Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor

Proc Natl Acad Sci U S A. 1984 May;81(10):3034-8. doi: 10.1073/pnas.81.10.3034.

Abstract

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, beta-phorbol 12,13-dibutyrate, and beta-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 (beta-phorbol, alpha-phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values 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 of 125I-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acids / analysis
  • Carcinogens / pharmacology*
  • Carcinoma, Squamous Cell
  • Cell Line
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors
  • Humans
  • Kinetics
  • Phorbol Esters / pharmacology*
  • Phorbols / pharmacology*
  • Phosphorylation
  • Protein Kinase C
  • Protein Kinases / metabolism
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism*
  • Tyrosine

Substances

  • Amino Acids
  • Carcinogens
  • Phorbol Esters
  • Phorbols
  • Receptors, Cell Surface
  • Tyrosine
  • Epidermal Growth Factor
  • Protein Kinases
  • ErbB Receptors
  • Protein Kinase C