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(Received for publication, May 17, 1996)
From the The fibroblast growth factor receptors (FGFRs)
are a family of receptor protein tyrosine kinases that have been shown
to mediate a variety of cellular processes including angiogenesis,
wound healing, tumorigenesis, and embryonic development. Distinct FGFR
mutations in individuals with autosomal dominant disorders of bone
growth and development provide a unique opportunity to determine the
function of FGFRs during embryonic development. To determine the
consequences of these mutations on receptor function, we have made
mutations in Xenopus FGFR1 (XFGFR1) and FGFR2
(XFGFR2) that correspond to several of the mutations identified
in these dysmorphic syndromes. Analysis of mutant receptor proteins
expressed in Xenopus oocytes indicates that all but one
have elevated tyrosine kinase activity relative to their wild-type
counterparts. Those mutations that give an unpaired cysteine residue in
the extracellular domain result in intermolecular disulfide bond
formation and covalent receptor dimerization. Microinjection of
Xenopus embryos with RNA encoding mutant receptors with
elevated tyrosine kinase activity results in ligand-independent
induction of mesoderm in animal pole explants. Wild-type XFGFR1 and
XFGFR2 do not induce mesoderm when injected at similar doses.
Co-injection of RNA encoding a dominant negative FGF receptor, lacking
the tyrosine kinase domain, together with RNA encoding various
activated FGFRs inhibits mesoderm induction by a receptor activated by
a transmembrane domain mutation or extracellular mutations that
introduce an unpaired cysteine residue into the extracellular domain
but does not inhibit mesoderm induction by receptors bearing a tyrosine
kinase domain mutation. These results indicate that different point
mutations may activate FGFRs by distinct mechanisms and that
ligand-independent FGFR activation may be a feature in common to many
skeletal disorders.
Volume 271, Number 40,
Issue of October 4, 1996
pp. 25049-25057
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
and¶
Department of Molecular Biology, Holland
Laboratory, American Red Cross, Rockville, Maryland 20855 and the
¶ Department of Anatomy and Cell Biology, George Washington
University Medical Center, Washington, D. C. 20037
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