FGFR1 P252X mutants bind ligand with enhanced affinity

has a Stoichiometric coefficient of 2 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> Edited: Rothfels, K, 2012-05-16 Authored: Rothfels, K, 2012-02-09 Reviewed: Ezzat, S, 2012-05-15

http://purl.obolibrary.org/obo/HINO_0008124

has a Stoichiometric coefficient of 2

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).

Edited: Rothfels, K, 2012-05-16

Authored: Rothfels, K, 2012-02-09

Reviewed: Ezzat, S, 2012-05-15

Pubmed7874169

Pubmed16140923

Reactome, http://www.reactome.org

Pubmed18056464

Pubmed11121055

Pubmed15282208

Pubmed14613973

http://purl.obolibrary.org/obo/HINO_0024954

http://purl.obolibrary.org/obo/HINO_0026123

http://purl.obolibrary.org/obo/CHEBI_28815

http://purl.obolibrary.org/obo/HINO_0017094

FGFR1 P252X mutants bind ligand with enhanced affinity

HINO:0008124

FGFR1 P252X mutants bind ligand with enhanced affinity

ReactomeREACT_121358

Reactome Database ID Release 432023451

http://purl.obolibrary.org/obo/INO_0000040