Constitutive dimerization of FGFR3 cysteine mutants

Stable Identifier
Reaction [transition]
Homo sapiens
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Activating mutations in FGFR3 that introduce a mutant cysteine residue to the Ig2-Ig3 linker domain or the extracellular juxtamembrane region have been identified in the lethal neonatal disorder thanatophoric dysplasia (Tavormina, 1995a, b; Rousseau, 1996; reviewed in Webster and Donoghue, 1997; Burke, 1998). The presence of the mutant cysteine residue causes ligand-independent dimerization of the receptor through Cys-mediated intramolecular disulphide bonds and leads to increased biological signaling without changing the intrinsic kinase activity of the receptor (d'Avis, 1998; Adar, 2002). More recently, the same mutations, arising somatically, have been identified in a range of cancers including bladder, prostrate and cervical cancer, as well as in multiple myeloma and head and neck squamous cell carcinoma (reviewed in Wesche, 2011).
Literature References
PubMed ID Title Journal Year
8845844 Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)

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

Hum Mol Genet 1996
9154000 FGFR activation in skeletal disorders: too much of a good thing

Donoghue, DJ, Webster, MK

Trends Genet 1997
7773297 Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3

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

Nat Genet 1995
8589699 Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I

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

Hum Mol Genet 1995
9538690 Fibroblast growth factor receptors: lessons from the genes

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

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

Haglund, K, Wesche, J, Haugsten, EM

Biochem J 2011
12009017 Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization

Yayon, A, David, P, Monsonego-Ornan, E, Adar, R

J Bone Miner Res 2002
9438390 Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I

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

Cell Growth Differ 1998
Functional status

Gain of function of FGFR3 cysteine mutants [plasma membrane]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
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