QSulf1, a Heparan Sulfate 6-O-Endosulfatase, Inhibits Fibroblast Growth Factor Signaling in Mesoderm Induction and Angiogenesis

The signaling activities of multiple developmental ligands require sulfated heparan sulfate (HS) proteoglycans as coreceptors. QSulf1 and its mammalian orthologs are cell surface HS 6-O-endosulfatases that are expressed in embryonic mesodermal and neural progenitors and promote Wnt signal transducti...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (14), p.4833-4838
Main Authors: Wang, Shouwen, Ai, Xingbin, Freeman, Stephen D., Pownall, Mary E., Lu, Qun, Kessler, Daniel S., Emerson, Charles P., McKnight, Steven L.
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Biological Sciences
Cell lines
Cellular biology
Dimerization
Embryonic Induction
Embryos
Enzymes
Fibroblast Growth Factors - antagonists & inhibitors
Fibroblast Growth Factors - metabolism
Heparan sulfate
Heparin
Ligands
Mesoderm
Messenger RNA
Neovascularization, Physiologic - physiology
Receptors
Reverse Transcriptase Polymerase Chain Reaction
Signal transduction
Signal Transduction - physiology
Sulfatases - physiology
Sulfation
Xenopus
Xenopus laevis - embryology
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Summary:The signaling activities of multiple developmental ligands require sulfated heparan sulfate (HS) proteoglycans as coreceptors. QSulf1 and its mammalian orthologs are cell surface HS 6-O-endosulfatases that are expressed in embryonic mesodermal and neural progenitors and promote Wnt signal transduction. In this study, we have investigated the function of QSulf1 in fibroblast growth factor (FGF) signaling, which requires 6-O-sulfated HS for FGF receptor (FGFR) dimerization and tyrosine kinase activation. Here, we report that QSulf1 inhibits FGF2- and FGF4-induced mesoderm formation in the Xenopus embryo and FGF-dependent angiogenesis in the chicken embryo through 6-O-desulfation of cell surface HS. QSulf1 regulates FGF signaling through inhibition of HS-mediated FGFR1 activation by interfering with FGF-HS-FGFR1 ternary complex formation. Furthermore, QSulf1 can produce enzymatically modified soluble heparin that acts as a potent inhibitor of FGF2-induced angiogenesis in the chicken embryo. QSulf1, therefore, has dual regulatory functions as a negative regulator of FGF signaling and a positive regulator of Wnt signaling. Therefore, QSulf1 provides another reagent to produce enzymatically modified heparin compounds, in vivo and in vitro, to modulate cellular signaling in stem cell-based therapies to promote tissue regeneration and in cancer therapies to control cell growth and block angiogenesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401028101