Reactome: A Curated Pathway Database

FGFR2 mutant receptor activation (R-HSA-1839126)

Species Homo sapiens

Summation

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).

Locations in the PathwayBrowser
Additional Information
Compartment plasma membrane , cytosol , extracellular region
Diseases
Name Identifier Synonyms
cancer 162 [malignant tumor, malignant neoplasm, primary cancer]
bone development disease 0080006
Literature References
pubMedId Title Journal Year
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
17552943 Syndromic craniosynostosis: from history to hydrogen bonds Orthod Craniofac Res 2007
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
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
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
9816310 Immunohistochemical detection of K-sam protein in stomach cancer Clin Cancer Res 1996
10626794 Deletion of the carboxyl-terminal exons of K-sam/FGFR2 by short homology-mediated recombination, generating preferential expression of specific messenger RNAs Cancer Res 1999
11003564 Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer J Cancer Res Clin Oncol 2000
18381441 FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival Cancer Res 2008
20101236 Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets Oncogene 2010
11056689 Characterization of fibroblast growth factor receptor 2 overexpression in the human breast cancer cell line SUM-52PE Breast Cancer Res 2000
17505008 AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor Clin Cancer Res 2007
19103595 Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform J Biol Chem 2009
18337450 Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis Mol Cancer Res 2008
9266968 Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations Oncogene 1997