Tumor Promoters Block Tyrosine-Specific Phosphorylation of the Epidermal Growth Factor Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1984-05, Vol.81 (10), p.3034-3038
• Main Authors: Friedman, BethAnn, Frackelton, A. Raymond, Ross, Alonzo H., Connors, Jean M., Fujiki, Hirota, Sugimura, Takashi, Rosner, Marsha Rich
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - analysis; Antibodies; Biochemistry; Carcinogens; Carcinogens - pharmacology; Carcinoma, Squamous Cell; Cell culture techniques; Cell growth; Cell Line; Epidermal Growth Factor - metabolism; ErbB Receptors; Humans; Kinetics; Phorbol Esters - pharmacology; Phorbols; Phorbols - pharmacology; Phosphorylation; Protein Kinase C; Protein Kinases - metabolism; Receptors; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - metabolism; Tumors; Tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.81.10.3034

Tyrosine-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by three chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, β -phorbol 12,13-dibutyrate, and β -phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A), and polyacetates (aplysiatoxin and debromoaplysiatoxin) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (β -phorbol, α -phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of125I-labeled EGF to A431 cells. Scatchard analysis, however, revealed two apparent EGF receptors in this cell type. The dose-responses for tumor-promoter inhibition of EGF receptor tyrosine phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of tyrosine by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.