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Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model.
Biochem J. 2011 May 15; 436(1):71-81.BJ

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+Show Affiliations

School of Biosciences, University of Birmingham, Edgbaston B15 2TT, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21355848

Citation

Wheldon, Lee M., et al. "Identification and Characterization of an Inhibitory Fibroblast Growth Factor Receptor 2 (FGFR2) Molecule, Up-regulated in an Apert Syndrome Mouse Model." The Biochemical Journal, vol. 436, no. 1, 2011, pp. 71-81.
Wheldon LM, Khodabukus N, Patey SJ, et al. Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. Biochem J. 2011;436(1):71-81.
Wheldon, L. M., Khodabukus, N., Patey, S. J., Smith, T. G., Heath, J. K., & Hajihosseini, M. K. (2011). Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. The Biochemical Journal, 436(1), 71-81. https://doi.org/10.1042/BJ20100884
Wheldon LM, et al. Identification and Characterization of an Inhibitory Fibroblast Growth Factor Receptor 2 (FGFR2) Molecule, Up-regulated in an Apert Syndrome Mouse Model. Biochem J. 2011 May 15;436(1):71-81. PubMed PMID: 21355848.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. AU - Wheldon,Lee M, AU - Khodabukus,Naila, AU - Patey,Susannah J, AU - Smith,Terence G, AU - Heath,John K, AU - Hajihosseini,Mohammad K, PY - 2011/3/2/entrez PY - 2011/3/2/pubmed PY - 2011/12/13/medline SP - 71 EP - 81 JF - The Biochemical journal JO - Biochem J VL - 436 IS - 1 N2 - 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/21355848/Identification_and_characterization_of_an_inhibitory_fibroblast_growth_factor_receptor_2__FGFR2__molecule_up_regulated_in_an_Apert_Syndrome_mouse_model_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20100884 DB - PRIME DP - Unbound Medicine ER -