Signaling by FGFR in disease

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R-HSA-1226099
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Pathway
Species
Homo sapiens
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A number of skeletal and developmental diseases have been shown to arise as a result of mutations in the FGFR1, 2 and 3 genes. These include dwarfism syndromes (achondroplasia, hypochondroplasia and the neonatal lethal disorders thanatophoric dysplasia I and II), as well as craniosynostosis disorders such as Pfeiffer, Apert, Crouzon, Jackson-Weiss and Muenke syndromes (reviewed in Webster and Donoghue 1997; Burke, 1998, Cunningham, 2007; Harada, 2009). These mutations fall into four general regions of the receptor: a) the immunoglobulin (Ig)-like domain II-III linker region, b) the alternatively spliced second half of the Ig III domain, c) the transmembrane domain and d) the tyrosine kinase domain (reviewed in Webster and Donoghue, 1997). With the exception of mutations in class b), which affect only the relevant splice variant, these mutations may be present in either the 'b' or 'c' isoforms. These activating mutations affect FGFR function by altering or expanding the ligand-binding range of the receptors (see for instance Ibrahimi, 2004a), by promoting ligand-independent dimerization (for instance, Galvin,1996; Neilson and Friesel, 1996; d'Avis,1998) or by increasing the activity of the kinase domain (for instance, Webster, 1996; Naski, 1996; Tavormina, 1999; Bellus, 2000). Thus, a number of the point mutations found in FGFR receptors alter their activity without altering their intrinsic kinase activity. Many of the mutations that promote constitutive dimerization do so by creating or removing cysteine residues; the presence of an unpaired cysteine in the receptor is believed to promote dimerization through the formation of intramolecular disulphide bonds (Galvin, 1996; Robertson, 1998). Paralogous mutations at equivalent positions have been identified in more than one FGF receptor, sometimes giving rise to different diseases. For instance, mutation of the highly conserved FGFR2 Ser252-Pro253 dipeptide in the region between the second and third Ig domain is responsible for virtually all cases of Apert Syndrome (Wilkie, 1995), while paralogous mutations in FGFR1 (S252R) and FGFR3 (P250R) are associated with Pfeiffer and Crouzon syndromes, respectively (Bellus, 1996). FGFR4 is unique in that mutations of this gene are not known to be associated with any developmental disorders.

Recently, many of the same activating mutations in the FGFR genes that have been characterized in skeletal and developmental disorders have begun to be identified in a range of cancers (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011; Wesche, 2011). The best established link between a somatic mutation of an FGFR and the development of cancer is in the case of FGFR3, where 50% of bladder cancers have mutations in the FGFR3 coding sequence. Of these mutations, which largely match the activating mutations seen in thanatophoric dysplasias, over half occur at a single residue (S249C) (Cappellen, 1999; van Rhijn, 2002). Activating mutations have also been identified in the coding sequences of FGFR1, 2 and 4 (for review, see Wesche, 2011)

In addition to activating point mutations, the FGFR1, 2 and 3 genes are subject to misregulation in cancer through gene amplification and translocation events, which are thought to lead to overexpression and ligand-independent dimerization (Weiss, 2010; Turner, 2010; Kunii, 2008; Takeda, 2007; Chesi, 1997; Avet-Loiseau, 1998; Ronchetti, 2001). It is important to note, however, that in each of these cases, the amplification or translocation involve large genomic regions encompassing additional genes, and the definitive roles of the FGFR genes in promoting oncogenesis has not been totally established. In the case of FGFR1, translocation events also give rise to FGFR1 fusion proteins that contain the intracellular kinase domain of the receptor fused to a dimerization domain from the partner gene. These fusions, which are expressed in a pre-leukemic myeloproliferative syndrome, dimerize constitutively based on the dimerization domain provided by the fusion partner and are constitutively active (reviewed in Jackson, 2010).

Literature References
PubMed ID Title Journal Year
8640234 Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia

Naski, MC, Wang, Q, Xu, J, Ornitz, DM

Nat Genet 1996
9207791 Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3

Chesi, M, Nardini, E, Brents, LA, Schröck, E, Ried, T, Kuehl, WM, Bergsagel, PL

Nat Genet 1997
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
20094046 Fibroblast growth factor signalling: from development to cancer

Turner, N, Grose, RP

Nat Rev Cancer 2010
20226962 8p11 myeloproliferative syndrome: a review

Jackson, CC, Medeiros, LJ, Miranda, RN

Hum Pathol 2010
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
21367659 Targeting mutant fibroblast growth factor receptors in cancer

Greulich, H, Pollock, PM

Trends Mol Med 2011
9154000 FGFR activation in skeletal disorders: too much of a good thing

Webster, MK, Donoghue, DJ

Trends Genet 1997
9538690 Fibroblast growth factor receptors: lessons from the genes

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

Trends Biochem Sci 1998
21711248 Fibroblast growth factors and their receptors in cancer

Wesche, J, Haglund, K, Haugsten, EM

Biochem J 2011
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
9438390 Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I

d'Avis, PY, Robertson, SC, Meyer, AN, Bardwell, WM, Webster, MK, Donoghue, DJ

Cell Growth Differ 1998
21160078 Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer

Weiss, J, Sos, ML, Seidel, D, Peifer, M, Zander, T, Heuckmann, JM, Ullrich, RT, Menon, R, Maier, S, Soltermann, A, Moch, H, Wagener, P, Fischer, F, Heynck, S, Koker, M, Schöttle, J, Leenders, F, Gabler, F, Dabow, I, Querings, S, Heukamp, LC, Balke-Want, H, Ansén, S, Rauh, D, Baessmann, I, Altmüller, J, Wainer, Z, Conron, M, Wright, G, Russell, P, Solomon, B, Brambilla, E, Brambilla, C, Lorimier, P, Sollberg, S, Brustugun, OT, Engel-Riedel, W, Ludwig, C, Petersen, I, Sänger, J, Clement, J, Groen, H, Timens, W, Sietsma, H, Thunnissen, E, Smit, E, Heideman, D, Cappuzzo, F, Ligorio, C, Damiani, S, Hallek, M, Beroukhim, R, Pao, W, Klebl, B, Baumann, M, Buettner, R, Ernestus, K, Stoelben, E, Wolf, J, Nürnberg, P, Perner, S, Thomas, RK

Sci Transl Med 2010
10471491 Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas

Cappellen, D, De Oliveira, C, Ricol, D, de Medina, S, Bourdin, J, Sastre-Garau, X, Chopin, D, Thiery, JP, Radvanyi, F

Nat Genet 1999
8841188 Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes

Bellus, GA, Gaudenz, K, Zackai, EH, Clarke, LA, Szabo, J, Francomano, CA, Muenke, M

Nat Genet 1996
8798788 Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains

Neilson, KM, Friesel, R

J Biol Chem 1996
10053006 A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene

Tavormina, PL, Bellus, GA, Webster, MK, Bamshad, MJ, Fraley, AE, McIntosh, I, Szabo, J, Jiang, W, Jabs, EW, Wilcox, WR, Wasmuth, JJ, Donoghue, DJ, Thompson, LM, Francomano, CA

Am J Hum Genet 1999
17552943 Syndromic craniosynostosis: from history to hydrogen bonds

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

Orthod Craniofac Res 2007
20179196 FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer

Turner, N, Pearson, A, Sharpe, R, Lambros, M, Geyer, F, Lopez-Garcia, MA, Natrajan, R, Marchio, C, Iorns, E, Mackay, A, Gillett, C, Grigoriadis, A, Tutt, A, Reis-Filho, JS, Ashworth, A

Cancer Res 2010
12461689 Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

van Rhijn, BW, van Tilborg, AA, Lurkin, I, Bonaventure, J, de Vries, A, Thiery, JP, van der Kwast, TH, Zwarthoff, EC, Radvanyi, F

Eur J Hum Genet 2002
8599935 Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia

Webster, MK, Donoghue, DJ

EMBO J 1996
8755573 Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras

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

Proc Natl Acad Sci U S A 1996
11429702 Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations

Ronchetti, D, Greco, A, Compasso, S, Colombo, G, Dell'Era, P, Otsuki, T, Lombardi, L, Neri, A

Oncogene 2001
9865713 High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies

Avet-Loiseau, H, Li, JY, Facon, T, Brigaudeau, C, Morineau, N, Maloisel, F, Rapp, MJ, Talmant, P, Trimoreau, F, Jaccard, A, Harousseau, JL, Bataille, R

Cancer Res 1998
19066716 FGFR3-related dwarfism and cell signaling

Harada, D, Yamanaka, Y, Ueda, K, Tanaka, H, Seino, Y

J Bone Miner Metab 2009
11055896 Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype

Bellus, GA, Spector, EB, Speiser, PW, Weaver, CA, Garber, AT, Bryke, CR, Israel, J, Rosengren, SS, Webster, MK, Donoghue, DJ, Francomano, CA

Am J Hum Genet 2000
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Name Identifier Synonyms
bone development disease 0080006
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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