title: Fibroblast growth factor receptor 4 (FGFR4) mediates signaling to the prolactin but not the FGFR4 promoter.
abstract: Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of activities. Signaling of the 23 members of the FGF family is mediated through FGFR1-4. We show that FGF-19, which selectively binds FGFR4, can induce prolactin (PRL) but not growth hormone expression. FGF-19 also stimulated MAPK activation, an effect that was abrogated by a soluble dominant negative (dn) form of FGFR4. The response of the pituitary PRL promoter to FGF maps to an Ets-Pit1 binding site. We have previously shown that the hematopoietic zinc finger-containing transcription factor Ikaros (Ik) regulates FGFR4 as part of an overlapping site with that for an Ets-type factor in the FGFR4 promoter. Thus, we examined whether FGF-19 might regulate its own receptor through the Ets-Ik element in the FGFR4 promoter. Ets stimulated and dn-Ets inhibited basal FGFR4 and PRL promoter activity. In contrast, Ets enhanced FGF-19-induced PRL activation but failed to confer an effect for FGF-19 on the FGFR4 promoter. We conclude that FGFR4 mediates FGF-19 signaling to the PRL promoter. Our data also suggest a possible functional role for Ik in sorting Ets signals to the FGFR4 promoter, as distinct from the PRL promoter, where Ets partners with Pit1.
authors.affiliation: Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shunjiang
authors.initials: S
authors.lastname: Yu
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D011388:Prolactin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: C117476:FGF19 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D011388:Prolactin; C496371:FGFR4 protein, human; C496373:Fgfr4 protein, rat; D051499:Receptor, Fibroblast Growth Factor, Type 4