Dimerization of FGFR3 point mutants with enhanced kinase activity

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R-HSA-2033476
Type
Reaction [transition]
Species
Homo sapiens
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Activating point mutations G380R, N540K and K650E/M/N/Q in FGFR3 have been identified in achondroplasia, hypochondroplasia and thanatophoric dysplasia I and II (reviewed in Webster and Donoghue, 1997, Burke, 1998). These mutants, which occur in the transmembrane and the kinase domain, have been shown to undergo ligand-independent dimerization and autophosphorylation when transfected into NIH 3T3 cells, although the extent of constitutive activation varies depending on the precise mutation (Webster and Donoghue, 1996; Webster, 1996; Naski, 1996; Bellus, 2000). In addition, some of the mutants retain the ability to respond to exogenous ligand, while others appear to be completely ligand-independent (Naski, 1996; Goriely, 2009). Interestingly, the extent of kinase activation correlates with the severity of the resulting condition, with the K650M and E mutations associated with thanatophoric dysplasia showing the higher levels of kinase activity than the G380R mutation associated with achondroplasia (Naski, 1996; Bellus, 2000; Goriely, 2009). More recently, these same mutations, along with G382D, N540S, K650T, and G97C, have also been identified in a range of cancers, most notably in bladder cancer and multiple myeloma (Zhang, 2005; Ronchetti, 2001; van Rhijn, 2002; Lindgren, 2006; reveiewed in Wesche, 2011; Greulich and Pollock, 2011).

Literature References
PubMed ID Title Journal Year
21367659 Targeting mutant fibroblast growth factor receptors in cancer

Greulich, H, Pollock, PM

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

Webster, MK, Donoghue, DJ

Trends Genet 1997
8754806 Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II

Webster, MK, d'Avis, PY, Robertson, SC, Donoghue, DJ

Mol Cell Biol 1996
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
19855393 Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

Goriely, A, Hansen, RM, Taylor, IB, Olesen, IA, Jacobsen, GK, McGowan, SJ, Pfeifer, SP, McVean, GA, Rajpert-De Meyts, E, Wilkie, AO

Nat Genet 2009
15880580 Constitutive activating mutation of the FGFR3b in oral squamous cell carcinomas

Zhang, Y, Hiraishi, Y, Wang, H, Sumi, KS, Hayashido, Y, Toratani, S, Kan, M, Sato, JD, Okamoto, T

Int J Cancer 2005
16532037 Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q

Lindgren, D, Liedberg, F, Andersson, A, Chebil, G, Gudjonsson, S, Borg, A, Månsson, W, Fioretos, T, Höglund, M

Oncogene 2006
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
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
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
Participants
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Disease
Name Identifier Synonyms
bone development disease 0080006
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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