OR01-3 Molecular mechanisms of EphA4-mediated signal modulation of the growth hormone (GH)-Insulin-like growth factor 1 (IGF1) axis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR01-Cell Specific GH & IGF-1 Signaling
Basic
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:00 PM
Room 134 (Moscone Center)
Takahiro Sawada*1, Daiki Arai1, Xuefeng Jing1, Masayasu Miyajima2, Qingfa Chen1, Kazuki Kawakami1, Kenryo Furushima1 and Kazushige Sakaguchi1
1Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan, 2Wakayama Medical University, Wakayama, Japan
The GH-IGF1 axis plays an important role in postnatal body growth. We reported a novel 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 (1). EphA4 forms a complex with GH receptor (GHR), Janus kinase 2 (JAK2) and signal transducers and activators of transcription 5B (STAT5B) and enhances Igf1 expression predominantly via the JAK2-dependent pathway with some direct effect on STAT5B. We also found that EphA4 regulates IGF1 signal transduction through PI-3 kinase, but not the signal through MAP kinase which is generally the main player of cell proliferation. Epha4 knockout mice show a gene dose-dependent short stature and low levels of Igf1 mRNA expression in liver and many other tissues despite normal plasma GH levels. In this study, we examined molecular interaction mechanisms that regulate STAT5B activation and IGF1 synthesis via the GHR/EphA4/JAK2 complex. We constructed several deletion and chimeric mutants of GHR and EphA4, and studied their interactions. EphA4 binds to GHR at both extracellular and intracellular domains. We have also determined that STAT5B binds to the amino-terminal kinase domain of EphA4. To study the importance of GHR for the JAK2-independent and EphA-mediated activation of STAT5B, we suppressed GHR expression in Jak2-/- mouse fibroblasts using lentivirus-mediated expression of Ghr shRNA. Upon stimulation with ephrin-A1, reduction of GHR expression decreased STAT5B phosphorylation, suggesting a supporting function of GHR in this signaling pathway. On the other hand, amplification mechanisms of the JAK2-dependent signal by EphA4 are now being studied using mutants of GHR and EphA4. They appear to be related with the complex formation of GHR/EphA4/JAK2/STAT5B, in which STAT5B binds to both GHR and EphA4 to be a substrate of JAK2. Thus, we have clarified two molecular mechanisms how EphA4 interacts with other molecules in enhancing IGF1 production; direct binding and activation of STAT5B, and enhancement of the GHR/JAK2-mediated STAT5B activation through complex formation with GHR, JAK2 and STAT5B.

(1) Xuefeng Jing, Masayasu Miyajima, Takahiro Sawada, Qingfa Chen, Keiji Iida, Kenryo Furushima, Daiki Arai, Kazuo Chihara, and Kazushige Sakaguchi: Crosstalk of Humoral and Cell-Cell Contact-Mediated Signals in Postnatal Body Growth. Cell Reports 2: 652-665, 2012

Nothing to Disclose: TS, DA, XJ, MM, QC, KK, KF, KS

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