Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome.
The fibroblast growth factor receptors (FGFRs) are a family of ligand-activated, membrane-spanning tyrosine kinases. Mutations in several human FGFR genes have been identified as playing a role in certain disorders of bone growth and development. One of these, Crouzon syndrome, an autosomal dominant disorder causing craniosynostosis, has been associated with mutations in the human FGFR-2 gene. We report here that microinjection of Xenopus embryos with RNA encoding an FGFR-2 protein bearing a Cys332-->Tyr mutation (FGFR-2CS) found in Crouzon syndrome results in fibroblast growth factor (FGF)-independent induction of mesoderm in animal pole explants. Wild-type FGFR-2 did not induce mesoderm when injected at similar doses. The effects of the mutant receptor were blocked by co-expression of dominant negative mutants of either Raf or Ras. Analysis of the mutant receptor protein expressed in Xenopus oocytes indicates that it forms covalent homodimers, does not bind radiolabeled FGF, and has increased tyrosine phosphorylation. These results indicate that FGFR-2CS forms an intermolecular disulfide bond resulting in receptor dimerization and ligand-independent activation that may play a role in the etiology of Crouzon syndrome.
Neilson
K M
KM
Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Friesel
R E
RE
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001755:Blastocyst / Q000166:cytology / Q000502:physiology; D003001:Cloning, Molecular; D003394:Craniofacial Dysostosis / Q000235:genetics*; D017931:DNA Primers; D004625:Embryo, Nonmammalian / Q000502:physiology; D005260:Female; D006801:Humans; D008648:Mesoderm / Q000502:physiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology; D010957:Plasmids; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis
D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D029867:Xenopus Proteins; C496353:FGFR2 protein, human; C496357:Fgfr2 protein, Xenopus; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2