Lack of L-Iduronic Acid in Heparan Sulfate Affects Interaction with Growth Factors and Cell Signaling

Research output: Contribution to journalArticle

Abstract

HSEPI (glucuronyl C5-epimerase) catalyzes the conversion of D-glucuronic acid to L-iduronic acid in heparan sulfate (HS) biosynthesis. Disruption of the Hsepi gene in mice 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 L-iduronic acid residues but shows up-regulated N- and 6-O-sulfation compared with wild type (WT) MEF HS. In medium fortified with 10% fetal calf serum, the Hsepi(-/-) MEFs proliferated and migrated similarly to WT cells. Under starvation conditions, both cell types showed attenuated proliferation and migration that could be restored by the addition of FGF2 to WT cells, whereas Hsepi(-/-) cells were resistant. Moreover, ERK phosphorylation following FGF2 stimulation was delayed in Hsepi(-/-) compared with WT cells. Assessment of HS-growth factor interaction by nitrocellulose filter trapping revealed a strikingly aberrant binding property of FGF2 and glia-derived neurotropic factor to Hsepi(-/-) but not to WT HS. glia-derived neurotropic factor 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.

Details

Authors
  • Juan Jia
  • Marco Maccarana
  • Xiao Zhang
  • Maxim Bespalov
  • Ulf Lindahl
  • Jin-Ping Li
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)15942-15950
JournalJournal of Biological Chemistry
Volume284
Issue number23
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes