title: Selective cleavage of ErbB4 by G-protein-coupled gonadotropin-releasing hormone receptor in cultured hypothalamic neurons.
abstract: Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic neurons (GnRH neurons). GnRH neurons have a GnRH receptor belonging to the G-protein-coupled receptors. The stimulation of this receptor activates extracellular signal-regulated kinase (ERK). In the present study, we found that epidermal growth factor receptor (EGFR) and ErbB4 were expressed in immortalized GnRH neurons (GT1-7 cells). AG1478, a relatively specific inhibitor of the ErbB family, and small interfering RNA (siRNA) for ErbB4 inhibited the GnRH-induced activation of ERK in GT1-7 cells, suggesting that EGFR and ErbB4 were necessary for the activation. In addition, GnRH induced the cleavage of ErbB4 and accumulation of an 80-kDa fragment. After treatment of the cells with 50 nM GnRH for 5 min, about 80% of ErbB4 was cleaved. Biotinylation of cell surface proteins revealed that more than 70% of the cell surface ErbB4 was cleaved by GnRH treatment. A higher concentration and longer treatment were necessary for GnRH to induce ErbB4 cleavage than ERK activation. TAPI-2, an inhibitor of tumor necrosis factor-α-converting enzyme (TACE), and siRNA for TACE inhibited the cleavage of ErbB4, suggesting that TACE was involved. After ErbB4 cleavage, the activation of ERK by neuregulin 1 was almost completely inhibited. These results suggest that the down-regulation of ErbB4 expression is induced by G-protein-coupled receptor stimulation.
authors: Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan. higasa@med.u-ryukyu.ac.jp
authors: Sayomi
authors: S
authors: Higa-Nakamine
authors: Noriko
authors: N
authors: Maeda
authors: Seikichi
authors: S
authors: Toku
authors: Tomoko
authors: T
authors: Yamamoto
authors: Matee
authors: M
authors: Yingyuenyong
authors: Masahiro
authors: M
authors: Kawahara
authors: Hideyuki
authors: H
authors: Yamamoto
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D066247:Receptor, ErbB-4; D011966:Receptors, LHRH / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D020890:Neuregulin-1; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse