Insulin-like growth factor (IGF)-I regulates IGF-binding protein-5 gene expression through the phosphatidylinositol 3-kinase, protein kinase B/Akt, and p70 S6 kinase signaling pathway

Expression of the insulin-like growth factor-binding protein 5 (IGFBP-5) ge ne in vascular smooth muscle cells is up-regulated by IGF-I through an IGF- I receptor-mediated mechanism. In this study, we studied the possible invol vement of the mitogen-activated protein kinase (MAPK) and PI 3-kinase signa ling pathways in mediating IGF-I-regulated IGFBP-5 gene expression. The add ition of Des(1-3)IGF-1, an IGF analog with reduced affinity to IGFBPs, resu lted in a transient activation of p44 and p42 MAPK. Inhibition of the MAPK activation by PD98059, however, did not affect IGF-I-stimulated IGFBP-5 exp ression. Des(1-3)IGF-I treatment also strongly activated PI 3-kinase. This activation was probably mediated through IRS-1, because IGF-1 stimulation r esulted in a significant increase in IRS-1- but not IRS-2-associated PI 3-k inase activity, This activation occurred within 5 min and was sustained at high levels for over 6 h. Likewise, Des(1-3)IGF-I caused a long lasting act ivation of PKB/Akt and p70(s6k). When LY294002 and wortmannin, two specific inhibitors of PI 3-kinase, were added with Des(1-3)IGF-I, the IGF-I-regula ted IGFBP-5 expression was negated. The addition of rapamycin, which inhibi ts IGF-I-induced p70(s6k) activation, significantly inhibited IGF-I-regulat ed IGFBP-5 gene expression, These results suggest that the action of IGF-I on IGFBP-5 gene expression requires the activation of the PI 3-kinase-PKB/A kt-p70(s6k) pathway but not the MAPK pathway in vascular smooth muscle cell s.