title: FGFR3 intracellular mutations induce tyrosine phosphorylation in the Golgi and defective glycosylation.
abstract: Mutations of the Fibroblast Growth Factor Receptor 3 (FGFR3) gene have been implicated in a series of skeletal dysplasias including hypochondroplasia, achondroplasia and thanatophoric dysplasia. The severity of these diseases ranges from mild dwarfism to severe dwarfism and to perinatal lethality, respectively. Although it is considered that the mutations give rise to constitutively active receptors, it remains unclear how the different mutations are functionally linked to the severity of the different pathologies. By examining various FGFR3 mutations in a HEK cell culture model, including the uncharacterized X807R mutation, it was found that only the mutations affecting the intracellular domain, induced premature receptor phosphorylation and inhibited receptor glycosylation, suggesting that premature receptor tyrosine phosphorylation of the native receptor inhibits its glycosylation. Moreover, these mutations appeared to be associated with elevated receptor signaling in the Golgi apparatus. In conclusion, although pathological severity could not be correlated with a single factor arising from FGFR3 mutations, these results suggest that intracellular domain mutations define a distinct means by which mutated FGFR3 could disrupt bone development.
authors.affiliation: INSERM U781, Hôpital des Enfants Malades, 149 rue de Sèvres-75015 Paris, France. lindagibbs@bigfoot.com
authors.forename: Linda
authors.initials: L
authors.lastname: Gibbs
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D001847:Bone Diseases / Q000473:pathology; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D022083:Cytoplasmic Structures / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D020126:Brefeldin A; D019000:Phosphotyrosine; D051498:Receptor, Fibroblast Growth Factor, Type 3; D008239:Lysine; D015739:Nocodazole