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Growth Hormone (GH)-Stimulated Insulin-Like Growth Factor I Gene Expression Is Mediated by a Tyrosine Phosphorylation Pathway Depending on C-Terminal Region of Human GH Receptor in Human GH Receptor-Expressing Ba/F3 Cells

Department of Materials Science and Engineering (H.Y.), Nagoya Institute of Technology, Nagoya 466-8555; Department of Animal Science (M.T.), Nippon Veterinary and Animal Science University, Tokyo 180-8602; and Department of Biochemistry (N.N., N.N., K.N.) Faculty of Medicine, Mie University, Mie 514-8507, Japan

Address all correspondence and requests for reprints to: Dr. Hideo Yoshizato, Department of Bioscience, Nagoya Institute of Technology, Gokiso-cyo, Showa-ku, Nagaya 466-8555, Japan. E-mail: h-yoshi{at}ks.kyy.nitech.ac.jp.

The signaling pathway of GH-stimulated IGF-I gene expression is still unclear, although it has been reported that the Janus kinase (JAK)-signal transducers and activators of transcription (STAT)5b pathway plays an important role in liver IGF-I expression. In this study, the GH-dependent IGF-I gene expression and its intracellular signaling mechanism have been examined in mouse pro-B, Ba/F3 cells stably expressing human GH receptor (Ba/F3-hGHR). The IGF-I gene expression was stimulated by human GH (0.01-10 nM) in a dose-dependent fashion in Ba/F3-hGHR cells. The specific inhibitors for JAK2 remarkably suppressed the GH-induced IGF-I gene expression, but MAPK or phosphatidylinositol 3 kinase-specific inhibitors failed to block the GH stimulation of the IGF-I gene expression. However, genistein, a nonspecific tyrosine kinase inhibitor that does not inhibit JAK2 and STAT5 phosphorylation, significantly suppressed the GH-induced IGF-I gene expression. Additionally, a Ba/F3-hGHR mutant that contained the truncated C-terminal hGHR up to D351 showed no IGF-I gene expression in response to human GH. The D351 form normally has the GH-induced JAK/STAT5 tyrosine phosphorylation. These results suggest that the JAK-STAT5 pathway and the novel tyrosine phosphorylation pathway, dependent on signaling from the C-terminal region of hGHR, might be involved in the GH-stimulated IGF-I gene expression in Ba/F3 cells.

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