Alpha-1 adrenergic receptor transactivates signal transducer and activator of transcription-3 (Stat3) through activation of Src and epidermal growth factor receptor (EGFR) in hepatocytes

✍ Scribed by Chang Han; William C. Bowen; George K. Michalopoulos; Tong Wu

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 507 KB
• Volume: 216
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21420

✦ Synopsis

Abstract

Hepatocytes express adrenergic receptors (ARs) that modulate several functions, including liver regeneration, hepatocyte proliferation, glycogenolysis, gluconeogenesis, synthesis of urea and fatty acid metabolism. Adrenergic hepatic function in adults is mainly under the control of α~1~‐ARs; however, the mechanism through which they influence diverse processes remains incompletely understood. This study describes a novel α~1~‐AR‐mediated transactivation of signal transducer and activator of transcription‐3 (Stat3) in primary and transformed hepatocytes. Treatment of primary rat hepatocytes with the α~1~‐AR agonist, phenylephrine (PE), induced a rapid phosphorylation of Stat3. PE also increased Stat3 phosphorylation, DNA binding and transcription activity in transformed human hepatocellular carcinoma cells (Hep3B). The PE‐induced Stat3 phosphorylation, DNA binding and reporter activity were completely blocked by the selective α~1~‐AR antagonist, prazosin. In addition, transfection of Hep3B cells with human α~1B~‐AR expression vector also enhanced Stat3 phosphorylation and reporter activity. Moreover, overexpression of RGS2, a protein inhibitor of G~q/11~ signaling, blocked PE‐induced Stat3 phosphorylation and reporter activity. The observations that PE induced the formation of c‐Src‐Stat3 binding complex and phosphorylation of epidermal growth factor receptor (EGFR) and that inhibiting Src and EGFR prevented PE‐induced Stat3 activation indicate the involvement of Src and EGFR. Taken together, these observations demonstrate a novel α~1~‐AR‐mediated Stat3 activation that involves G~q/11~, Src, and EGFR in hepatic cells. J. Cell. Physiol. 216: 486–497, 2008. © 2008 Wiley‐Liss, Inc.