Signaling by FGFR in disease

Stable Identifier
R-HSA-1226099
DOI
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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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
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Nat Genet 1997
8640234 Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia

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

Nat Genet 1996
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

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Proc Natl Acad Sci U S A 1998
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Nat Rev Cancer 2010
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Hum Pathol 2010
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Trends Genet 1997
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Cancer Res 2008
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Cell Growth Differ 1998
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10471491 Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas

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

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

Friesel, R, Neilson, KM

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

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

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Proc Natl Acad Sci U S A 1996
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Oncogene 2001
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Am J Hum Genet 2000
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
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