Constitutive Activation of Fibroblast Growth Factor Receptor-2 by a Point Mutation Associated with Crouzon Syndrome

doi:10.1074/jbc.270.44.26037

Constitutive Activation of Fibroblast Growth Factor Receptor-2 by a Point Mutation Associated with Crouzon Syndrome (*)

From the Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855

^¶ To whom correspondence should be addressed:
Dept. of Molecular Biology, Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855.
Tel.: 301-738-0865; Fax: 301-738-0465; friesel{at}usa.red-cross.org.

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 Cys 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.

Footnotes

↵^§ Supported by National Institutes of Health Predoctoral Training Grant T32-HL-07698. This work was performed in partial fulfillment of the requirements for the degree of Doctor of Philosophy from the Graduate Program in Genetics, School of Arts and Sciences, George Washington University, Washington, D. C. 20037.
↵* This work was supported by National Institutes of Health Grant HD29561 (to R. E. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

FGF

fibroblast growth factor

FGFR

FGF receptor

BSA

bovine serum albumin.
↵² K. M. Neilson and R. E. Friesel, unpublished observation.
- Received August 24, 1995.