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).
Bonaventure, J, Munnich, A, El Ghouzzi, V, Rousseau, F, Legeai-Mallet, L, Le Merrer, M, Delezoide, AL
Donoghue, DJ, Webster, MK
Wilcox, WR, Lachman, RS, Cohn, DH, Wasmuth, JJ, Thompson, LM, Wilkin, DJ, Rimoin, DL, Shiang, R, Zhu, YZ, Tavormina, PL
Cohn, DH, Wasmuth, JJ, Shiang, R, Rimoin, DL, Zhu, YZ, Tavormina, PL
Burke, D, Malcolm, S, Blundell, TL, Wilkes, D
Haglund, K, Wesche, J, Haugsten, EM
Yayon, A, David, P, Monsonego-Ornan, E, Adar, R
Bardwell, WM, Donoghue, DJ, d'Avis, PY, Robertson, SC, Webster, MK, Meyer, AN
Gain of function of FGFR3 cysteine mutants [plasma membrane]
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