Details

Autor(en) / Beteiligte

• Sellers, Lynda A.

Titel

Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

Ist Teil von

• The Journal of biological chemistry, 1999-08, Vol.274 (34), p.24280-24288

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

1999

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The human sst4 receptor, recombinantly expressed in Chinese hamster ovary cells, 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 βγ-sequestrant, transducin. Somatostatin-induced proliferation was abolished by the MEK1 inhibitor, PD 98059, whereas the Src inhibitor, PP1, had no effect. A marked increase was observed in the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) 10 min after sst4 receptor activation, which was blocked by pertussis toxin, decreased by PP1 and the βγ-sequestrant, but unaffected by PD 98059. In contrast, the somatostatin-induced phosphorylation of ERK obtained at 4 h, although sensitive to both pertussis toxin and transducin, was unaffected by PP1 but ablated by PD 98059. Protein kinase C inhibition also abolished this somatostatin-induced sustained phosphorylation of ERK, together with the associated increase in cell proliferation. Expression of dominant negative Ras (N17) failed to significantly reduce the proliferative effect mediated by the sst4 receptor but markedly attenuated the acute phase of the somatostatin-induced phosphorylation of ERK obtained at 10 min. In contrast, the phosphorylation induced at 4 h was unaffected. We conclude that ERK activation by Gi/o-coupled sst4receptors involves a Src and Ras-dependent acute phase, but the proliferative response is dependent upon the prolonged ERK-induced activity, mediated by protein kinase C.