Effect of herbimycin A on tyrosine kinase receptors and platelet derived growth factor (PDGF)-induced signal transduction.
Herbimycin A is widely used as an inhibitor of Src family protein tyrosine kinases but is also reported to induce the downregulation of epidermal growth factor (EGF) receptor number in A431 cells without inhibiting its tyrosine kinase activity. To determine the specificity of the receptor downregulation, we examined its effect on a variety of cell lines which express different levels of EGF receptor and on other tyrosine kinase receptors. Long-term herbimycin A treatment decreased the amounts of all the tyrosine kinase receptors examined in a dose-dependent manner. It also reduced ligand-stimulated receptor autophosphorylation in accordance with the reduction in the receptor level. Herbimycin A inhibited platelet derived growth factor (PDGF)-induced tyrosine phosphorylation of cellular proteins and DNA synthesis in NIH3T3 cells but did not affect the serum-stimulated DNA synthesis. PDGF-induced tyrosine phosphorylation and activation of c-Src was inhibited but the protein level of c-Src was not reduced by herbimycin A. The reduced level of c-Src kinase activity correlated with the levels of both PDGF receptor and DNA synthesis. These results indicate that the herbimycin A treatment selectively downregulates receptor tyrosine kinases, independent of the number of receptors, and suggest that c-Src is to some degree involved in the selective inhibition of PDGF-induced mitogenesis by herbimycin A.
Murakami
Y
Y
Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan.
Fukazawa
H
H
Mizuno
S
S
Uehara
Y
Y
D016475:3T3 Cells; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016227:Benzoquinones; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007624:KB Cells; D047029:Lactams, Macrocyclic; D051379:Mice; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects
D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D004247:DNA; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D047029:Lactams, Macrocyclic; D010982:Platelet-Derived Growth Factor; D011809:Quinones; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011972:Receptor, Insulin; D017479:Receptors, Platelet-Derived Growth Factor; D017828:Rifabutin; D014443:Tyrosine; D019061:src-Family Kinases; C020754:herbimycin