FGFR2c mutants bind an expanded range of ligands

Stable Identifier
R-HSA-2033472
Type
Reaction [binding]
Species
Homo sapiens
Compartment
plasma membrane, extracellular region
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
FGFR2c mutants bind an expanded range of ligands
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Mutations in the highly conserved Pro-Ser dipeptide repeat of FGFR2 have been identified both in Apert syndrome and in endometrial and ovarian cancers (Wilkie, 1995; Dutt, 2008; Pollock, 2007; Byron, 2010). Missense S252W or P253R mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). In the context of endometrial cancer, these mutations are mutually exclusive with KRAS mutations, but are associated at high frequency with PTEN mutations (Byron, 2008). The S252W and P253R mutations allow the receptor to bind to an expanded range of ligands, such that the mesenchymal splice form (FGFR2c) is anomalously activated by the mesenchymal ligands FGF7 and FGF10, establishing an autocrine signaling loop. These mutations also increase the binding affinity for the receptor's normal epithelial ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).

Literature References
PubMed ID Title Journal Year
7719344 Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome

Wilkie, AO, Slaney, SF, Oldridge, M, Poole, MD, Ashworth, GJ, Hockley, AD, Hayward, RD, David, DJ, Pulleyn, LJ, Rutland, P

Nat Genet 1995
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
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
10618369 Structural interactions of fibroblast growth factor receptor with its ligands

Stauber, DJ, DiGabriele, AD, Hendrickson, WA

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

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

Hum Mol Genet 2004
9502772 Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome

Lomri, A, Lemonnier, J, Hott, M, de Parseval, N, Lajeunie, E, Munnich, A, Renier, D, Marie, PJ

J Clin Invest 1998
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
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
11121055 Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome

Yu, K, Herr, AB, Waksman, G, Ornitz, DM

Proc Natl Acad Sci U S A 2000
Participants
Input
Output
Participates
as an event of
Functional status

Gain of function of FGFR2c mutants with enhanced ligand binding [plasma membrane]

Disease Entity
Status
Disease
Name Identifier Synonyms
female reproductive endometrioid cancer DOID:3001 endometrioid tumor (morphologic abnormality), endometrioid neoplasm
ovarian cancer DOID:2394 ovarian neoplasm, malignant tumour of ovary, neoplasm of ovary (disorder), ovary neoplasm, primary malignant neoplasm of ovary and other uterine adnexa (disorder), ovarian cancer, tumor of the Ovary, ovary cancer, malignant Ovarian tumor, primary ovarian cancer, malignant tumor of ovary (disorder)
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  (2012-01-09)
Cite Us!