Fibroblast growth factors (FGFs) and their surface receptors (FGFRs) are critical components of many important biological processes including bone development. The four known FGFRs (FGFR1-FGFR4) are receptor tyrosine kinases (RTKs) activated by binding FGFs and heparin or heparan sulfate proteoglycans to their extracellular ligand binding domain resulting in FGFR dimerization and protein tyrosine kinase activation. It has been shown that the docking protein FRS2 plays a major role in mediating the intracellular signaling pathways following FGF stimulation. Other proteins implicated in FGF signaling include Shc, Gab1, Shp2 and Stat1 among others. Gene inactivation experiments in mice have shown that FGFR2 and FGFR3 play an important role in bone development. Moreover, mutations primarily in Fgfr2 and Fgfr3 were shown to be responsible for a variety of bone and skeletal disorders including Crouzon, Apert, Jackson- Weiss, achondroplasia and thanatophoric dysplasia syndromes. The goal of this proposal is to obtain a comprehensive view of the intracellular signaling pathways that are responsible for mediating bone development in response to FGFR2 and FGFR3 activation.
The specific aims of this proposal are to: (1) investigate the specific roles of the Fgfr3b and Fgfr3c isoforms in bone development by creating isoform specific knock-out mice, (2) develop genetically modified mice to explore the biological role of the docking protein FRS2 in Fgfr2c mediated bone development, (3) determine the role of FRS2 in human Icraniosynostosis syndrome using murine models, (4) identify FRS2 dependent and independent signaling Ipathways downstream of FGFR2 and FGFR3, and (5) determine the role of the SH2 domain containing IProtein 3BP2 in signaling via FGFR2 and FGFR3. Mutations in 3BP2 were found in cherubism, an lautosomal dominant inherited syndrome characterized by excessive bone degradation. Our goals will be accomplished by applying genetic, biochemical, structural and cell biological approaches. The information obtained from these studies will provide a detailed molecular view of how FGF signaling mediated by FGFR2 and FGFR3 and the docking protein FRS2 control bone development. It will also provide a framework for understanding diseases caused by mutations in FGFRs enabling the design of novel treatments for skeletal disorders such as craniosynostosis, achondroplasia, hypochondroplasia and thanatophoric dysplasia. ? ?
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