Activated G Protein-coupled Receptor Induces Tyrosine Phosphorylation of STAT3 and Agonist-selective Serine Phosphorylation via Sustained Stimulation of Mitogen-activated Protein Kinase

• Published in: The Journal of biological chemistry 1999-06, Vol.274 (23), p.16423-16430
• Main Authors: Sellers, Lynda A., Feniuk, Wasyl, Humphrey, Patrick P.A., Lauder, Heather
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.23.16423

The peptide hormone somatostatin exhibits antiproliferative activity by interacting with the G protein-coupled sst 2 or sst 5 receptor types. We show here that somatostatin at the human recombinant sst 4 receptor induced a concentration-dependent increase in proliferation (EC 50 20 n m ) with a maximal response 5-fold greater than that produced by its synthetic analog, L-362,855. Analysis of the phosphorylation status of extracellular signal-regulated kinase (ERK)1 and ERK2 showed temporal differences in the changes evoked by the agonists. Phosphorylation induced by somatostatin (100 n m ) peaked 10 min after the application and produced a response that continued for at least 4 h. In contrast, L-362,855 (1 μ m ) showed transient phosphorylation that had declined to basal levels by 1 h. However, both agonists induced rapid and sustained tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) which was pertussis toxin-insensitive. Serine phosphorylation of STAT3 was only apparent after somatostatin treatment and was abolished by pertussis toxin or PD 98059, together with the associated increases in proliferation. Mitogen-activated protein/ERK kinase-1 inhibition also decreased the time interval over which somatostatin-induced ERK phosphorylation was observed (