Ectodomain shedding-dependent transactivation of epidermal growth factor receptors in response to insulin-like growth factor type I.
Diverse extracellular stimuli activate the ERK1/2 MAPK cascade by transactivating epidermal growth factor (EGF) receptors. Here, we have examined the role of EGF receptors in IGF-I-stimulated ERK1/2 activation in several cultured cell lines. In human embryonic kidney 293 cells, IGF-I triggered proteolysis of heparin binding (HB)-EGF, increased tyrosine autophosphorylation of EGF receptors, stimulated EGF receptor inhibitor (AG1478)-sensitive ERK1/2 phosphorylation, and promoted EGF receptor endocytosis. In a mixed culture system that employed IGF-I receptor null murine embryo fibroblasts (MEFs) (R(-) cells) to detect paracrine signals produced by MEFs expressing the human IGF-I receptor (R(+) cells), stimulation of R(+) cells provoked rapid activation of green fluorescent protein-tagged ERK2 in cocultured R(-) cells. The R(-) cell response was abolished by either the broad-spectrum matrix metalloprotease inhibitor batimastat or by AG1478, indicating that it resulted from the proteolytic generation of an EGF receptor ligand from adjacent R(+) cells. These data suggest that the paracrine production of EGF receptor ligands leading to EGF receptor transactivation is a general property of IGF-I receptor signaling. In contrast, the contribution of transactivated EGF receptors to IGF-I-stimulated downstream events, such as ERK1/2 activation, varies in a cell type-dependent manner.
Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, 816 Clinical Sciences Building, P.O. Box 250624, Charleston, South Carolina 29425, USA.
Hesham M
HM
El-Shewy
Francine L
FL
Kelly
Liza
L
Barki-Harrington
Louis M
LM
Luttrell
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000502:physiology; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019899:Paracrine Communication; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D051381:Rats; D017451:Receptors, Somatomedin / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D011799:Quinazolines; D017451:Receptors, Somatomedin; D013876:Thiophenes; D020032:Tyrphostins; C101044:RTKI cpd; D014443:Tyrosine; D010649:Phenylalanine; D007334:Insulin-Like Growth Factor I; C080985:batimastat; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate