FGFR2c mutant binding FGFs FGFR2c mutants bind an expanded range of ligands Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Mutations in the highly conserved Pro-Ser dipeptide repeat of FGFR2 have been identified both in Apert syndrome and in endometrial and ovarian cancers (Wilkie, 1995; Dutt, 2008; Pollock, 2007; Byron, 2010). Missense S252W or P253R 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). In the context of endometrial cancer, these mutations are mutually exclusive with KRAS mutations, but are associated at high frequency with PTEN mutations (Byron, 2008). The S252W and P253R mutations allow the receptor to bind to an expanded range of ligands, such that the mesenchymal splice form (FGFR2c) is anomalously activated by the mesenchymal ligands FGF7 and FGF10, establishing an autocrine signaling loop. These mutations also increase the binding affinity for the receptor's normal epithelial 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).<br><br> Pubmed10618369 Pubmed11121055 Pubmed15282208 Pubmed17525745 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed7719344 Pubmed9502772 Reactome Database ID Release 432033472 Reactome, http://www.reactome.org ReactomeREACT_120984 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs FGFR2c mutants with enhanced ligand binding