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

The peptide hormone somatostatin exhibits antipro liferative activity by in teracting with the G protein-coupled sst, or sst, receptor types. We show h ere that somatostatin at the human recombinant sst, receptor induced a conc entration-dependent increase in proliferation (EC50 20 nM) with a maximal r esponse 5-fold greater than that produced by its synthetic analog, L-362,85 5. Analysis of the phosphorylation status of extracellular signal-regulated kinase (ERK)1 and ERK2 showed temporal differences in the changes evoked b y the agonists, Phosphorylation induced by somatostatin (100 nM) peaked 10 min after the application and produced a response that continued for at lea st 4 h. In contrast, L-362,855 (1 mu M) showed transient phosphorylation th at had declined to basal levels by I h, However, both agonists induced rapi d and sustained tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) which was pertussis toxin-insensitive. Serine p hosphorylation 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 inhibiti on also decreased the time interval over which somatostatin-induced ERK pho sphorylation was observed (<2 h), We conclude that the difference in the ma gnitude of the proliferative response evoked by the two agonists at the sst (4) receptor can be accounted for by their differential ability to phosphor ylate STAT3 on serine residues and supports the concept that selective sign aling can be achieved through pharmacological diversity.