Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras
| Jazyk: | English |
|---|---|
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d63e81aaec7884e574e9f50955acc37 https://europepmc.org/articles/PMC38845/ |
| Rights: | OPEN |
| Přírůstkové číslo: | edsair.doi.dedup.....0d63e81aaec7884e574e9f50955acc37 |
| Autor: | April N. Meyer, Daniel J. Donoghue, Kristen C. Hart, Melanie K. Webster, Brendan D. Galvin |
| Jazyk: | angličtina |
| Rok vydání: | 1996 |
| Předmět: |
musculoskeletal diseases
congenital hereditary and neonatal diseases and abnormalities Receptor ErbB-2 Recombinant Fusion Proteins Molecular Sequence Data Biology Transfection Receptor tyrosine kinase Craniosynostoses Mice medicine Animals Humans Point Mutation Amino Acid Sequence Kinase activity Cloning Molecular Receptor Fibroblast Growth Factor Type 2 Sequence Deletion Multidisciplinary Base Sequence Fibroblast growth factor receptor 2 Fibroblast growth factor receptor 1 Crouzon syndrome Receptor Protein-Tyrosine Kinases 3T3 Cells Syndrome Genes erbB-2 medicine.disease Molecular biology Receptors Fibroblast Growth Factor Fibroblast growth factor receptor Pfeiffer syndrome biology.protein Signal transduction Research Article |
| Popis: | Crouzon syndrome is an autosomal dominant condition primarily characterized by craniosynostosis. This syndrome has been associated with a variety of amino acid point mutations in the extracellular domain of fibroblast growth factor receptor 2 (FGFR2). FGFR2/Neu chimeras were generated by substituting the extracellular domain of Neu with that of FGFR2 containing the following Crouzon mutations: Tyr-340-->His; Cys-342-->Tyr; Cys-342-->Arg; Cys-342-->Ser; Ser-354-->Cys: and delta17 (deletion of amino acids 345-361). Each of the mutant chimeric FGFR2/Neu constructs stimulated focus formation in NIH 3T3 cells, indicating that Crouzon mutations can stimulate signal transduction through a heterologous receptor tyrosine kinase. In vitro kinase assay results indicate that FGFR2 receptors containing Crouzon mutations have increased tyrosine kinase activity and, when analyzed under nonreducing conditions, exhibited disulfide-bonded dimers. Thus the human developmental abnormality Crouzon syndrome arises from constitutive activation of FGFR2 due to aberrant intermolecular disulfide-bonding. These results together with our earlier observation that achondroplasia results from constitutive activation of the related receptor FGFR3, leads to the prediction that other malformation syndromes attributed to FGFRs, such as Pfeiffer syndrome and Thanatophoric dysplasia, also arise from constitutive receptor activation. |
| Databáze: | OpenAIRE |
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