Inhibition of FGF Signaling via Sulf1

Boston Biomedical Research Institute
posted on 05/12/2011

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Background: The signaling activities of multiple developmental ligands are controlled by heparan sulfate proteoglycans (HSPGs). HSPGs function as co-receptors to control ligand-receptor interactions for signaling, which requires sulfated sugar residues along heparan sulfate (HS) chains.
QSulf1 and its mammalian orthologs are cell surface HS 6-O endosulfatases that are expressed in mesodermal and neural stem cell progenitor lineages in embryos and promote Wnt signal transduction through modulation of Wnt ligand interaction with its Frizzled receptor.
In this study, we have investigated the function of QSulf1 in FGF signaling, which requires 6-O sulfated HS to function as a co-receptor in controlling receptor dimerization and tyrosine kinase activation.
Here, we report that QSulf1 inhibits FGF2- and FGF4-induced mesoderm formation in the Xenopus embryo and angiogenesis in the chick embryo, providing evidence that QSulf1 has dual negative and positive regulatory functions to control FGF and Wnt signaling in embryonic patterning.
QSulf1 regulates FGF signaling through inhibition of HS-mediated FGFR1 receptor activation, which can be rescued by extracellular soluble heparin.
Furthermore, QSulf1-modified soluble heparin is a potent inhibitor of FGF2-induced angiogenesis in the chick embryo by interfering with FGF-HS-FGFR1 ternary complex formation.
Application: The enzymatic specificity of QSulf1 for HS modification of growth factor signaling provides a novel reagent to produce enzymatically-modified heparin compounds, in vivo and in vitro.
This activity offers potential applications in stem cell-based therapies to promote tissue regeneration and in cancer therapies to control cell growth and block angiogenesis.
Status: US. patent application filed March, 2004