The pp60v-src tyrosine kinase desensitizes epidermal growth factor binding to 3T3 fibroblasts by two distinct protein kinase C-independent mechanisms.
Protein kinase C (Ca2+/phospholipid-dependent enzyme) is known to phosphorylate the epidermal growth factor receptor and reduce its affinity for epidermal growth factor. Transformation of 3T3 fibroblasts by the oncogenic tyrosine kinase pp60v-src is accompanied by an elevation of cellular diacylglycerol and partial activation of protein kinase C (Wolfman, A., Wingrove, T. G., Blackshear, P. J., and Macara, I. G. (1987) J. Biol. Chem. 262, 16546-16552). We therefore asked whether pp60v-src can down-modulate the epidermal growth factor receptor. We report that within 15 min of activating temperature-sensitive pp60v-src, binding of 125I-labeled epidermal growth factor to 3T3 cells falls at least 50%. Two distinct processes control the down-modulation by pp60v-src. The first is rapid and transient, while the second requires protein synthesis and persists long after inactivation of pp60v-src. Surprisingly, both mechanisms seem to be protein kinase C-independent. Both operate by decreasing the affinity of the epidermal growth factor receptor for its ligand.
D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D015688:Oncogene Protein pp60(v-src); D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013816:Thermodynamics
D012191:Retroviridae Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); D013755:Tetradecanoylphorbol Acetate