K-252a inhibits the increase in c-fos transcription and the increase in intracellular calcium produced by nerve growth factor in PC12 cells

K‐252a, a kinase inhibitor isolated from the culture broth of Nocardiopsis sp., selectively inhibits, in a dose‐ and time‐dependent fashion, the increased transcription of the protooncogene c‐fos induced by nerve growth factor in PC12 cells. Induction of c‐fos by epidermal growth factor, A23187, dBcAMP, or TPA in the same cells is not affected. Pretreatment with K‐252a for 30 min results in a complete inhibition of the nerve growth factor‐induced increase in intracellular calclum. Increases in intracellular calcium induced by carbachol or by high K+ are not altered. K‐252a derivatives selective for the inhibition of various known kinases were used to inhibit the nerve growth factor‐dependent induction of c‐fos mRNA, the nerve growth factor‐dependent increase in intracellular calcium levels, and the nerve growth factor‐dependent outgrowth of neurites. K‐252a is the most effective inhibitor of all three of these actions of nerve growth factor. The possible mechanisms by which K‐252a acts on PC12 cells are considered in the light of the characteristics of the inhibitions seen here.