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48892Evidence3001

Source:http://www.reactome.org/biopax/48892Evidence3001

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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).
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