FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models.
This review describes recent progress in the field of fibroblast growth factor receptors (FGFRs) with an emphasis on the role of FGFR mutants in skeletal malformations. This family of four receptors contains the most frequent germline mutations in humans. More than 75 mutations have been recorded, which account for more than seven skeletal syndromes. The common cause for all the mutant phenotypes is gain-of-function by receptor activation through three major mechanisms: receptor dimerization, kinase activation, and increased affinity for FGF. The severity of the disease is correlated with both the extent of receptor activation and the specific tissue in which the mutant receptor form is expressed. Paradoxically, the consequence of receptor activation is inhibition of chondrocyte cell growth through signaling pathways that are cell-type specific. The structure of the FGFR-FGF complex and its possible ternary complex with heparin explain the mechanism of receptor dimerization in the ectodomain and the possible contribution by some of the mutations to this process. Analysis of FGFR3 mutant mice produced by gene targeting as models for human disease, and studies in cell lines, have begun to delineate the novel signaling pathways of FGFR3 and to define possible targets for therapy.
Kannan
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Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Givol
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D000818:Animals; D001847:Bone Diseases / Q000235:genetics* / Q000378:metabolism*; D019281:Dimerization; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism; D018095:Germ-Line Mutation; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D008024:Ligands; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D006493:Heparin; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3