EFFECTS OF INSULIN-LIKE GROWTH-FACTOR-II ON THE GENERATION OF INOSITOL TRISPHOSPHATE, DIACYLGLYCEROL AND CAMP IN HUMAN FIBROBLASTS

In human fibroblasts, exogenous insulin-like growth factor-II (IGF-II) induce a rapid redistribution of mannose 6-phosphate/IGF-II receptors. To analyze the mechanism transducing the IGF-II signal the phosphoinositide hydrolysis, 1,2-diacylglycerol and cAMP formation were studied after incubation with IGFs. While IGF-I (10 nM, 30 s) increased the inositol trisphosphate formation IGF-II (10 nM, up to 10 min) failed to affect phosphoinositide hydrolysis and had neither an effect on basal concentrations of diacylglycerol containing arachidonic acid or myristic acid nor on intracellular cAMP. On the contrary, pretreatment with IGF-II for 10 min enhanced the cAMP production stimulated by bradykinin (10 nM, 3 min) by 2.5-fold whereas no additive effects of IGF-II on the increased ligand binding to the mannose 6-phosphate/IGF-II receptor in response to bradykinin were observed. These results indicate that in fibroblasts the rapid IGF-II-induced redistribution of mannose 6-phosphate/IGF-II receptors is not mediated by inositol trisphosphate, diacylglycerol or cAMP, but that IGF-II may modulate permissively other agonist-generated signals.