title: Crosstalk of humoral and cell-cell contact-mediated signals in postnatal body growth.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jing
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sawada
authors.forename: Qingfa
authors.initials: Q
authors.lastname: Chen
authors.forename: Keiji
authors.initials: K
authors.lastname: Iida
authors.forename: Kenryo
authors.initials: K
authors.lastname: Furushima
authors.forename: Daiki
authors.initials: D
authors.lastname: Arai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Chihara
authors.forename: Kazushige
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D049628:Body Size / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D018628:Gene Dosage; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D036122:Receptor, EphA4; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2