Prolonged activation of extracellular signal-regulated kinase by a proteinkinase C-dependent and N17Ras-insensitive mechanism mediates the proliferative response of G(i/o)-coupled somatostatin sst(4) receptors

The human sst, receptor, recombinantly expressed in Chinese hamster ovary c ells, mediates proliferative activity of the peptide hormone somatostatin. This effect was shown to involve activation of pertussis toxin-sensitive G proteins and was inhibited by overexpression of the beta gamma-sequestrant, transducin. Somatostatin-induced proliferation was abolished by the MEK1 i nhibitor, PD 98059, whereas the Src inhibitor, PP1, had no effect. A marked increase was observed in the phosphorylation of extracellular signal-regul ated kinase 1 and 2 (ERK1 and ERK2) 10 min after sst, receptor activation, which was blocked by pertussis toxin, decreased by PP1 and the beta gamma-s equestrant, but unaffected by PD 98059. In contrast, the somatostatin-induc ed phosphorylation of ERK obtained at 4 h, although sensitive to both pertu ssis toxin and transducin, was unaffected by PP1 but ablated by PD 98059. P rotein kinase C inhibition also abolished this somatostatin-induced sustain ed phosphorylation of ERK together with the associated increase in cell pro liferation. Expression of dominant negative Ras (N17) failed to significant ly reduce the proliferative effect mediated by the sst, receptor but marked ly attenuated the acute phase of the somatostatin-induced phosphorylation o f ERK obtained at 10 min. In contrast, the phosphorylation induced at 4 h w as unaffected. We conclude that ERK activation by G(i/o)-coupled sst, recep tors involves a Src and Ras dependent acute phase, but the proliferative re sponse is dependent upon the prolonged ERK-induced activity, mediated by pr otein kinase C.