Title

The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease.

Document Type

Journal Article

Publication Date

12-24-2010

Journal

The Journal of biological chemistry

Volume

285

Issue

52

Inclusive Pages

41143–41151

DOI

10.1074/jbc.M110.153791

Keywords

Amyloidogenic Proteins; Amyloidosis; Animals; Antibodies, Monoclonal; Biomarkers; CHO Cells; Carbohydrate Sequence; Cell Proliferation; Cricetinae; Cricetulus; Disease Models, Animal; Endothelial Cells; Female; Heparitin Sulfate; Humans; Male; Mice; Neoplasms; Rats; Rats, Wistar; Single-Chain Antibodies; Tumor Necrosis Factor-alpha

Abstract

Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of extracellular effector ligands and thereby is thought to regulate a diverse array of biologic processes. The specificity of HS-ligand interactions is determined by the arrangement of sulfate groups on HS, which creates distinct binding motifs. Biologically important HS motifs are expected to exhibit regulated expression, yet there is a profound lack of tools to identify such motifs; consequently, little is known of their structures and functions. We have identified a novel phage display-derived antibody (NS4F5) that recognizes a highly regulated HS motif (HS(NS4F5)), which we have rigorously identified as (GlcNS6S-IdoA2S)(3). HS(NS4F5) exhibits a restricted expression in healthy adult tissues. Blocking HS(NS4F5) on cells in culture resulted in reduced proliferation and enhanced sensitivity to apoptosis. HS(NS4F5) is up-regulated in tumor endothelial cells, consistent with a role in endothelial cell activation. Indeed, TNF-α stimulated endothelial expression of HS(NS4F5), which contributed to leukocyte adhesion. In a mouse model of severe systemic amyloid protein A amyloidosis, HS(NS4F5) was expressed within amyloid deposits, which were successfully detected by microSPECT imaging using NS4F5 as a molecularly targeted probe. Combined, our results demonstrate that NS4F5 is a powerful tool for elucidating the biological function of HS(NS4F5) and can be exploited as a probe to detect novel polysaccharide biomarkers of disease processes.

Peer Reviewed

1

Open Access

1

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