Reactome: A Curated Pathway Database

Activated point mutants of FGFR2 (R-HSA-2033519)

Species Homo sapiens


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.

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.

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).

Locations in the PathwayBrowser
Additional Information
Compartment plasma membrane , cytosol , extracellular region
Name Identifier Synonyms
cancer 162 [malignant tumor, malignant neoplasm, primary cancer]
bone development disease 0080006
Literature References
pubMedId Title Journal Year
18552176 Drug-sensitive FGFR2 mutations in endometrial carcinoma Proc Natl Acad Sci U S A 2008
17525745 Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes Oncogene 2007
20106510 FGFR2 mutations are rare across histologic subtypes of ovarian cancer Gynecol Oncol 2010
11325814 Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers Cancer Res 2001
9538690 Fibroblast growth factor receptors: lessons from the genes Trends Biochem Sci 1998
9154000 FGFR activation in skeletal disorders: too much of a good thing Trends Genet 1997
11121055 Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome Proc Natl Acad Sci U S A 2000
15282208 Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities Hum Mol Genet 2004
18757403 Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation Cancer Res 2008
17803937 A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases Mol Cell 2007
9539778 Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain Proc Natl Acad Sci U S A 1998
17552943 Syndromic craniosynostosis: from history to hydrogen bonds Orthod Craniofac Res 2007
7874169 A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome Nat Genet 1994
7719344 Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome Nat Genet 1995
8841188 Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes Nat Genet 1996
8696350 Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome Nat Genet 1996
7773297 Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3 Nat Genet 1995