Signaling by FGFR3 point mutants in cancer

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R-HSA-8853338
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Homo sapiens
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The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically.

Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000)

In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).


Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).

More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014).

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
10377013 Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3

Bellus, GA, Bamshad, MJ, Przylepa, KA, Dorst, J, Lee, RR, Hurko, O, Jabs, EW, Curry, CJ, Wilcox, WR, Lachman, RS, Rimoin, DL, Francomano, CA

Am J Med Genet 1999
7773297 Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3

Tavormina, PL, Shiang, R, Thompson, LM, Zhu, YZ, Wilkin, DJ, Lachman, RS, Wilcox, WR, Rimoin, DL, Cohn, DH, Wasmuth, JJ

Nat Genet 1995
9279753 Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis

Reardon, W, Wilkes, D, Rutland, P, Pulleyn, LJ, Malcolm, S, Dean, JC, Evans, RD, Jones, BM, Hayward, R, Hall, CM, Nevin, NC, Baraister, M, Winter, RM

J Med Genet 1997
7913883 Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia

Shiang, R, Thompson, LM, Zhu, YZ, Church, DM, Fielder, TJ, Bocian, M, Winokur, ST, Wasmuth, JJ

Cell 1994
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
7847369 Achondroplasia is defined by recurrent G380R mutations of FGFR3

Bellus, GA, Hefferon, TW, Ortiz de Luna, RI, Hecht, JT, Horton, WA, Machado, M, Kaitila, I, McIntosh, I, Francomano, CA

Am J Hum Genet 1995
11466624 Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours

Sibley, K, Stern, P, Knowles, MA

Oncogene 2001
8589699 Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I

Tavormina, PL, Rimoin, DL, Cohn, DH, Zhu, YZ, Shiang, R, Wasmuth, JJ

Hum Mol Genet 1995
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
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
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
7670477 A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia

Bellus, GA, McIntosh, I, Smith, EA, Aylsworth, AS, Kaitila, I, Horton, WA, Greenhaw, GA, Hecht, JT, Francomano, CA

Nat Genet 1995
8845844 Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)

Rousseau, F, El Ghouzzi, V, Delezoide, AL, Legeai-Mallet, L, Le Merrer, M, Munnich, A, Bonaventure, J

Hum Mol Genet 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
7647778 Stop codon FGFR3 mutations in thanatophoric dwarfism type 1

Rousseau, F, Saugier, P, Le Merrer, M, Munnich, A, Delezoide, AL, Maroteaux, P, Bonaventure, J, Narcy, F, Sanak, M

Nat Genet 1995
19749790 Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner

di Martino, E, L'Hote, CG, Kennedy, W, Tomlinson, DC, Knowles, MA

Oncogene 2009
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
8078586 Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia

Rousseau, F, Bonaventure, J, Legeai-Mallet, L, Pelet, A, Rozet, JM, Maroteaux, P, Le Merrer, M, Munnich, A

Nature 1994
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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