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Binding of FGF2 to size-fractionated heparan sulfate from porcine tissues
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-97177OAI: oai:DiVA.org:uu-97177DiVA: diva2:171999
Available from: 2008-04-30 Created: 2008-04-30 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Role of Heparan Sulfate Structure in FGF-Receptor Interactions and Signaling
Open this publication in new window or tab >>Role of Heparan Sulfate Structure in FGF-Receptor Interactions and Signaling
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) belongs to the glycosaminoglycan family of polysaccharides and is found attached to protein cores on cell surfaces and in the extracellular matrix. The HS backbone consists of alternating hexuronic acid and glucosamine units and undergoes a number of modification reactions creating HS chains with alternating highly and low modified domains, where high degree of modification correlates with high negative charge. Fibroblast growth factors (FGFs) and their receptors (FRs) both bind to HS, which affect formation of the FGF–FR complexes on the cell surfaces. Activated FRs can trigger several intracellular signaling pathways leading thereby to diverse cellular responses.

Work presented in this thesis focuses on the effect of HS and its structures on FGF–FR complex formation and FGF-induced signaling. Studies with short, highly modified oligosaccharides and FGF1 and 2 combined with FR1c, 2c, 3c or 4 showed a correlation between the overall degree of modification and amount/stability of FGF–FR complexes. Our findings imply that several HS structures, differently modified but with the same negative charge density are equal in their ability to support complex formation. Co-application of oligosaccharides with FGF2 to HS-deficient cells and investigation of the thereby induced cell signaling confirmed our findings with a cell-free system. The oligosaccharide with the highest modification degree displayed the biggest impact on cell signaling, which was FGF2 concentration dependent. Studies with long HS polysaccharides with preserved high and low modified domains suggest that the proportion between these two types of domains and also the structure of the low modified domains are of importance for the FGF–HS–FR complex formation and cell activation capacity.

This work illuminates several aspects in how HS structure influences the interplay between FGFs and FRs and contributes to the understanding of what factors affect a cell’s response following FGF stimulation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 39 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 349
Biochemistry, heparan sulfate, oligosaccharide, fibroblast growth factor, fibroblast growth factor signaling, Biokemi
urn:nbn:se:uu:diva-8717 (URN)978-91-554-7193-4 (ISBN)
Public defence
2008-05-22, C10:305, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-04-30 Created: 2008-04-30 Last updated: 2011-06-17Bibliographically approved

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Spillmann, Dorothe
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