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Superagonistic behaviour of epidermal growth factor/transforming growth factor-alpha chimaeras: correlation with receptor routing after ligand-induced internalization

By A. E. Lenferink, R. H. Kramer, M. J. van Vugt, M. K&#246, P. P. Di Fiore, E. J. van Zoelen and M. L. van de Poll

Abstract

Human epidermal growth factor (EGF) and human transforming growth factor alpha (TGF-alpha) are structurally related polypeptide growth factors that exert their mitogenic activity through interaction with a common cell-surface receptor, the epidermal growth factor receptor (EGFR). The biological effect induced by these two ligands is quantitatively similar in most cases; in some test systems, however, TGF-alpha functions as a more potent form of EGF. In this study, we have compared EGF, TGF-alpha and ten previously described chimaeras of these two ligands in terms of their ability to generate a mitogenic response in cells carrying the human EGFR, and observed that three of the mutant growth factors (E3T, E4T and T3E4T) are mitogenic at concentrations 10-fold lower than that of either wild-type EGF or TGF-alpha. No difference in tyrosine kinase activity of the receptor towards an external substrate was observed after binding of the various mutants. It has been established before [Ebner and Derynck (1991) Cell Regulation 2, 599-612] that EGF and TGF-alpha differ in the processing of the receptor-ligand complex after internalization, as a result of their different pH sensitivities of receptor binding. Similar measurements on our chimaeric mutants revealed that the above superagonists show an enhanced pH dependence of binding in comparison with EGF. Furthermore, induction of receptor recycling by these superagonists is largely comparable with that induced by TGF-alpha. No superagonistic behaviour was observed on a cell-line containing an EGFR/erbB-2 chimaera which does not show ligand-induced internalization. These data show that EGF/TGFalpha chimaeras can be more active than the naturally occurring ligands, and that receptor recycling after ligand-induced internalization seems to be a prerequisite for this phenomenon

Topics: Animals, Receptor, Epidermal Growth Factor, Epidermal Growth Factor, Humans, Hydrogen-Ion Concentration, Protein-Tyrosine Kinases, Mice, Recombinant Fusion Proteins, Phosphorylation, Transforming Growth Factor alpha, Mitogens, Mutation, Cell Line, Ligands, Settore MED/04 - Patologia Generale
Year: 1997
OAI identifier: oai:air.unimi.it:2434/196141
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