FGFR2 mutant receptor activation

Stable Identifier
R-HSA-1839126
Type
Pathway
Species
Homo sapiens
Compartment
plasma membrane, cytosol, extracellular region
ReviewStatus
5/5
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FGFR2 mutant receptor activation
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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). 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).
Literature References
PubMed ID Title Journal Year
17505008 AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor

Takeda, M, Arao, T, Yokote, H, Komatsu, T, Yanagihara, K, Sasaki, H, Yamada, Y, Tamura, T, Fukuoka, K, Kimura, H, Saijo, N, Nishio, K

Clin Cancer Res 2007
18757403 Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

Byron, SA, Gartside, MG, Wellens, CL, Mallon, MA, Keenan, JB, Powell, MA, Goodfellow, PJ, Pollock, PM

Cancer Res 2008
11325814 Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers

Jang, JH, Shin, KH, Park, JG

Cancer Res 2001
17525745 Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

Pollock, PM, Gartside, MG, Dejeza, LC, Powell, MA, Mallon, MA, Davies, H, Mohammadi, M, Futreal, PA, Stratton, MR, Trent, JM, Goodfellow, PJ

Oncogene 2007
9154000 FGFR activation in skeletal disorders: too much of a good thing

Webster, MK, Donoghue, DJ

Trends Genet 1997
20101236 Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets

Turner, N, Lambros, MB, Horlings, HM, Pearson, A, Sharpe, R, Natrajan, R, Geyer, FC, van Kouwenhove, M, Kreike, B, Mackay, A, Ashworth, A, van de Vijver, MJ, Reis-Filho, JS

Oncogene 2010
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

Robertson, SC, Meyer, AN, Hart, KC, Galvin, BD, Webster, MK, Donoghue, DJ

Proc Natl Acad Sci U S A 1998
19103595 Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform

Cha, JY, Maddileti, S, Mitin, N, Harden, TK, Der, CJ

J Biol Chem 2009
11003564 Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer

Shin, EY, Lee, BH, Yang, JH, Shin, KS, Lee, GK, Yun, HY, Song, YJ, Park, SC, Kim, EG

J Cancer Res Clin Oncol 2000
9538690 Fibroblast growth factor receptors: lessons from the genes

Burke, D, Wilkes, D, Blundell, TL, Malcolm, S

Trends Biochem Sci 1998
15282208 Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities

Ibrahimi, OA, Zhang, F, Eliseenkova, AV, Itoh, N, Linhardt, RJ, Mohammadi, M

Hum Mol Genet 2004
18381441 FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival

Kunii, K, Davis, L, Gorenstein, J, Hatch, H, Yashiro, M, Di Bacco, A, Elbi, C, Lutterbach, B

Cancer Res 2008
11056689 Characterization of fibroblast growth factor receptor 2 overexpression in the human breast cancer cell line SUM-52PE

Tannheimer, SL, Rehemtulla, A, Ethier, SP

Breast Cancer Res 2000
20106510 FGFR2 mutations are rare across histologic subtypes of ovarian cancer

Byron, SA, Gartside, MG, Wellens, CL, Goodfellow, PJ, Birrer, MJ, Campbell, IG, Pollock, PM

Gynecol Oncol 2010
10626794 Deletion of the carboxyl-terminal exons of K-sam/FGFR2 by short homology-mediated recombination, generating preferential expression of specific messenger RNAs

Ueda, T, Sasaki, H, Kuwahara, Y, Nezu, M, Shibuya, T, Sakamoto, H, Ishii, H, Yanagihara, K, Mafune, K, Makuuchi, M, Terada, M

Cancer Res 1999
18337450 Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis

Cha, JY, Lambert, QT, Reuther, GW, Der, CJ

Mol Cancer Res 2008
9816310 Immunohistochemical detection of K-sam protein in stomach cancer

Hattori, Y, Itoh, H, Uchino, S, Hosokawa, K, Ochiai, A, Ino, Y, Ishii, H, Sakamoto, H, Yamaguchi, N, Yanagihara, K, Hirohashi, S, Sugimura, T, Terada, M

Clin Cancer Res 1996
17552943 Syndromic craniosynostosis: from history to hydrogen bonds

Cunningham, ML, Seto, ML, Ratisoontorn, C, Heike, CL, Hing, AV

Orthod Craniofac Res 2007
9266968 Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

Lorenzi, MV, Castagnino, P, Chen, Q, Chedid, M, Miki, T

Oncogene 1997
17803937 A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases

Chen, H, Ma, J, Li, W, Eliseenkova, AV, Xu, C, Neubert, TA, Miller, WT, Mohammadi, M

Mol Cell 2007
18552176 Drug-sensitive FGFR2 mutations in endometrial carcinoma

Dutt, A, Salvesen, HB, Chen, TH, Ramos, AH, Onofrio, RC, Hatton, C, Nicoletti, R, Winckler, W, Grewal, R, Hanna, M, Wyhs, N, Ziaugra, L, Richter, DJ, Trovik, J, Engelsen, IB, Stefansson, IM, Fennell, T, Cibulskis, K, Zody, MC, Akslen, LA, Gabriel, S, Wong, KK, Sellers, WR, Meyerson, M, Greulich, H

Proc Natl Acad Sci U S A 2008
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
Cross References
Mondo
Authored
Rothfels, K  (2012-02-10)
Reviewed
Ezzat, S  (2012-05-15)
Created
Rothfels, K  (2011-10-27)
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