COMPARATIVE MITOGENIC POTENCIES OF EGF AND TGF-ALPHA AND THEIR DEPENDENCE ON RECEPTOR-LIMITATION VERSUS LIGAND-LIMITATION

Transforming growth factor alpha (TGF alpha) has been reported to be a more potent agonist when compared to epidermal growth factor (EGF) in several systems while acting via their common receptor, the epidermal growth factor receptor (EGFR). It has been postulated, that this incr eased potency is mediated by the increased recycling of EGFR upon acti vation by TGF alpha as against receptor activation by EGF. The authors test this hypothesis by simultaneously measuring mitogenesis and the dynamics of surface receptor number in response to these ligands in NR 6 mouse fibroblasts expressing the EGFR. The data demonstrates that in creased receptor recycling due to endosomal dissocation of TGF alpha c an indeed realise an increased mitogenic potency relative to EGF under appropriate cellular and experimental conditions (i.e. situations in which the increase in the number of occupied receptors due to receptor sparing by TGF alpha represents additional mitogenic signalling capac ity). However, this difference in receptor trafficking does not unique ly determine the relative potencies of these ligands since TGF alpha i s a less potent mitogen compared to EGF when experimental conditions a re dominated by the effects of ligand trafficking on growth factor ava ilability. Thus, the relative potencies of these growth factors are de termined in a given context by the relative importance of ligand and r eceptor trafficking effects which determine the availability of these signalling components. These results are consistent with a suggested m odel of hormone responsiveness which favours dissociative ligands (suc h as TGF alpha) in receptor-limited situations and non-dissociative li gands (such as EGF) in the case of ligand limitation.