FGFR1c P252X mutants bind ligand with enhanced affinity

Stable Identifier
Reaction [binding]
Homo sapiens
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The missense mutation C775G in exon 5 of FGFR1 encodes a Pro252R gain-of-function mutation that causes Pfeiffer syndrome, an autosomal dominant disorder characterized by premature fusion of bones in the skull and syndactyly of the hands and feet (Muenke, 1994). FGFR1 P252R binds to FGF1, FGF2, FGF4, and FGF6 with 2-5 fold-enhanced affinity, and with 30-fold affinity to FGF9. The enhanced ligand-affinity of the mutant receptor is the result of an additional set of ligand-receptor hydrogen bonds; in particular for FGF9, the additional receptor contacts are thought to compete with FGF9 autoinhibitory dimerization (Ibrahimi, 2004a). The increase in ligand-binding affinity in the absence of an expansion of ligand binding range is thought to account for the milder limb phenotype of Pfeiffer syndrome relative to FGFR2-mediated Apert syndrome (Yu, 2000; Ibrahimi, 2004b).

Somatic mutations in FGFR1 at P252 have also been identified in melanoma (P252S; Ruhe, 2007) and in lung cancer (P252T; Davies, 2005). Based on analogy to the FGFR1 P252R mutation that is found in Pfeiffer syndrome, these mutations are also predicted to increase the ligand-binding affinity of the receptor and to result in increased signaling, although this remains to be directly demonstrated for the S/T alleles (Ibrahimi, 2004a).

Literature References
PubMed ID Title Journal Year
16140923 Somatic mutations of the protein kinase gene family in human lung cancer

Easton, DF, Dicks, E, Stratton, MR, Davies, H, Cooper, CS, Tofts, C, Teh, BT, Edkins, S, Teague, J, Pierotti, MA, Futreal, PA, Webb, A, Forbes, S, Flanagan, AM, Kosmidou, V, Lakhani, SR, Laman, R, Jones, D, Knowles, M, Hinton, J, Hunter, C, Yates, A, Greenman, C, Halliday, K, Yuen, ST, Hills, K, O'Meara, S, Perry, J, Malkowicz, B, Menzies, A, Parker, A, Nicholson, AG, Clements, J, Edwards, K, Green, A, Looijenga, LH, Harrison, R, Lugg, R, Leung, SY, Butler, A, Stephens, P, Stephens, Y, Stevens, C, Cole, J, Brackenbury, L, Small, A, Brasseur, F, Smith, R, Buck, G, Solomon, H, Raine, K, Barthorpe, S, Shepherd, R, Bignell, G, Petty, R, Avis, T, Weber, BL, West, S, Widaa, S, Goldstraw, P, Gorton, M, Gray, K, Wooster, R, Varian, J

Cancer Res 2005
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
18056464 Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines

Tay, LS, Streit, S, Lee, TC, Ullrich, A, Loo, HL, Lim, SJ, Venkatesh, B, Foo, P, Mann, C, Luo, M, Peng, K, Wong, CH, Ong, H, Wong, W, Gaertner, S, Tay, A, Pok, S, Hart, S, Peter, S, Hoefler, H, Bezler, M, Ruhe, JE, Ho, HK, Knyazev, P, Iacobelli, S, Brenner, S, Knyazeva, T, Specht, K

Cancer Res 2007
14613973 Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity

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

Hum Mol Genet 2004
7874169 A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome

Rutland, P, Robin, NH, Reardon, W, Pulleyn, LJ, Losken, HW, Hehr, A, Schell, U, Muenke, M, Malcolm, S, Schinzel, A

Nat Genet 1994
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
Normal reaction
Functional status

Gain of function of FGFR1c P252X mutants [plasma membrane]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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