Genetic and molecular analysis of growth retardation caused by growth hormone insensitivity

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GH is regarded as an essential hormone for postnatal body growth that mainly works through IGF1 production in liver and other tissues, and the whole signaling process is named GH-IGF1 axis. We identified EphA4 as an essential binding partner of GHR. EphA4 binds to GHR and augments activation of the JAK2/STAT5B pathway. In addition, EphA4 directly binds to and phosphorylates STAT5B. Through these interactions, EphA4 transcriptionally enhances IGF1 production in liver cells as well as in others. Epha4 KO mice show short stature in an Epha4 gene dose-dependent fashion, and respond well to IGF1 but not to GH treatment.