitution of homologous regions of transforming growth factor alpha (TGF-alpha) 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-alpha (mEGF/TGF-alpha44-50) results in complex features that belie this initial simplistic assumption. Comparison of EGF and mEGF/TGF-alpha44-50 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-alpha44-50 was more potent than EGF, despite its low affinity. When ...Continue Reading

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