Modulation of the epidermal growth factor receptor by mitogenic ligands: effects of bombesin and role of protein kinase C.
The binding of 125I-epidermal growth factor (EGF) to cellular receptors is rapidly and acutely modulated by a set of structurally unrelated tumour and growth promoting factors. These ligands interact with specific receptors which do not recognize EGF but, through an indirect mechanism, decrease the apparent affinity of the EGF receptor population. This novel mechanism of receptor regulation, named transmodulation, should be distinguished from the reduction in total receptor number caused by the homologous ligand (downregulation) and from the change in affinity produced by the binding of agonists or antagonists to the same receptor site. There is strong evidence that protein kinase C is directly involved in the mediation of EGF receptor transmodulation. Mammalian peptides structurally related to the amphibian tetradecapeptide, bombesin, are potent mitogens for Swiss 3T3 cells, and their mitogenic effects are mediated by specific, high-affinity receptors which do not recognize other mitogens for these cells. We have used this family of novel mitogenic peptides to test rigorously the fundamental features of EGF receptor transmodulation. The results presented here demonstrate that peptides of the bombesin family cause a rapid, highly temperature-dependent decrease in the affinity of 125I-EGF for its receptor in Swiss 3T3 cells. This effect is elicited through specific receptors for these peptides. Our findings further indicate that the decrease in 125I-EGF binding caused by bombesin-related peptides is mediated by protein kinase C. The role of protein kinase C as a point of convergence in the action of all transmodulating agents is discussed.
D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D010703:Phorbol Esters / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*
D010703:Phorbol Esters; D010982:Platelet-Derived Growth Factor; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011493:Protein Kinase C; D001839:Bombesin; D002118:Calcium