FGFR2 mutants with enhanced kinase activity Dimerization of FGFR2 point mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11781872 Pubmed17525745 Pubmed17552943 Pubmed17803937 Pubmed18552176 Pubmed18757403 Pubmed9857065 Reactome Database ID Release 432033479 Reactome, http://www.reactome.org ReactomeREACT_120878 Reviewed: Ezzat, S, 2012-05-15 Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998). Due to the highly conserved nature of these residues across all four FGF receptors, it is generally believed that these germline mutations in FGFR2 are also activating, though this remains to be demonstrated experimentally.<br><br><br>As further support of this notion, activating point mutations in the kinase domain of FGFR2 have also been identified in endometrial, uterine and cervical cancers (Pollock, 2007; Dutt, 2008), and in some cases have been shown to have enhanced kinase activity and to support anchorage-independent growth in NIH 3T3 cells (Dutt, 2008). Knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival (Dutt, 2008; Byron, 2008). Kinase-domain mutants show elevated levels of activity relative to the wild-type even in the absence of receptor phosphorylation, and although their kinase activity is further enhanced upon trans-autophosphorylation, the extent of this is less than that seen in the wild-type, suggesting that the mutant alleles are capable of of supporting ligand-independent activation (Chen, 2007)<br> has a Stoichiometric coefficient of 2 FGFR2 mutant dimers with enhanced kinase activity