title: Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model.
abstract: AS (Apert syndrome) is a congenital disease composed of skeletal, visceral and neural abnormalities, caused by dominant-acting mutations in FGFR2 [FGF (fibroblast growth factor) receptor 2]. Multiple FGFR2 splice variants are generated through alternative splicing, including PTC (premature termination codon)-containing transcripts that are normally eliminated via the NMD (nonsense-mediated decay) pathway. We have discovered that a soluble truncated FGFR2 molecule encoded by a PTC-containing transcript is up-regulated and persists in tissues of an AS mouse model. We have termed this IIIa-TM as it arises from aberrant splicing of FGFR2 exon 7 (IIIa) into exon 10 [TM (transmembrane domain)]. IIIa-TM is glycosylated and can modulate the binding of FGF1 to FGFR2 molecules in BIAcore-binding assays. We also show that IIIa-TM can negatively regulate FGF signalling in vitro and in vivo. AS phenotypes are thought to result from gain-of-FGFR2 signalling, but our findings suggest that IIIa-TM can contribute to these through a loss-of-FGFR2 function mechanism. Moreover, our findings raise the interesting possibility that FGFR2 signalling may be a regulator of the NMD pathway.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, UK.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Wheldon
authors.forename: Naila
authors.initials: N
authors.lastname: Khodabukus
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Patey
authors.forename: Terence G
authors.initials: TG
authors.lastname: Smith
authors.forename: John K
authors.initials: JK
authors.lastname: Heath
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hajihosseini
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005091:Exons; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3