Transactivation of the epidermal growth factor receptor is involved in 12-O-tetradecanoylphorbol-13-acetate-induced signal transduction.
The mechanism of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion is still not well understood even though it is thought to be related to the protein kinase C/mitogen-activated protein kinase/AP-1 pathway. Recently, TPA was also found to induce epidermal growth factor receptor (EGFR) activity. Here, we investigated whether the EGFR is a necessary component for TPA-induced signal transduction associated with tumor promotion. We demonstrated that potent inhibitors of the EGFR, PD153035 and AG1478, blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs), AP-1 activity, and cell transformation. Egfr gene deficiency blocked TPA-induced ERK activity and AP-1 binding activity. The blocking of the ectodomain of the EGFR by a monoclonal antibody depressed TPA-induced ERK activity and AP-1 DNA binding activity. The use of a neutralizing antibody for heparin-binding EGF, one of the ligands of EGFR, blocked TPA-induced phosphorylation of ERKs. BB-94, a potent inhibitor of matrix metalloproteinases, which are activators of ectodomain shedding of EGFR ligands, also blocked TPA-induced ERK activity, AP-1 DNA binding, and cell transformation but had no effect on EGF-induced signal transduction. Anti-EGFR, anti-heparin-binding EGF, and BB-94 each blocked TPA-induced EGFR phosphorylation, but only anti-EGFR could block EGF-induced EGFR phosphorylation. Based on these results, we conclude that the EGFR is required for mediating TPA-induced signal transduction. EGFR transactivation induced by TPA is a mechanism by which the EGFR mediates TPA-induced tumor promotion-related signal transduction.
Chen
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N
Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
Ma
W Y
WY
She
Q B
QB
Wu
E
E
Liu
G
G
Bode
A M
AM
Dong
Z
Z
D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D013876:Thiophenes / Q000494:pharmacology; D018808:Transcription Factor AP-1; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology
D002273:Carcinogens; D004791:Enzyme Inhibitors; D008024:Ligands; D011799:Quinazolines; D013876:Thiophenes; D018808:Transcription Factor AP-1; D020032:Tyrphostins; C101044:RTKI cpd; D010649:Phenylalanine; D004247:DNA; C080985:batimastat; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline