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Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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2000 In: J. Biol. Chem., Vol. 275, 24653-60 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 275, 24653-60 p.
URN: urn:nbn:se:uu:diva-91086OAI: oai:DiVA.org:uu-91086DiVA: diva2:163681
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
In thesis
1. Heparan Sulfate Regulation of Fibroblast Growth Factor (FGF) Receptor-1 Signal Transduction
Open this publication in new window or tab >>Heparan Sulfate Regulation of Fibroblast Growth Factor (FGF) Receptor-1 Signal Transduction
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibroblast growth factors (FGFs) constitute a family (currently FGF-1 to FGF-23) of polypeptides that are essential in embryonal development and adult physiology, in animals from nematodes to humans. FGFs bind to four receptor tyrosine kinases, denoted FGFR-1 to FGFR-4. For proper function, the FGFs and their receptors depend on specific polysaccharide co-receptors, denoted heparan sulfate (HS). This thesis describes HS regulation of FGFR-1 signal transduction using blood vessel endothelial cells as a model.

We have determined HS structural features, necessary for FGF-2 induced FGFR-1 activation, using chemically modified heparin, which is structurally related to HS. Modified heparin, lacking sulfation at the 6-O position was inhibitory for FGFR-1 kinase activation and FGF-2 induced angiogenesis. Inhibition of blood vessel formation using modified heparin could be useful in treatment of diseases characterized by excess blood vessel formation. The critical role of HS sulfation for proper growth factor function was further underscored using an embryonal stem (ES) cell model. ES cells lacking expression of two isoforms of N-deacetyl N-sulfotransferase, NDST-1 and –2, failed to undergo embryonal development and to establish a vascular system. Exogenous heparin could not support development, but HS delivered from other ES cells allowed formation of primitive vessels and subsequent sprouting angiogenesis.

We have, furthermore, shown that the mechanism whereby HS supports FGF receptor activation is qualitative, as well as quantitative. Kinase activity could be induced by FGF-2 in the absence of HS, but this allowed only selected phosphorylation. In the presence of HS, the kinase activity was stabilized, allowing a broader spectrum of phosphorylation of sites on the FGF receptor itself as well as on cytoplasmic substrates. Finally, using selected microarrays, we have examined the potential regulation of enzymes in the HS biosynthesis pathway and of different proteoglycans to which HS is attached. Overall, we found no evidence for dramatic regulation on the transcriptional level, but could identify specific upregulation of HS proteoglycan syndecan-2, during blood vessel formation in vitro.

In conclusion, our studies demonstrate selective and complex regulation of HS synthesis and structure, essential in guiding growth factor function during health and disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 41 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1307
Pathology, FGF, FGFR, dimerisation, signal transduction, heparan sulfate, proteoglycan, heparin, VEGF, embryonal stem cell, endothelial cell, differentiation, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-3783 (URN)91-554-5809-2 (ISBN)
Public defence
2003-12-05, Rudbeckssalen, Rudbecklaboratoriet, Uppsala, 09:15
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved

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