FGFR2b mutants bind an expanded range of ligands

Stable Identifier
Reaction [binding]
Homo sapiens
FGFR2b somatic mutants bind an expanded range of ligands
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Apert sydrome is the most severe of the craniosynostosis syndromes and results almost entirely from two missense mutations in the conserved Ser252 and Pro253 residues in the IgII-IgIII linker of FGFR2 (Wilkie, 1995). These mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). More recently, the same mutations arising somatically have been identified in endometrial and ovarian cancer (Dutt, 2008; Byron, 2008; Pollock, 2007).

The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).

Literature References
PubMed ID Title Journal Year
7719344 Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome

Rutland, P, Pulleyn, LJ, Poole, MD, Oldridge, M, Hockley, AD, Hayward, RD, David, DJ, Wilkie, AO, Slaney, SF, Ashworth, GJ

Nat Genet 1995
18757403 Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

Pollock, PM, Wellens, CL, Goodfellow, PJ, Gartside, MG, Mallon, MA, Powell, MA, Byron, SA, Keenan, JB

Cancer Res 2008
17525745 Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

Futreal, PA, Pollock, PM, Goodfellow, PJ, Gartside, MG, Stratton, MR, Davies, H, Mallon, MA, Mohammadi, M, Dejeza, LC, Powell, MA, Trent, JM

Oncogene 2007
10618369 Structural interactions of fibroblast growth factor receptor with its ligands

Stauber, DJ, DiGabriele, AD, Hendrickson, WA

Proc Natl Acad Sci U S A 2000
10490103 Structural basis for FGF receptor dimerization and activation

Hubbard, SR, Schlessinger, J, Plotnikov, AN, Mohammadi, M

Cell 1999
8663044 Receptor specificity of the fibroblast growth factor family

MacArthur, CA, Colvin, JS, McEwen, DG, Ornitz, DM, Gao, G, Coulier, F, Goldfarb, M, Xu, J

J Biol Chem 1996
15282208 Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities

Eliseenkova, AV, Linhardt, RJ, Itoh, N, Zhang, F, Mohammadi, M, Ibrahimi, OA

Hum Mol Genet 2004
10574949 Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity

Chellaiah, M, Yuan, W, Ornitz, DM, Chellaiah, A

J Biol Chem 1999
9502772 Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome

Lomri, A, Munnich, A, de Parseval, N, Renier, D, Lajeunie, E, Hott, M, Marie, PJ, Lemonnier, J

J Clin Invest 1998
18552176 Drug-sensitive FGFR2 mutations in endometrial carcinoma

Akslen, LA, Cibulskis, K, Greulich, H, Dutt, A, Sellers, WR, Chen, TH, Winckler, W, Wyhs, N, Ziaugra, L, Zody, MC, Salvesen, HB, Meyerson, M, Stefansson, IM, Trovik, J, Wong, KK, Ramos, AH, Richter, DJ, Gabriel, S, Nicoletti, R, Onofrio, RC, Grewal, R, Hanna, M, Hatton, C, Engelsen, IB, Fennell, T

Proc Natl Acad Sci U S A 2008
20106510 FGFR2 mutations are rare across histologic subtypes of ovarian cancer

Pollock, PM, Wellens, CL, Campbell, IG, Goodfellow, PJ, Gartside, MG, Birrer, MJ, Byron, SA

Gynecol Oncol 2010
11121055 Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome

Herr, AB, Ornitz, DM, Yu, K, Waksman, G

Proc Natl Acad Sci U S A 2000
Functional status

Gain of function of FGFR2b mutants with enhanced ligand binding [plasma membrane]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
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