Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Heparan Sulfate Regulation of Fibroblast Growth Factor (FGF) Receptor-1 Signal Transduction
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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. , p. 41
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1307
Keywords [en]
Pathology, FGF, FGFR, dimerisation, signal transduction, heparan sulfate, proteoglycan, heparin, VEGF, embryonal stem cell, endothelial cell, differentiation
Keywords [sv]
Patologi
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-3783ISBN: 91-554-5809-2 (print)OAI: oai:DiVA.org:uu-3783DiVA, id: diva2:163685
Public defence
2003-12-05, Rudbeckssalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
Open this publication in new window or tab >>Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
Show others...
2000 In: J. Biol. Chem., Vol. 275, p. 24653-60Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91086 (URN)
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
2. Heparan sulfate expression is critical in vascular development
Open this publication in new window or tab >>Heparan sulfate expression is critical in vascular development
Show others...
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91087 (URN)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2011-06-28Bibliographically approved
3. Differential tyrosine phosphorylation of fibroblast growth factor (FGF) receptor-1 and receptor proximal signal transduction in response to FGF-2 and heparin
Open this publication in new window or tab >>Differential tyrosine phosphorylation of fibroblast growth factor (FGF) receptor-1 and receptor proximal signal transduction in response to FGF-2 and heparin
Show others...
2003 In: Exp. Cell Research, Vol. 278, p. 190-198Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91088 (URN)
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
4. Regulation of syndecan family members in fibroblast growth factor receptor-2-induced endothelial cell differentiation
Open this publication in new window or tab >>Regulation of syndecan family members in fibroblast growth factor receptor-2-induced endothelial cell differentiation
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91089 (URN)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2010-01-13Bibliographically approved

Open Access in DiVA

fulltext(465 kB)1433 downloads
File information
File name FULLTEXT01.pdfFile size 465 kBChecksum SHA-1
6123a47263ef4e3c04fba08c698f152175020eaa3269244500325e8c2f5c1db288f0b18d
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Department of Genetics and Pathology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 1433 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 925 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf