Specific inhibition of cytoplasmic protein tyrosine kinases by herbimycin A in vitro.
Herbimycin A is an antibiotic which reverses transformation caused by various src related oncogenes. The reversion of transformation is restricted to cells transformed by tyrosine kinase coding oncogenes, and accompanies a decrease in kinase activity of the oncogene products. We have shown in vitro that herbimycin A directly inactivates p60v-src kinase by conjugating with SH group(s) of the kinase, raising the possibility that the molecular target of the antibiotic for reversion of v-src transformation is the p60v-src itself. To investigate the relevance of its in vitro tyrosine kinase inactivating activity to in vivo transformation reversing activity, we examined the specificity of herbimycin A for inhibition of cAMP-dependent kinase, protein kinase C and p210bcr-abl tyrosine kinase in vitro. Herbimycin A had no inhibitory effect on the activities of cAMP-dependent kinase or protein kinase C, whereas the SH-reagent N-(9-acridinyl)maleimide, which inactivates p60v-crc in vitro by a mechanism similar to that of herbimycin A, blocked the two serine/threonine kinases. On the other hand, the activity of p210bcr-abl tyrosine kinase was inhibited by herbimycin A treatment. The results indicate that herbimycin A specifically binds to reactive SH group(s) of cytoplasmic protein tyrosine kinases, and confer the biochemical basis for its selectivity in reversing cell transformation.
Fukazawa
H
H
Department of Antibiotics, National Institute of Health, Tokyo, Japan.
Li
P M
PM
Yamamoto
C
C
Murakami
Y
Y
Mizuno
S
S
Uehara
Y
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones; D002478:Cells, Cultured / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine
D000470:Alkaloids; D016227:Benzoquinones; D007546:Isoquinolines; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D015688:Oncogene Protein pp60(v-src); D011493:Protein Kinase C; D019311:Staurosporine