PathwayStep4190 PathwayStep4193 PathwayStep4191 PathwayStep4192 PathwayStep4189 PathwayStep4188 PathwayStep4185 PathwayStep4184 PathwayStep4187 PathwayStep4186 Dimerization of FGFR2 point mutants with enhanced kinase activity Autocatalytic phosphorylation of FGFR2 point mutants with enhanced kinase activity Autocatalytic phosphorylation of FGFR2c mutants with enhanced ligand binding Point mutants of FGFR2 bind and are inactivated by tyrosine kinase inhibitors Dimerization of FGFR2 ligand-independent mutants Autocatalytic phosphorylation of FGFR2 ligand-independent mutants Autocatalytic phosphorylation of FGFR2b mutants with enhanced ligand binding FGFR2b mutants bind an expanded range of ligands FGFR2c mutants bind an expanded range of ligands FP-1039 acts as a ligand-trap for FGFR2b-binding ligands in endometrial cancer Activated point mutants of FGFR2 Authored: Rothfels, K, 2012-02-09 Autosomal dominant mutations in FGFR2 are associated with the development of a range of skeletal disorders including Beare-Stevensen cutis gyrata syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Crouzon syndrome and Apert Syndrome (reveiwed in Burke, 1998; Webster and Donoghue 1997; Cunningham, 2007). Mutations that give rise to Crouzon, Jackson-Weiss and Pfeiffer syndromes tend to cluster in the third Ig-like domain of the receptor, either in exon IIIa (shared by the IIIb and the IIIc isoforms) or in the FGFR2c-specific exon IIIc. These mutations frequently involve creation or removal of a cysteine residue, leading to the formation of an unpaired cysteine residue that is thought to promote intramolecular dimerization and thus constitutive, ligand-independent activation (reviewed in Burke, 1998; Webster and Donoghue, 1997; Cunningham, 2007). Mutations in FGFR2 that give rise to Apert Syndrome cluster to the highly conserved Pro-Ser dipeptide in the IgII-Ig III linker; mutations in the paralogous residues of FGFR1 and 3 give rise to Pfeiffer and Muenke syndromes, respectively (Muenke, 1994; Wilkie, 1995; Bellus, 1996). Development of Beare-Stevensen cutis gyrata is associated with mutations in the transmembrane-proximal region of the receptor (Przylepa, 1996), and similar mutations in FGFR3 are linked to the development of thanatophoric dysplasia I (Tavormina, 1995a). These mutations all affect FGFR2 signaling without altering the intrinsic kinase activity of the receptor.<br><br><br>Activating point mutations have also been identified in FGFR2 in ~15% of endometrial cancers, as well as to a lesser extent in ovarian and gastric cancers (Dutt, 2008; Pollock, 2007; Byron, 2010; Jang, 2001). These mutations are found largely in the extracellular region and in the kinase domain of the receptor, and parallel activating mutations seen in autosomal dominant disorders described above.<br><br><br>Activating mutations in FGFR2 are thought to contribute to receptor activation through diverse mechanisms, including constitutive ligand-independent dimerization (Robertson, 1998), expanded range and affinity for ligand (Ibrahimi, 2004b; Yu, 2000) and enhanced kinase activity (Byron, 2008; Chen, 2007). Edited: Rothfels, K, 2012-05-16 Pubmed11121055 Pubmed11325814 Pubmed15282208 Pubmed17525745 Pubmed17552943 Pubmed17803937 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed7719344 Pubmed7773297 Pubmed7874169 Pubmed8696350 Pubmed8841188 Pubmed9154000 Pubmed9538690 Pubmed9539778 Reactome Database ID Release 432033519 Reactome, http://www.reactome.org ReactomeREACT_120863 Reviewed: Ezzat, S, 2012-05-15