FGFR1 P252X mutants bind ligand with enhanced affinity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11121055 Pubmed14613973 Pubmed15282208 Pubmed16140923 Pubmed18056464 Pubmed7874169 Reactome Database ID Release 432023451 Reactome, http://www.reactome.org ReactomeREACT_121358 Reviewed: Ezzat, S, 2012-05-15 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).<br><br>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).<br> has a Stoichiometric coefficient of 2 FGFR1 P252X mutant dimers bound to FGFs FGFR1c-binding FGFs FGFR1 P252X mutants