FAST RECEPTOR-INDUCED FORMATION OF GLYCEROPHOSPHOINOSITOL-4-PHOSPHATE, A PUTATIVE NOVEL INTRACELLULAR MESSENGER IN THE RAS PATHWAY

Glycerophosphoinositols are phosphoinositide metabolites whose levels are constitutively elevated in Ras-transformed cells. Here, we show th at one of these compounds, glycerophosphoinositol-4-phosphate (GroPIns -4-P) responds acutely to the stimulation of the epidermal growth fact or receptor, with a fast,massive and transient increase. The mechanism leading to GroPIns-4-P formation involves the activation of phosphoin ositide-3 kinase and the small GTP-binding protein Rac, since GroPIns- 4-P was neither formed in cells expressing the dominant negative form of Rac nor in cells treated with the phosphoinositide-3 kinase inhibit or wortmannin. GroPIns-4-P has been previously shown to inhibit adenyl yl cyclase. Accordingly, epidermal growth factor also decreased the ba sal, cholera toxin-stimulated, and forskolin-stimulated cyclic AMP lev els with kinetics similar to those of GroPIns-4-P formation, suggestin g that GroPIns-4-P mediates this inhibitory effect. The hormone-induce d formation of GroPIns-4-P was detected in several cell lines of vario us origin, suggesting that GroPIns-4-P is a novel intracellular messen ger of the Ras pathway, possibly able to convey information from tyros ine kinase receptors to the cyclic AMP cascade.