Abstract
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.
Highlights
Receptors [2, 3]
We report that mutation of Cys332 3 Tyr of Xenopus fibroblast growth factor receptors (FGFRs)-2, analogous to the Cys342 3 Tyr mutation most commonly found in Crouzon syndrome, promotes activation of the mutant receptor in the absence of ligand
Several mutations have been identified in the IgIII domain of human FGFR-2 in individuals with Crouzon syndrome [17, 18, 31]
Summary
Receptors [2, 3]. The FGFs have been shown to bind to lower affinity cell surface heparan sulfate proteoglycans [1, 2]. By late neurula stages animal caps from embryos injected with FGFR-2CS RNA (Fig. 1d) elongated in a manner similar to control caps treated with FGF-1 (Fig. 1b).
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