TAILIEUCHUNG - Báo cáo khoa học: The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor

The eye lens is composed of fiber cells that differentiate from epithelial cells on its anterior surface. In concert with this differentiation, a set of proteins essential for lens function is synthesized, and the cellular organelles are degraded. | ễFEBS Journal The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation processing and ubiquitylation of the receptor Jacky Bonaventure1 2 Linda Gibbs2 William C. Horne3 and Roland Baron3 1 Institut Curie Universite Paris Sud Orsay France 2 Department of MedicalGenetics INSERM U393 HopitalNecker Paris France 3 Department of Cell Biology and Orthopaedics Yale University Schoolof Medicine New Haven CT USA Keywords Cbl FGFR3 mutation phosphorylation ubiquitylation Correspondence J. Bonaventure Institut Curie CNRS UMR 146 Bat. 110 Universite Paris Sud 91400 Orsay France Fax 33 1 69 86 53 01 Tel 33 1 69 86 71 80 E-mail R. Baron Department of Cell Biology and Orthopaedics Yale University Schoolof Medicine PO Box 208044 New Haven CT 208044 USA Fax 1 203 785 2744 Tel 1 203 785 4150 E-mail Received 5 February 2007 revised 16 April 2007 accepted 18 April 2007 doi Recurrent missense fibroblast growth factor receptor 3 FGFR3 mutations have been ascribed to skeletal dysplasias of variable severity including the lethal neonatal thanatophoric dysplasia types I TDI and II TDII . To elucidate the role of activating mutations causing TDI on receptor trafficking and endocytosis a series of four mutants located in different domains of the receptor were generated and transiently expressed. The putatively elongated X807R receptor was identified as three isoforms. The fully glycosylated mature isoform was constitutively but mildly phosphorylated. Similarly mutations affecting the extracellular domain R248C and Y373C induced moderate constitutive receptor phosphorylation. By contrast the K650M mutation affecting the tyrosine kinase 2 TK2 domain produced heavy phosphorylation of the nonglycosylated and mannose-rich isoforms that impaired receptor trafficking through the Golgi network. This resulted in defective expression of the mature isoform at

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