Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model

Wheldon, Lee M., Khodabukus, Naila, Patey, Susannah J., Smith, Terence Gordon, Heath, John K. and Hajihosseini, Mohammad K. 2011. Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. Biochemical Journal 436 (1) , pp. 71-81. 10.1042/BJ20100884

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Optometry and Vision Sciences
Subjects:	Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords:	: Apert syndrome, fibroblast growth factor receptor 2 (FGFR2), mRNA splicing, nonsense-mediated decay (NMD) pathway.
Publisher:	Biochemical Society
ISSN:	0264-6021
Funders:	CRUK
Last Modified:	03 Feb 2017 04:14
URI:	https://orca.cardiff.ac.uk/id/eprint/53370

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