FGFR3 point mutants with enhanced kinase activity Dimerization of FGFR3 point mutants with enhanced kinase activity 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). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11429702 Pubmed12461689 Pubmed15880580 Pubmed16532037 Pubmed19855393 Pubmed21367659 Pubmed21711248 Pubmed8599935 Pubmed8640234 Pubmed8754806 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 432033476 Reactome, http://www.reactome.org ReactomeREACT_120782 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 FGFR3 point mutant dimers with enhanced kinase activity