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 that one of these compounds, glycerophosphoinositol-4-phosphate (GroPIns-4-P) responds acutely to the stimulation of the epidermal growth factor receptor, with a fast, massive and transient increase. The mechanism leading to GroPIns-4-P formation involves the activation of phosphoinositide-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 inhibitor wortmannin. GroPIns-4-P has been previously shown to inhibit adenylyl cyclase. Accordingly, epidermal growth factor also decreased the basal, cholera toxin-stimulated, and forskolin-stimulated cyclic AMP levels with kinetics similar to those of GroPIns-4-P formation, suggesting that GroPIns-4-P mediates this inhibitory effect. The hormone-induced formation of GroPIns-4-P was detected in several cell lines of various origin, suggesting that GroPIns-4-P is a novel intracellular messenger of the Ras pathway, possibly able to convey information from tyrosine kinase receptors to the cyclic AMP cascade.
Falasca
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Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Chieti, Italy.
Carvelli
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A
Iurisci
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Qiu
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RG
Symons
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MH
Corda
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D016475:3T3 Cells; D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D051381:Rats; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D007295:Inositol Phosphates; C062528:glycero-3-phosphoinositol 4-phosphate; D004815:Epidermal Growth Factor; C091533:glycerophosphoinositol 4,5-bisphosphate; D000242:Cyclic AMP; D066246:ErbB Receptors