Substrate Specificity of Heparanases from Human Hepatoma and Platelets

Pikas, Dagmar Sandbäck; Li, Jinping; Vlodavsky, Israël; Lindahl, Ulf

doi:10.1074/jbc.273.30.18770

Cited by 252 publications

(199 citation statements)

References 51 publications

(51 reference statements)

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“…In contrast, unmodified heparan sulphate domains, detected with anti-K5 mAb and consisting of N-acetylglucosamine-glucuronic acid residues, remained unchanged. Since heparanase preferentially cleaves sulphated heparan sulphate and the glomerular heparanase content was increased in patients with overt diabetic nephropathy and inversely correlated with levels of modified heparan sulphate in the GBM, it is conceivable that the reduction of modified heparan sulphate in the GBM was due to degradation by heparanase, whereas the unmodified heparan sulphate domains, which are resistant to heparanase degradation [26], may represent the nascent chains of heparan sulphate or the large fragments of sparsely sulphated heparan sulphate after heparanase degradation. In support of this notion, pretreatment of normal human kidney sections with the active recombinant human heparanase did not reduce the presence of unmodified heparan sulphate (detected by anti-K5 mAb), whereas a complete loss or significant reduction of modified heparan sulphate domains (detected with antibodies JM403 and EW3D10 or HS4C3 respectively) was seen.…”

Section: Discussionmentioning

confidence: 99%

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

et al. 2007

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Aims/hypothesis Recent studies suggest that loss of heparan sulphate in the glomerular basement membrane (GBM) of the kidney with diabetic nephropathy is due to the increased production of heparanase, a heparan sulphate-degrading endoglycosidase. Our present study addresses whether heparan sulphate with different modifications is differentially reduced in the GBM and whether heparanase selectively cleaves heparan sulphate with different domain specificities. Methods The heparan sulphate content of renal biopsies (14 diabetic nephropathy, five normal) were analysed by immunofluorescence staining with four anti-heparan sulphate antibodies: JM403, a monoclonal antibody (mAb) recognising N-unsubstituted glucosamine residues; two phage displayderived single chain antibodies HS4C3 and EW3D10, defining sulphated heparan sulphate domains; and anti-K5 antibody, an mAb recognising unmodified heparan sulphate domains. Results We found that modified heparan sulphate domains (JM403, HS4C3 and EW3D10), but not unmodified domains (anti-K5) and agrin core protein were reduced in the GBM of kidneys from patients with diabetic nephropathy, compared with controls. Glomerular heparanase levels were increased in diabetic nephropathy kidneys and inversely correlated with the amounts of modified heparan sulphate domains. Increased heparanase production and loss of JM403 staining in the GBM Diabetologia (2008) 51:372-382

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Section: Discussionmentioning

confidence: 99%

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

et al. 2007

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“…Despite the biological significance of heparanase, less effort has been made to understand how structural cues within HS structure may direct cleavage or the sequence of events during HS depolymerization by heparanase. This is largely because structurally heterogeneous polysaccharides were used in the previous investigations (6). Only limited studies have been carried out using structurally defined oligosaccharide substrates or polysaccharides with simplified sulfation patterns (11,12).…”

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confidence: 99%

“…It hydrolyzes the glycosidic bonds between GlcUA and glucosamine residues that are located in the low sulfated domain of HS (6). The action of heparanase modulates the functions of HS to bind to a multitude of proteins, including growth factors and their receptors, chemokines, enzymes, and extracellular matrix proteins.…”

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confidence: 99%

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

Peterson

Liu

2012

Journal of Biological Chemistry

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Background: Heparanase is involved in the pathology of many diseases. Results: Heparanase cleaves heparan sulfate (HS) oligosaccharides in either consecutive or gapped cleavage mode. Conclusion: The susceptibility of glycosidic linkage bonds to heparanase degradation is sensitive to the nonreducing end saccharide structure of the cleavage site. Significance: The results will help us to understand the pathophysiological effects of HS that arise from heparanase activity.

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“…Heparanase is an endo-␤-D-glucuronidase capable of cleaving heparan sulfate (HS) 1 side chains at a limited number of sites, yielding HS fragments of still appreciable size (ϳ5-7 kDa) (1)(2)(3). Participating in extracellular matrix (ECM) degradation and remodeling, heparanase activity has been traditionally correlated with the metastatic potential of tumor-derived cells (4 -7).…”

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confidence: 99%

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

Gingis-Velitski¹,

Zetser²,

Flugelman

et al. 2004

Journal of Biological Chemistry

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Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intra-chain sites. Blood-borne neutrophils, macrophages, mast cells, and platelets exhibit heparanase activity that is thought to be stored in specific granules. The degranulated heparanase is implicated in extravasation of metastatic tumor cells and activated cells of the immune system. Degranulation and heparanase release in response to an inflammatory stimulus or platelet activation would facilitate cellular extravasation directly, by altering the composition and structural integrity of the extracellular matrix, or indirectly, by releasing HS-bound proinflammatory cytokines and chemokines. We hypothesized that in addition to such indirect effect, the released heparanase may also locally affect and activate neighboring cells such as endothelial cells. Here, we provide evidence that addition of the 65-kDa latent heparanase to endothelial cells enhances Akt signaling. Heparanase-mediated Akt phosphorylation was independent of its enzymatic activity or the presence of cell membrane HS proteoglycans and was augmented by heparin. Moreover, addition of heparanase stimulated phosphatidylinositol 3-kinasedependent endothelial cell migration and invasion. These results suggest, for the first time, that heparanase activates endothelial cells and elicits angiogenic responses directly. This effect appears to be mediated by as yet unidentified heparanase receptor.Heparanase is an endo-␤-D-glucuronidase capable of cleaving heparan sulfate (HS) 1 side chains at a limited number of sites, yielding HS fragments of still appreciable size (ϳ5-7 kDa) (1-3). Participating in extracellular matrix (ECM) degradation and remodeling, heparanase activity has been traditionally correlated with the metastatic potential of tumor-derived cells (4 -7). Similarly, heparanase has been shown to facilitate cell invasion associated with angiogenesis, autoimmunity, and inflammation (6 -9). Among the few cell types that express heparanase under normal physiological conditions, platelets possess a high heparanase activity and were used as a source for heparanase purification (2, 10). In fact, serum heparanase is mainly derived from activated platelets (11). Heparanase was localized to tertiary granules of neutrophils (12, 13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively. Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8, 14, 15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14). In addition, heparanase may facilitate the release of a multitude of HS-bound growth factors, cytokines and chemokines that would, in tu...

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Substrate Specificity of Heparanases from Human Hepatoma and Platelets

Cited by 252 publications

References 51 publications

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

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