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FGFR regulation in human developmental disorders

Melanie Webster

Appointment Period: 1996-1997 / Grant Year: [12]

Melanie WebsterFibroblast growth factor receptors (FGFRs), in response to binding of FGF ligands, transmit signals which regulate the growth and differentiation of many tissues. It was recently observed that point mutations in different domains of three of the four FGFRs cause a number of common human skeletal abnormalities, including dwarfism and premature fusion of the skull bones. In the past year we have demonstrated that many of these mutations result in unregulated, ligand-independent tyrosine kinase activity of the mutant FGFRs, and we are currently building on these studies.

One mutation in particular, in the highly conserved activation loop of the FGFR3 tyrosine kinase domain, has proven useful to probe the signal transduction pathway used by this receptor. We have constructed both normal and mutant FGFR3 kinase domains, in the absence of ligand-binding or membrane-spanning domains, which were targeted to three different subcellular locations: the inner surface of the plasma membrane, the cytoplasm, or the nucleus. Each of the mutant kinase domains had enhanced biological activity, as measured both by in vitro and in vivo assays, and all constructs were expressed in the predicted locations. Surprisingly, the membrane-localized mutant kinase domain, but not the full-length mutant receptor, acted as a potent mitogen and oncogene, resulting in the formation of foci of transformed fibroblasts in culture. Furthermore, both the wild-type membrane-localized kinase domain (which had no apparent kinase activity) and the mutant membrane-localized kinase domain, were able to send signals to the cell nucleus to induce the activity of transcription factors. These results indicate that 1) FGFR3 has the potential to act as an oncogene under certain circumstances 2) the extracellular and transmembrane domains appear to inhibit FGFR tyrosine kinase activity 3) the reported nuclear relocalization of FGFRs in response to ligand may not play an important role in mitogenesis or signaling and 4) localization to the plasma membrane is critical for signaling by FGFRs. Future studies will be directed at comparing biological signaling by the four different FGFRs, and further defining the mechanisms by which particular point mutations cause constitutive receptor activation.

PUBLICATIONS (resulting from this training)

Webster MK, Donoghue DJ. (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 15:520-7.

Galvin BD, Hart KC, Meyer AN, Webster MK, Donoghue DJ. (1996) Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras. Proc Natl Acad Sci USA 93:7894-9.

Webster MK, d'Avis PY, Robertson SC, Donoghue DJ. (1996) Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol. 16:4081-7.

Webster MK, Donoghue DJ. (1997) FGFR activation in skeletal disorders: too much of a good thing. Trends Genet. 13:178-82.

Webster MK, Donoghue DJ. (1997) Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain. Mol Cell Biol. 17:5739-47.

Chen LI, Webster MK, Meyer AN, Donoghue DJ. (1997) Transmembrane domain sequence requirements for activation of the p185c-neu receptor tyrosine kinase. J Cell Biol. 137:619-31.

d'Avis PY, Robertson SC, Meyer AN, Bardwell WM, Webster MK, Donoghue DJ. (1998) Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ. 9:71-8.

Robertson SC, Meyer AN, Hart KC, Galvin BD, Webster MK, Donoghue DJ. (1998) Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. Proc Natl Acad Sci USA 95:4567-72.

Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA. (1999) A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 64:722-31.

Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. (2000) Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 67(6):1411-21.