Activated G protein-coupled receptor induces tyrosine phosphorylation of STAT3 and agonist-selective serine phosphorylation via sustained stimulation of mitogen-activated protein kinase. Resultant effects on cell proliferation

• Published in: The Journal of biological chemistry 1999-06, Vol.274 (23), p.16423-16430
• Main Authors: Sellers, L A, Feniuk, W, Humphrey, P P, Lauder, H
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Division - drug effects; CHO Cells; Cricetinae; DNA-Binding Proteins - metabolism; ets-Domain Protein Elk-1; Fibroblast Growth Factor 2 - pharmacology; Humans; Kinetics; MAP Kinase Kinase 1; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Peptides, Cyclic - pharmacology; Pertussis Toxin; Phosphorylation; Potassium Channels - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins; Receptors, Somatostatin - agonists; Receptors, Somatostatin - metabolism; Serine - metabolism; STAT3 Transcription Factor; Trans-Activators - metabolism; Transcription Factors; Tyrosine - metabolism; Virulence Factors, Bordetella - pharmacology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.23.16423

The peptide hormone somatostatin exhibits antiproliferative activity by interacting with the G protein-coupled sst2 or sst5 receptor types. We show here that somatostatin at the human recombinant sst4 receptor induced a concentration-dependent increase in proliferation (EC50 20 nM) 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 nM) peaked 10 min after the application and produced a response that continued for at least 4 h. In contrast, L-362,855 (1 microM) 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 (