Publications (39) View all
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Article: Functional overlap between chondroitin and heparan sulfate proteoglycans during VEGF-induced sprouting angiogenesis.
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ABSTRACT: Heparan sulfate proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between heparan sulfate proteoglycans and chondroitin sulfate proteoglycans during sprouting angiogenesis. Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of heparan sulfate biosynthesis. Cells unable to produce heparan sulfate instead increase their production of chondroitin sulfate that binds key angiogenic growth factors such as vascular endothelial growth factor A, transforming growth factor β, and platelet-derived growth factor B. Lack of heparan sulfate proteoglycan production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of transforming growth factor β and platelet-derived growth factor B signal transduction. The present study provides direct evidence for a previously undefined functional overlap between chondroitin sulfate proteoglycans and heparan sulfate proteoglycans during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of proteoglycans in the vasculature.Arteriosclerosis Thrombosis and Vascular Biology 02/2012; 32(5):1255-63. · 6.37 Impact Factor -
Article: Heparan sulfate proteoglycans as multifunctional cell regulators: cell surface receptors.
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ABSTRACT: Proteoglycans are macromolecules expressed on the cell surfaces and in the extracellular matrix of most animal tissues (Annu Rev Biochem 68:729-777, 1999; Int Rev Cell Mol Biol 276:105-159, 2009). Heparan sulfate proteoglycans (HSPGs) are essential for animal development and homeostasis, and are involved in various pathological processes. The functions of HSPGs are largely exerted through interaction of the heparan sulfate (HS) side chains with different types of ligands, including diverse molecules such as cytokines, enzymes, and pathogens. One of the important roles of cell surface HSPGs is to mediate cytokine-induced cell signaling through interaction with growth factors (GFs) and their cognate receptors. A selective dependence of GFs for different structural features of HS has been demonstrated by applying cell models that are mutated variously in HS structure due to deficiency in enzymes involved in the biosynthesis of HS chains.Methods in molecular biology (Clifton, N.J.) 01/2012; 836:239-55. -
Article: Structural basis of oligosaccharide receptor recognition by human papillomavirus.
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ABSTRACT: High risk human papillomavirus types 16 (HPV16) and 18 (HPV18) can cause cervical cancer. Efficient infection by HPV16 and HPV18 pseudovirions requires interactions of particles with cell-surface receptor heparan sulfate oligosaccharide. To understand the virus-receptor interactions for HPV infection, we determined the crystal structures of HPV16 and HPV18 capsids bound to the oligosaccharide receptor fragment using oligomeric heparin. The HPV-heparin structures revealed multiple binding sites for the highly negatively charged oligosaccharide fragment on the capsid surface, which is different from previously reported virus-receptor interactions in which a single type of binding pocket is present for a particular receptor. We performed structure-guided mutagenesis to generate mutant viruses, and cell binding and infectivity assays demonstrated the functional role of viral residues involved in heparin binding. These results provide a basis for understanding virus-heparan sulfate receptor interactions critical for HPV infection and for the potential development of inhibitors against HPV infection.Journal of Biological Chemistry 01/2011; 286(4):2617-24. · 4.77 Impact Factor -
Article: The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease.
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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.Journal of Biological Chemistry 12/2010; 285(52):41143-51. · 4.77 Impact Factor -
Article: The Heparan Sulfate Motif (GlcNS6S-IdoA2S)3, Common in Heparin, Has a Strict Topography and Is Involved in Cell Behavior and Disease
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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 (HSNS4F5), which we have rigorously identified as (GlcNS6S-IdoA2S)3. HSNS4F5 exhibits a restricted expression in healthy adult tissues. Blocking HSNS4F5 on cells in culture resulted in reduced proliferation and enhanced sensitivity to apoptosis. HSNS4F5 is up-regulated in tumor endothelial cells, consistent with a role in endothelial cell activation. Indeed, TNF-α stimulated endothelial expression of HSNS4F5, which contributed to leukocyte adhesion. In a mouse model of severe systemic amyloid protein A amyloidosis, HSNS4F5 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 HSNS4F5 and can be exploited as a probe to detect novel polysaccharide biomarkers of disease processes.Journal of Biological Chemistry 12/2010; 285(52):41143-41151. · 4.77 Impact Factor
