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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Hart, K. C. Galvin, B. D. Robertson, S. C. Meyer, A. N. Webster, M. K. Donoghue, D. J. |
| Description | Author Affiliation: Robertson SC ( Department of Chemistry and Biochemistry, Center for Molecular Genetics, University of California at San Diego, La Jolla, CA 92093-0367.); |
| Abstract | Multiple human skeletal and craniosynostosis disorders, including Crouzon, Pfeiffer, Jackson-Weiss, and Apert syndromes, result from numerous point mutations in the extracellular region of fibroblast growth factor receptor 2 (FGFR2). Many of these mutations create a free cysteine residue that potentially leads to abnormal disulfide bond formation and receptor activation; however, for noncysteine mutations, the mechanism of receptor activation remains unclear. We examined the effect of two of these mutations, W290G and T341P, on receptor dimerization and activation. These mutations resulted in cellular transformation when expressed as FGFR2/Neu chimeric receptors. Additionally, in full-length FGFR2, the mutations induced receptor dimerization and elevated levels of tyrosine kinase activity. Interestingly, transformation by the chimeric receptors, dimerization, and enhanced kinase activity were all abolished if either the W290G or the T341P mutation was expressed in conjunction with mutations that eliminate the disulfide bond in the third immunoglobulin-like domain (Ig-3). These results demonstrate a requirement for the Ig-3 cysteine residues in the activation of FGFR2 by noncysteine mutations. Molecular modeling also reveals that noncysteine mutations may activate FGFR2 by altering the conformation of the Ig-3 domain near the disulfide bond, preventing the formation of an intramolecular bond. This allows the unbonded cysteine residues to participate in intermolecular disulfide bonding, resulting in constitutive activation of the receptor. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 8 |
| Volume Number | 95 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1998-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Musculoskeletal Abnormalities Genetics Point Mutation Receptor Protein-Tyrosine Kinases Receptors, Fibroblast Growth Factor Amino Acid Sequence Animals COS Cells Craniofacial Dysostosis Cysteine Dimerization Disulfides Immunoglobulins Chemistry Models, Molecular Molecular Sequence Data Protein Structure, Secondary Biosynthesis Metabolism Receptor, Fibroblast Growth Factor, Type 2 Recombinant Fusion Proteins Recombinant Proteins Transfection Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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