Heparanase: busy at the cell surface

Fux, Liat; Ilan, Neta; Sanderson, Ralph D.; Vlodavsky, Israël

doi:10.1016/j.tibs.2009.06.005

Cited by 207 publications

(232 citation statements)

References 72 publications

(132 reference statements)

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“…Syndecans act as co-receptors to integrins (37), and latent heparanase can bind to syndecan1 and syndecan4 (38). Whereas syndecan1 is expressed mainly in epithelial cells and transiently in condensing mesenchyme during embryogenesis (37,39), syndecan4 is widely expressed and co-localizes with ␤1 and ␤3 integrins in focal adhesion sites (37).…”

Section: Heparanase-induced Akt Activation Is Blocked By Pp2 But Invomentioning

confidence: 99%

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

Riaz

Ilan²,

Vlodavsky³

et al. 2013

Journal of Biological Chemistry

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Background: Heparanase levels are associated with tumor metastasis. Latent heparanase induces the prosurvival PI3K-AKT pathway via uncharacterized mechanisms. Results: AKT activation by heparanase involved PI3K p110␣, RAS, RICTOR, a PP2-sensitive kinase, FAK or PYK2, and ␤1 or ␤3 integrin-mediated adhesion. Conclusion:The heparanase receptor(s) intimately cooperates with integrins during induction of the PI3K-AKT pathway. Significance: Key steps in the heparanase-PI3K-AKT axis were identified.

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Section: Heparanase-induced Akt Activation Is Blocked By Pp2 But Invomentioning

confidence: 99%

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

Riaz

Ilan²,

Vlodavsky³

et al. 2013

Journal of Biological Chemistry

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“…Namely, it is often forgotten that apart from exoglycosidases, another class of enzymes, endoglycosidases, are involved in GAG degradation. An example of such enzymes is heparanase that cleaves HS inside the chains, with the only, though not strong, preference to low sulfation sites (for a review, see Fux et al 2009). Heparanase is located in lysosomes and at cell surface (Fux et al 2009).…”

Section: Putative Mechanisms Of Srt-mediated Decreasing Of Gag Levelsmentioning

confidence: 99%

“…An example of such enzymes is heparanase that cleaves HS inside the chains, with the only, though not strong, preference to low sulfation sites (for a review, see Fux et al 2009). Heparanase is located in lysosomes and at cell surface (Fux et al 2009). One should take into consideration that GAGs play their physiological roles being linked to proteins, and thus, forming proteoglycans.…”

Section: Putative Mechanisms Of Srt-mediated Decreasing Of Gag Levelsmentioning

confidence: 99%

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Banecka-Majkutewicz

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2012

Arch. Immunol. Ther. Exp.

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Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in genes coding for lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Dysfunction of any of these enzymes results in the accumulation of GAGs, which leads to severe clinical symptoms and significantly shortened life span. Several kinds of therapies have been proposed to treat MPS, including bone marrow or stem cell transplantation, enzyme replacement therapy, and gene therapy. Another option is substrate reduction therapy (SRT), in which synthesis of GAGs is inhibited. Recent studies employing in vitro and animal models suggested that this therapy may be efficient in decreasing levels of GAGs in MPS cells, including those bearing two null alleles of the affected gene. Results of behavioral tests in animals as well as some preliminary clinical observations with pediatric patients corroborated the suggestions about possible efficacy of SRT in MPS treatment, including brain functions. Efficient reduction of GAG levels in MPS cells homozygous for null mutations may be intriguing in the commonly accepted scheme of SRT mode of action. In this paper, we propose an explanation of this phenomenon, based on already known facts. Thus, we suggest that SRT may lead to reduction of GAG levels in MPS cells due to inhibition of efficiency of GAG synthesis combined with (a) any readthrough of the stop codon, (b) dilution of already accumulated GAGs due to cell growth followed by cell divisions, and (c) action of endoglycosidases degrading GAGs, e.g., heparanase, in combination with functional GAG-specific hydrolases.

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“…Heparanase is secreted as an enzymatically inactive pro-heparanase and requires reuptake into the cell and processing by cathepsin-L in lysosomes (7) or α granules (8) in order to give rise to the enzymatically active heparanase protein. In recent years, it has become evident that heparanase is a complex protein with both enzymatic and nonenzymatic activities, depending on its location and cleavage (9)(10)(11)(12)(13). The degradation of HSPGs and remodeling of the ECM require the enzymatically active heparanase protein to be secreted into the extracellular space.…”

Section: Introductionmentioning

confidence: 99%