Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.
Cell Rep. 2012 Sep 27;2(3):652-65. doi: 10.1016/j.celrep.2012.08.021. Epub 2012 Sep 20.
The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the Janus kinase 2 (JAK2)/signal transducers and activators of the transcription 5B (STAT5B) signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Igf1 messenger RNA (mRNA) in the liver and many other tissues was also significantly reduced in Epha4-knockout mice, whereas pituitary Gh mRNA and plasma GH levels were not. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination.
生长激素（GH）-胰岛素样生长因子 1（IGF1）轴介导出生后身体生长。生长激素受体被认为是介导 Janus 激酶 2（JAK2）/转录 5B（STAT5B）信号向 IGF1 合成的唯一受体。在这里，我们报告了一条通过 EphA4 调节出生后身体生长的信号通路，EphA4 是 Eph 家族受体酪氨酸激酶的成员，也是细胞-细胞接触介导信号的介质。EphA4 与生长激素受体、JAK2 和 STAT5B 形成复合物，并主要通过 JAK2 依赖性途径增强 Igf1 表达，对 STAT5B 有一些直接影响。Epha4 基因缺陷的小鼠表现出基因剂量依赖性的身材矮小和低血浆 IGF1 水平。Epha4 基因敲除小鼠的肝脏和许多其他组织中的 Igf1 信使 RNA（mRNA）也显著减少，而垂体 Gh mRNA 和血浆 GH 水平没有。这些发现表明，局部细胞-细胞接触介导的 Ephrin/EphA4 信号与体液 GH 信号一样，在 IGF1 合成和体型决定中都很重要。
