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Lack of L-iduronic acid in heparan sulfate affects interaction with growth factors and cell signaling
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 23, 15942-15950 p.Article in journal (Refereed) Published
Abstract [en]

Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of D-glucuronic acid to L-iduronic acid in heparan sulfate (HS) biosynthesis. Disruption of the Hsepi gene in mouse yielded a lethal phenotype with selective organ defects, but had remarkably little effect on other organ systems. We have approached the underlying mechanisms by examining the course and effects of FGF2 signaling in a mouse embryonic fibroblast (MEF) cell line derived from the Hsepi-/- mouse. The HS produced by these cells is devoid of IdoA residues, but shows upregulated N- and 6-O-sulfation compared to wildtype (WT) MEF HS. In medium fortified with 10% FCS the Hsepi-/- MEFs proliferated and migrated similar to WT cells. Under starvation conditions both cell types showed attenuated proliferation and migration, that could be restored by addition of FGF2 to WT cells whereas Hsepi-/- cells were resistant. Moreover, ERK phosphorylation following FGF2 stimulation was delayed in Hsepi-/- compared to WT cells. Assessment of HS-growth factor interaction by nitrocellulose filter trapping revealed strikingly aberrant binding property of FGF2 and glia-derived neurotropic factor (GDNF) to Hsepi-/- but not to WT HS. GDNF has a key role in kidney development, defective in Hsepi-/- mice. By contrast, Hsepi-/- and WT HS interacted similarly and in conventional mode with FGF10. These findings correlate defective function of growth factors with their mode of HS interaction, and may help explain the partly modest organ phenotypes observed after genetic ablation of selected enzymes in HS biosynthesis.

Place, publisher, year, edition, pages
2009. Vol. 284, no 23, 15942-15950 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-103525DOI: 10.1074/jbc.M809577200ISI: 000266501000061PubMedID: 19336402OAI: oai:DiVA.org:uu-103525DiVA: diva2:218389
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
Open this publication in new window or tab >>Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) and heparin are linear polysaccharide chains covalently O-linked to serine residues within the core proteins, so called HS proteoglycans (PGs) or heparin PG. HSPGs are produced by almost all mammalian cells and known to play important roles in developmental processes, physiological and pathological conditions; whereas heparin PG is produced by mast cells and best known as an anticoagulant in clinic.

Biosynthesis of HS/heparin occurs in Golgi compartment and involves many enzymes, one of which is glucuronyl C5-epimerase (Hsepi) that catalyzes the conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA). Heparanase is an enzyme involved in metabolism of HS; it cleaves the linkage between GlcA and glucosamine residues in HS/heparin chains. Heparanase is expressed essentially by all cells and found up-regulated in many metastatic tumors.

This thesis focuses on the structure and functions of HS/heparin through studies on the implications of Hsepi and heparanase. My study demonstrated that the modification catalyzed by Hsepi is critical for HS-dependent function of growth factors, especially FGF2; heparanase is involved in regulation of HS biosynthesis and matrix metalloproteinases expression; moreover, my experimental data demonstrated the functions of heparin in mast cells, showing cleavage of heparin by heparanase contributes to modulation of protease storage in mast cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 470
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-107202 (URN)978-91-554-7571-0 (ISBN)
Public defence
2009-09-11, C10:301, BMC, Husargatan 3, Uppsala, 09:00 (English)
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Available from: 2009-08-20 Created: 2009-07-28 Last updated: 2009-08-20Bibliographically approved

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Li, Jin-Ping

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