K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells

K-252a, a kinase inhibitor isolated from the culture broth of Nocardiopsis sp., selectively inhibits the actions of nerve growth factor (NGF) on PC 12 cells. At a concentration of 200 nM, K-252a prevents neurite generation initiated by NGF, but not neurite generation produced by fibroblast growth factor or outgrowth produced by dibutyryl cAMP. K-252a also inhibits the induction of ornithine decarboxylase by NGF, but stimulates ornithine decarboxylase induction by epidermal growth factor. Stimulation of phosphatidylinositol breakdown by NGF was similarly inhibited by K-252a, while stimulation by epidermal growth factor was enhanced. The NGF-induced decrease in the phosphorylation of a soluble protein, Nsp 100, was prevented by K-252a. K-252a blocks the NGF-induced heterodown-regulation of the epidermal growth factor receptor, but not the epidermal growth factor-induced homodown-regulation of the epidermal growth factor receptor. K-252a, then, provides a new tool for the dissection and study of NGF-requiring processes.