The mitogenic effect of low affinity ligands is enhanced by overexpression of EGF receptors

Davies, D., Adam, R., Murray, M., Niyogi, S. and Chamberlin, S. (1996) The mitogenic effect of low affinity ligands is enhanced by overexpression of EGF receptors. FASEB Journal, 10 (6), [A1376].

Abstract

It is generally accepted that receptor binding affinity provides an adequate measure of ligand potency, and this is frequently used as the primary indicator in structure-function studies. In the case of the epidermal growth factor receptor (EGFR), we find that this relationship holds for cells expressing low numbers of EGFRs, however it breaks down where expression is in excess of 105 receptors/cell. In the latter case, we show that the response to EGF mutants which bind with low affinity (and also fail to fully activate the EGFR tyrosine kinase) is equivalent with EGF. This correlation is observed in all cells lines tested, and is therefore unlikely to be a consequence of different capacities to handle ligands (internalisation rate, ligand processing, etc). Our results can be explained in terms of a model in which a high number of EGFRs produces significantly higher concentrations of (signalling) receptor dimers at subsaturating ligand concentrations. Expressed mathematically, the model predicts that below 105 receptors/cell, the number of dimeric receptors formed at the steady state diverges rapidly when presented with a low as compared with a high affinity ligand. These results clearly demonstrate a hidden pitfall associated with use of genetically modified cells which overexpress EGFR; they also illustrate the selective advantage which high levels of EGFRs can confer on tumour cells. [Supported by the Cancer Research Campaign, UK and USDOE contract DE-AC05-960R22464 to L.M. Energy Res. Corp.].

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Contributors

Author: D. Davies

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