CAMP-SENSITIVE AND RAPAMYCIN-SENSITIVE REGULATION OF THE ASSOCIATION OF EUKARYOTIC INITIATION-FACTOR 4E AND THE TRANSLATIONAL REGULATOR PHAS-I IN AORTIC SMOOTH-MUSCLE CELLS

Incubating rat aortic smooth muscle cells with either platelet-derived growth factor B (PDGF) or insulin-like growth factor I (IGF-I) increased the phosphorylation of PHAS-I, an inhibitor of the mRNA cap binding protein, eukaryotic initiation factor (eIF) 4E, Phosphorylation of PHAS-I promoted dissociation of the PHAS-I-eIF-4E complex, an effect that could partly explain the stimulation of protein synthesis by the two growth factors. Increasing cAMP with forskolin decreased PHAS-I phosphorylation and markedly increased the amount of eIF-4E bound to PHAS-I, effects consistent with an action of cAMP to inhibit protein synthesis. Both PDGF and IGF-I activated p70(S6K), but only PDGF increased mitogen-activated protein kinase activity, Forskolin decreased by 50% the effect of PDGF on increasing p70(S6K), and forskolin abolished the effect of IGF-I on the kinase. The effects of PDGF and IGF-I on increasing PHAS-I phosphorylation, on dissociating the PHAS-I-eIF-4E complex, and on increasing p70(S6K) were abolished by rapamycin, The results indicate that IGF-I and PDGF increase PHAS-I phosphorylation in smooth muscle cells by the same rapamycin-sensitive pathway that leads to activation of p70(S6K).