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Fibroblast growth factors and their receptors: an information network controlling tissue growth, morphogenesis and
1Department of Biochemistry, University of Liverpool, U.K.
Abstract:
The stimulation of cellular metabolism by the nine fibroblast growth factors (FGFs) is mediated by a dual-receptor system. This comprises a family of four receptor tyrosine kinases (FGFR) and heparan sulphate proteoglycans (HSPG). The stimulation of cell division by FGFs has an obligate requirement for both partners of the dual-receptor system. The binding of the nine FGFs to the FGFRs is marked by a pattern of overlapping specificity despite alternative splicing events generating a large number of FGFR proteins. Thus many of the FGFR isoforms bind several FGFs. It is likely that each FGF requires a different pattern of sulphation within the heparan sulphate chains for binding. Therefore, the HSPG receptors may provide additional specificity, allowing a cell to fine tune its response to the FGFs present in the extracellular milieu. The HSPG receptors also control the availability of FGFs and hence regulate the transport of FGFs within a tissue. FGF-stimulated cell division would appear to have a mandatory requirement for the FGFs to be translocated to the nucleus via the cytosol after interacting with the dual-receptor system. The consequences of the potential direct action of FGFs in stimulating cell division are examined in the light of current models of signal transduction.
Insights
Fibroblast growth factors (FGFs) stimulate cell metabolism and division via dual receptors: receptor tyrosine kinases (FGFRs) and heparan sulphate proteoglycans (HSPGs). HSPGs add specificity and regulate FGF availability, crucial for cell response and division.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Fibroblast growth factors (FGFs) are key regulators of cellular metabolism and division.
- FGF signaling relies on a dual-receptor system involving FGF receptors (FGFRs) and heparan sulphate proteoglycans (HSPGs).
- Both FGFRs and HSPGs are essential for FGF-mediated stimulation of cell division.
Purpose of the Study:
- To elucidate the roles of FGFRs and HSPGs in FGF signaling.
- To investigate the specificity of FGF binding to FGFRs and HSPGs.
- To examine the mechanism of FGF-mediated cell division, including nuclear translocation.
Main Methods:
- Analysis of FGF-FGFR interactions, considering alternative splicing of FGFRs.
- Investigation of FGF-HSPG binding specificity based on heparan sulphate chain sulphation patterns.
- Examination of FGF translocation to the nucleus following receptor interaction.
Main Results:
- FGFRs exhibit overlapping specificities for binding multiple FGFs.
- HSPGs likely provide additional specificity for FGF binding through unique sulphation patterns.
- HSPGs regulate FGF availability and transport within tissues.
- FGF-stimulated cell division appears to require nuclear translocation of FGFs after receptor engagement.
Conclusions:
- The dual-receptor system (FGFRs and HSPGs) is critical for FGF-mediated cellular responses.
- HSPGs play a vital role in fine-tuning FGF signaling specificity and availability.
- Nuclear translocation of FGFs is a potential key step in FGF-stimulated cell division.