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Syndecan - Regulation and Function of its Glycosaminoglycan Chains
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The cell surface is an active area where extracellular molecules meet their receptors and affect the cellular fate by inducing for example cell proliferation and adhesion. Syndecans and integrins are two transmembrane molecules that have been suggested to fine-tune these activities, possibly in cooperation. Syndecans are proteoglycans, i.e. proteins with specific types of carbohydrate chains attached. These chains are glycosaminoglycans and either heparan sulfate (HS) or chondroitin sulfate (CS). Syndecans are known to influence cell adhesion and signaling. Integrins in turn, are important adhesion molecules that connect the extracellular matrix with the cytoskeleton, and hence can regulate cell motility. In an attempt to study how the two types of glycosaminoglycans attached to syndecan-1 can interact with integrins, a cell based model system was used and functional motility assays were performed. The results showed that HS, but not CS, on the cell surface was capable of regulating integrin-mediated cell motility.

Regulation of intracellular signaling is crucial to prevent abnormal cellular behavior. In the second part of this thesis, the aim was to see how the presentation of glycosaminoglycan chains to the FGF signaling complex could affect the cellular response. When attached to the plasma membrane via syndecan-1, CS chains could support the intracellular signaling, although not promoting as strong signals as HS. When glycosaminoglycans were attached to free ectodomains of syndecan-1, both types of chains sequestered FGF2 from the receptors to the same extent, pointing towards functional overlap between CS and HS.

To further study the interplay between HS and CS, their roles in the formation of pharyngeal cartilage in zebrafish were established. HS was important during chondrocyte intercalation and CS in the formation of the surrounding extracellular matrix. Further, the balance between the biosynthetic enzymes determined the ratio of HS and CS, and HS biosynthesis was prioritized over CS biosynthesis.

The results presented in this thesis provide further insight into the regulation of HS biosynthesis, as well as the roles of both HS and CS on the cell surface. It is evident, that in certain situations there is a strict requirement for a certain HS structure, albeit in other situations there is a functional overlap between HS and CS.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 884
Keyword [en]
heparan sulfate, chondroitin sulfate, integrin, cell motility, fibroblast growth factor signaling, pharyngeal cartilage, biosynthesis regulation
National Category
Cell and Molecular Biology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-197691ISBN: 978-91-554-8637-2 (print)OAI: oai:DiVA.org:uu-197691DiVA: diva2:613803
Public defence
2013-05-17, A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-04-25 Created: 2013-04-02 Last updated: 2013-08-30Bibliographically approved
List of papers
1. The Mutual Impact of Syndecan-1 and Its Glycosaminoglycan Chains-A Multivariable Puzzle
Open this publication in new window or tab >>The Mutual Impact of Syndecan-1 and Its Glycosaminoglycan Chains-A Multivariable Puzzle
2012 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 60, no 12, 936-942 p.Article in journal (Refereed) Published
Abstract [en]

Proteoglycans, with their core proteins and attached glycosaminoglycan chains, are recognized as important partners in many biological processes, yet often experimental analysis of their molecular action is considered for only part of these molecules: either the protein or the carbohydrate unit. In this article, we have tried to summarize, with an example of the syndecan family in general and more specifically with syndecan-1, what is known considering the mutual influence of these different components, and we follow whether the nature of the glycosaminoglycan chains matters for these effects. 

Keyword
syndecan-1, proteoglycan, glycosaminoglycan, heparan sulfate, chondroitin sulfate, function, interaction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-190326 (URN)10.1369/0022155412460242 (DOI)000311683500006 ()
Available from: 2013-01-10 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
2. Cell surface heparan sulfate chains are important for integrin mediated cell motility
Open this publication in new window or tab >>Cell surface heparan sulfate chains are important for integrin mediated cell motility
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-197672 (URN)
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2013-08-30
3. Role of glycosaminoglycans on syndecan-1 in fibroblast growth factor signaling
Open this publication in new window or tab >>Role of glycosaminoglycans on syndecan-1 in fibroblast growth factor signaling
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-197673 (URN)
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2013-08-30
4. On the Roles and Regulation of Chondroitin Sulfate and Heparan Sulfate in Zebrafish Pharyngeal Cartilage Morphogenesis
Open this publication in new window or tab >>On the Roles and Regulation of Chondroitin Sulfate and Heparan Sulfate in Zebrafish Pharyngeal Cartilage Morphogenesis
Show others...
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 40, 33905-33916 p.Article in journal (Refereed) Published
Abstract [en]

The present study addresses the roles of heparan sulfate (HS) proteoglycans and chondroitin sulfate (CS) proteoglycans in the development of zebrafish pharyngeal cartilage structures. uxs1 and b3gat3 mutants, predicted to have impaired biosynthesis of both HS and CS because of defective formation of the common proteoglycan linkage tetrasaccharide were analyzed along with ext2 and extl3 mutants, predicted to have defective HS polymerization. Notably, the effects on HS and CS biosynthesis in the respective mutant strains were shown to differ from what had been hypothesized. In uxs1 and b3gat3 mutant larvae, biosynthesis of CS was shown to be virtually abolished, whereas these mutants still were capable of synthesizing 50% of the HS produced in control larvae. extl3 and ext2 mutants on the other hand were shown to synthesize reduced amounts of hypersulfated HS. Further, extl3 mutants produced higher levels of CS than control larvae, whereas morpholino-mediated suppression of csgalnact1/csgalnact2 resulted in increased HS biosynthesis. Thus, the balance of the Extl3 and Csgalnact1/Csgalnact2 proteins influences the HS/CS ratio. A characterization of the pharyngeal cartilage element morphologies in the single mutant strains, as well as in ext2;uxs1 double mutants, was conducted. A correlation between HS and CS production and phenotypes was found, such that impaired HS biosynthesis was shown to affect chondrocyte intercalation, whereas impaired CS biosynthesis inhibited formation of the extracellular matrix surrounding chondrocytes.

Keyword
Protein Linkage Region, Molecular-Cloning, Hspg Synthesis, Cell Polarity, Growth-Plate, Expression, Ext2, Proteoglycans, Glypican, Xylose
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-185209 (URN)10.1074/jbc.M112.401646 (DOI)000309602100071 ()
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2012-11-22 Created: 2012-11-21 Last updated: 2017-12-07Bibliographically approved

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