title: Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia.
abstract: Mutations of fibroblast growth factor receptor 3 (FGFR3) are responsible for achondroplasia (ACH) and related dwarfing conditions in humans. The pathogenesis involves constitutive activation of FGFR3, which inhibits proliferation and differentiation of growth plate chondrocytes. Here we report that activating mutations in FGFR3 increase the stability of the receptor. Our results suggest that the mutations disrupt c-Cbl-mediated ubiquitination that serves as a targeting signal for lysosomal degradation and termination of receptor signaling. The defect allows diversion of actively signaling receptors from lysosomes to a recycling pathway where their survival is prolonged, and, as a result, their signaling capacity is increased. The lysosomal targeting defect is additive to other mechanisms proposed to explain the pathogenesis of ACH.
authors.affiliation: Research Center, Shriners Hospital for Children, and Departmentof Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Jay Y
authors.initials: JY
authors.lastname: Cho
authors.forename: Changsheng
authors.initials: C
authors.lastname: Guo
authors.forename: Monica
authors.initials: M
authors.lastname: Torello
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Lunstrum
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iwata
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
mesh_terms: D000130:Achondroplasia / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002455:Cell Division; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D025801:Ubiquitin; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3