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

Abstract

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 calcium. 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.

Effects of Anti-Nerve Growth Factor Antibody on Symptoms in the NC/Nga Mouse, an Atopic Dermatitis Model

“…The binding of NGF to the TrkA receptor is responsible for the transmission of NGF signals for mitogenesis and differentiation (54,55). K252a, a selective inhibitor of TrkA tyrosin kinase activity, can inhibit NGFinduced neuritic outgrowth in PC12 cells (56,57). The inhibition of cellular effects of NGF by K252a is mediated by the blocking of trk proto-oncogene tyrosine phosphorylation and kinase activities (58).…”

Enhanced expression of Ca2+ channels by nerve growth factor and the v‐src oncogene in rat phaeochromocytoma cells.

“…What are the similarities and differences in the cell signalling pathways activated by each of these tyrosine kinases? K252a, a protein kinase C inhibitor closely related to staurosporine, inhibited NGF-induced differentiation and c-fos transcription (Hashimoto, 1988;Koizumi, Contreras, Matsuda, Hama, Lazarovici & Guroff, 1988;Lazarovici et al 1989), but did not inhibit v-src-induced differentiation in PC12 cells (Rausch et al 1989). Staurosporine blocked both differentiation and enhancement of wo-CgTX binding sites in PC12 cells treated with NGF (Usowicz et al 1990).…”

Connective Tissue Growth Factor CCN2 Interacts with and Activates the Tyrosine Kinase Receptor TrkA

“…On activation, Trk also promote a rapid increase in cytoplasmic calcium level. This seems to arise from both release of intracellular stores and uptake of extracellular calcium (16,17). Moreover, activated Trk interact, directly or indirectly, with many cytoplasmic adaptor proteins, leading to a variety of biologic responses, including, cell proliferation and survival; axonal and dendritic growth and remodeling; assembly and remodeling of cytoskeleton; membrane trafficking and fusion; and synapse formation, function, and plasticity (18 (24).…”