Heparan Sulfate Chains of Syndecan-1 Regulate Ectodomain Shedding

Ramani, Vishnu C.; Pruett, Pamela S.; Thompson, Camilla A.; DeLucas, Lawrence D.; Sanderson, Ralph D.

doi:10.1074/jbc.m111.330803

Cited by 104 publications

(103 citation statements)

References 39 publications

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“…Interestingly, HS has been shown to bind and modulate the activity of several sheddases. 189,190 Contrary to our findings for syndecan-4, shedding of syndecan-1 is suppressed by the presence of HS GAG chains, 191 consistent with the acceleration of shedding of this proteoglycan by heparanase. 192 The juxtamembrane domain of syndecan-4 has been shown to be sensitive to proteolytic cleavage in vitro, 98 however we observed only a slight reduction in constitutive shedding of syndecan-4 after removal of this domain.…”

Section: Syndecan-4 Shedding In Cardiac Inflammation: Regulation Consupporting

confidence: 51%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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Section: Syndecan-4 Shedding In Cardiac Inflammation: Regulation Consupporting

confidence: 51%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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“…We previously demonstrated that syndecan-1 isolated from the CAG HPSE-high cells used in the present work is smaller in size than the syndecan-1 isolated from the HPSE-low cells, indicative of its heparan sulfate being trimmed by heparanase (23). This smaller form of syndecan-1 is also more rapidly shed from the cell surface, indicating that heparanase also influences syndecan-1 location (23,26). Moreover, when recombinant heparanase was added to glioma cells, it induced an accumulation of syndecan-1 within endosomes (31).…”

Section: Discussionmentioning

confidence: 99%

“…Images were taken using FEI Tecnai F20 electron microscope operated at 200 kv, and images were captured on a 4k ϫ 4k CCD camera. For Western blots of exosome proteins, samples were loaded onto a 10% or a 4 -20% gradient SDS-polyacrylamide gel (Bio-Rad), transferred to a positively charged nylon membrane (Nytran SPC, Schleicher & Schuell), and probed with antibody as described (26). Antibodies used were against: heparanase (affinity-purified polyclonal antibody 1453 (27)), flotillin-1 (Abcam), clathrin heavy chain (Abcam), and CD63 (Abcam).…”

Section: Methodsmentioning

confidence: 99%

Heparanase Regulates Secretion, Composition, and Function of Tumor Cell-derived Exosomes

Thompson

Purushothaman

Ramani

et al. 2013

Journal of Biological Chemistry

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302

322

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“…The syndecan 1 ectodomain can also influence Fgf2 mitogenic activity and migration (Eriksson and Spillmann, 2012;Chen et al, 2009). Upon treating cells with heparin lyase to remove attached HS chains, the amount of the syndecan 1 ectodomain in conditioned medium is increased, suggesting that having less HS on the core protein will increase the shedding (Ramani et al, 2012). One might speculate that the specific sulfation pattern of syndecan 1 CS/DS, like the absence of 2-O sulfation, would have an impact on the sensitivity for proteolytic action, so that shedding by matrilysin (Endo et al, 2003) results in an increased ectodomain and signals back to the cells (Eriksson and Spillmann, 2012).…”

Section: Discussionmentioning

confidence: 99%

Chondroitin/dermatan 2-O sulfotransferase potentiates Fgf2 induced cell migration

Nikolovska

Spillmann

Seidler

2014

Journal of Cell Science

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Fibroblast growth factor 2 (Fgf2) is involved in several biological functions. Fgf2 requires glycosaminoglycans, like chondroitin and dermatan sulfates (hereafter denoted CS/DS) as co-receptors. CS/ DS are linear polysaccharides composed of repeating disaccharide units and , which can be sulfated. Uronyl 2-O-sulfotransferase (Ust) introduces sulfation at the C2 of IdoUA and GlcUA resulting in over-sulfated units. Here, we investigated the role of Ust-mediated CS/DS 2-O sulfation in Fgf2-induced cell migration. We found that CHO-K1 cells overexpressing Ust contain significantly more CS/DS 2-O sulfated units, whereas Ust knockdown abolished CS/DS 2-O sulfation. These structural differences in CS/DS resulted in altered Fgf2 binding and increased phosphorylation of ERK1/2 (also known as MAPK3 and MAPK1, respectively). As a functional consequence of CS/DS 2-O sulfation and altered Fgf2 binding, cell migration and paxillin activation were increased. Inhibition of sulfation, knockdown of Ust and inhibition of FgfR resulted in reduced migration. Similarly, in 3T3 cells Fgf2 treatment increased migration, which was abolished by Ust knockdown. The proteoglycan controlling the CHO migration was syndecan 1. Knockdown of Sdc1 in CHO-K1 cells overexpressing Ust abolished cell migration. We conclude that the presence of distinctly sulfated CS/DS can tune the Fgf2 effect on cell migration.

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Heparan Sulfate Chains of Syndecan-1 Regulate Ectodomain Shedding

Cited by 104 publications

References 39 publications

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Heparanase Regulates Secretion, Composition, and Function of Tumor Cell-derived Exosomes

Chondroitin/dermatan 2-O sulfotransferase potentiates Fgf2 induced cell migration

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