Inhibition of PDGF-induced phosphoinositide-turnover by glucopiericidin A

Abstract

In the search for a substance which would specifically block a particular step in the signal transduction cascade, we identified glucopiericidin A produced by Streptomyces sp, as an inhibitor of phosphoinositide (PI)-turnover in phospholipase-C gamma 1 (PLC-gamma 1) overexpressing NM 3T3 fibroblasts (NIH 3T3 gamma 1). Glucopiericidin A inhibited the formation of inositol phosphate (IPt) in platelet-derived growth factor (PDGF)-stimulated NIH 3T3 gamma 1 cells with an IC50 of 5.0 mu M, In vitro enzyme assay showed the compound had no inhibitory effect on PLC-gamma 1 even at 100 mu M concentration. Glucopiericidin A reduced PDGF-induced tyrosine phosphorylations of proteins, including PDGF receptor and PLC-gamma 1, in the cells. In contrast, glucopiericidin A showed only a slight inhibitory effect on epidermal growth factor (EGF)- (EGF)-induced IPt production and protein tyrosine phosphorylations in A431 cells. These results suggest that glucopiericidin A inhibits PDGF-induced activation of PLC-gamma 1 by reducing the tyrosine kinase activity of the PDGF receptor and it more potently inhibits PI-turnover induced by PDGF than by EGF.