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FGFR2 mutant receptor activation

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). 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). 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). FGFR2 amplifications have been identified in 10% of gastric cancers, where they are associated with poor prognosis diffuse cancers (Hattori, 1996; Ueda, 1999; Shin, 2000; Kunii, 2008) , and in ~1% of breast cancers (Turner, 2010; Tannheimer, 2000). FGFR2 amplification often occur in conjunction with deletions of C-terminal exons, resulting in expression of a internalization- and degradation-resistant form of the receptor (Takeda, 2007; Cha, 2008, 2009). Signaling through overexpressed FGFR2 shows evidence of being ligand-independent and sensitive to FGFR inhibitors (Lorenzi, 1997; Takeda, 2007; Cha, 2009). More recently, FGFR2 fusion proteins have been identified in a number of cancers; these are thought to form constitutive ligand-independent dimers based on the dimerization domains of the 3' fusion partners and contribute to cellular proliferation and tumorigenesis in a kinase-inhibitor sensitive manner (Wu, 2013; Arai, 2013; Seo, 2012; reviewed in Parker, 2014).

from REACTOME source record: R-HSA-1839126
Type: pathway
Taxonomic scope
organism-specific biosystem
Homo sapiens

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