Autocatalytic phosphorylation of FGFR1 mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed10053006 Pubmed10918587 Pubmed11781872 Pubmed12112473 Pubmed16186508 Pubmed17525745 Pubmed18552176 Pubmed18772890 Pubmed19224897 Pubmed9857065 Reactome Database ID Release 432023460 Reactome, http://www.reactome.org ReactomeREACT_120859 Reviewed: Ezzat, S, 2012-05-15 The three kinase domain mutants of FGFR1 that have been identified in glioblastoma are predicted or have been shown to result in enhanced kinase activity. The N546K (Rand, 2005) residue lies in a stretch of 9 amino acids that are conserved between all four FGFRs. Mutation of the paralogous residue in FGFR3 (N540K) has been shown to result in weak ligand-independent contstitutive activation in the autosomal disorder hypochodroplasia (Raffioni, 1998). In FGFR2 mutation of the paralogous residue to lysine has been identified in endometrial cancer and been shown to result in enhanced kinase activity (Dutt, 2008; Pollock, 2008); germline mutations at this site in FGFR2 are also associated with the development of Crouzon and Pfeiffer syndromes (Kan, 2002). The FGFR1 N546K mutations has accelerated rates of autophosphorylation and supports transformation when transfected into Rat-1 cells (Lew, 2009).<br><br><br>The FGFR1 K656E (TCGA, 2008) mutation is paralogous to activating mutations in FGFR3 kinase domain associated with the development of thanatophoric dysplasias (Tavormina, 1999; Bellus, 2000; Hart, 2000), and has itself been shown to activating when expressed in neural crest cells (Petiot, 2002).<br><br><br>The FGFR1 R576W (Rand, 2005) mutation increases the hydrophobicity of the receptor, and is postulated to enhance protein-protein interactions and thereby increase the likelihood of autophosphorylation of adjacent tyrosine residues, although this has not been explicitly demonstrated.<br><br><br> has a Stoichiometric coefficient of 16 Activated FGFR1 mutant dimers with enhanced kinase activity FGFR1 mutant dimers with enhanced kinase activity