New thanatophoric dysplasia study results from University of Paris described
2007 AUG 14 -- New investigation results, "The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor," are detailed in a study published in FEBS Journal. "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," scientists in Paris, France report. "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 the cell surface. Normal processing was rescued by tyrosine kinase inhibitor treatment. Internalization of the R248C and Y373C mutant receptors, which form stable disulfide-bonded dimers at the cell surface was less efficient than the wild-type, whereas ubiquitylation was markedly increased but apparently independent of the E3 ubiquitin-ligase casitas B-lineage lymphoma (c-Cbl). Constitutive phosphorylation of c-Cbl by the K650M mutant appeared to be related to the intracellular retention of the receptor," wrote J. Bonaventure and colleagues, University of Paris. The researchers concluded: "Therefore, although mutation K650M affecting the TK2 domain induces defective targeting of the overphosphorylated receptor, a different mechanism characterized by receptor retention at the plasma membrane, excessive ubiquitylation and reduced degradation results from mutations that affect the extracellular domain and the stop codon." Bonaventure and colleagues published their study in FEBS Journal (The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS Journal, 2007;274(12):3078-93). For additional information, contact J. Bonaventure, Universite Paris Sud, Orsay and Dept. of Medical Genetics INSERM U393, Universite Paris Sud, Hopital Necker, Paris, France. The publisher's contact information for the FEBS Journal is: Blackwell Publishing Ltd., 9600 Garsington Rd., Oxford OX4 2DG, Oxon, England. Keywords: France, Paris, Dermatology, Thanatophoric Dysplasia. This article was prepared by Life Science Weekly editors from staff and other reports. Copyright 2007, Life Science Weekly via NewsRx.com.
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