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Heparan sulfate from fibroblasts carrying a hypomorphic mutation in Ext1 exhibit altered interaction with FGF2
Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
Manuskript (Övrigt vetenskapligt)
Identifikatorer
URN: urn:nbn:se:uu:diva-93950OAI: oai:DiVA.org:uu-93950DiVA, id: diva2:167608
Tillgänglig från: 2006-01-26 Skapad: 2006-01-26 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
Ingår i avhandling
1. EXT Proteins in Heparan Sulfate Biosynthesis
Öppna denna publikation i ny flik eller fönster >>EXT Proteins in Heparan Sulfate Biosynthesis
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Heparan sulfate (HS) is a long unbranched polysaccharide composed of alternating glucosamine and hexuronic (glucuronic or iduronic) acid residues. Modification by sulfate groups in various positions generates a highly heterogeneous molecule. HS is synthesized as a proteoglycan by virtually all cells, and play pivotal functions in signaling and developmental patterning, but also in pathogenic events such as tumor metastasis and microbial adhesion.

This thesis deals with the properties of enzymes involved in HS chain elongation. Polymerization of the HS chain is believed to be catalyzed by the EXT family of proteins. In humans, the EXT family consists of five members: EXT1, EXT2, EXTL1, EXTL2 and EXTL3; their respective functions in HS biosynthesis are not fully understood.

In this study, for the first time, successful in vitro HS polymerization on oligosaccharide acceptor substrates was demonstrated, using recombinant EXT1 and EXT1/EXT2 complex. EXT1 formed longer chains than EXT1/EXT2 and their mechanisms of sugar incorporation were different.

Suppression of EXT1 or EXT2 expression by siRNA in a human cell line resulted in reduction of HS chain length. In contrast, cells transfected with EXTL3 siRNA produced longer HS chains. Overexpression of soluble EXT1, alone or co-expressed with EXT2, resulted in increased chain length, whereas overexpression of soluble EXT2 or EXTL3 has no detectable effect on HS chain elongation.

Structural analysis of HS from fibroblasts isolated from mice with a hypomorphic mutation in Ext1 showed that they produced significantly shorter HS chains then the wild-type fibroblasts (20 and 70 kDa, respectively). The disaccharide composition of the HS produced by the mutant cells was virtually indistinguishable from that of the wild-type HS, however, the mutant HS chains contained higher proportions of unmodified regions. Mutant cells responded less efficiently than wild-type cells to low concentrations of FGF2, as analyzed by ERK phosphorylation assay.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 48
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 101
Nyckelord
Molecular biology, Molekylärbiologi
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-6303 (URN)91-554-6445-9 (ISBN)
Disputation
2006-02-10, Room C10:310, BMC, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2006-01-26 Skapad: 2006-01-26Bibliografiskt granskad

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