K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity.
The rat pheochromocytoma PC12 cell line differentiates into a sympathetic neuronal phenotype upon treatment with either nerve growth factor (NGF) or basic fibroblast growth factor. The alkaloid-like compound K-252a has been demonstrated to be a specific inhibitor of NGF-induced biological responses in PC12 cells (Koizumi, S., Contreras, M. L., Matsuda, Y., Hama, T., Lazarovici, P., and Guroff, G. (1988) J. Neurosci. Res. 8, 715-721). NGF interacts with the protein product of the proto-oncogene trk and rapidly stimulates the tyrosine phosphorylation of both p140prototrk and a number of cellular substrates. Here we show that these phosphorylation events are directly inhibited in PC12 cells by K252a in a dose-dependent manner, indicating that the site of action of this inhibitor is at the NGF receptor level. K-252a inhibits p140prototrk activity in vitro, demonstrating that K-252a has a direct effect on the p140prototrk tyrosine kinase. Though many of the biochemical responses to NGF in PC12 cells are mimicked by basic fibroblast growth factor and epidermal growth factor, K-252a has no effect on the action of these growth factors in PC12 cells, demonstrating that the initial biological events initiated by NGF are distinctive during neuronal differentiation.
Berg
M M
MM
Department of Cell Biology and Anatomy, Cornell University Medical College, New York, New York 10021.
Sternberg
D W
DW
Parada
L F
LF
Chao
M V
MV
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D026121:Indole Alkaloids; D009414:Nerve Growth Factors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011519:Proto-Oncogenes; D051381:Rats; D020917:Receptor, trkA; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism*
D002227:Carbazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D020917:Receptor, trkA