Heparanase mediates cell adhesion independent of its enzymatic activity

Goldshmidt, Orit; Zcharia, Eyal; Cohen, M. D.; Aingorn, Helena; Cohen, Irit; Nadav, Liat; Katz, Ben‐Zion; Geiger, Benjamin; Vlodavsky, Israël

doi:10.1096/fj.02-0773com

Cited by 173 publications

(178 citation statements)

References 52 publications

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“…Our work, and those of others, indicates that XHpaL is enzymatically active and processes HSPGs, whereas enzymatically inactive splice variants in various species bind HSPGs and promote cell adhesion and migration (Goldshmidt et al, 2003;Zetser et al, 2003;Sotnikov et al, 2004;Bertolesi et al, 2008). Our expression data argue that the different forms of heparanase are regulated tightly both spatially and temporally in the egg, embryo and the adult.…”

Section: Developmental Expression Of Heparanase 2667supporting

confidence: 69%

“…A third heparanase, Hpa short (HpaS), is produced in Xenopus and humans by alternative splicing of the heparanase gene in which exon 5 is skipped to produce a protein missing 58 residues (Nasser et al, 2007;Bertolesi et al, 2008). While the enzymatically active long form (Hpa Active) will degrade and remodel HSPGs, HpaS is not enzymatically active and promotes cell adhesion and migration (Goldshmidt et al, 2003;Zetser et al, 2003;Gingis-Velitski et al, 2004;Sotnikov et al, 2004;Bertolesi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Bertolesi

Michaiel

et al. 2011

Developmental Dynamics

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In Xenopus laevis embryos, heparanase, the enzyme that degrades heparan sulfate, is synthesized as a preproheparanase (XHpaL) and processed to become enzymatically active (XHpa active). A short nonenzymatic heparanase splice variant (XHpaS) is also expressed. Using immunohistochemistry, Western blot, and heparanase promoter analysis, we studied the dynamic developmental expression of the three heparanases. Our results indicate that (1) all three isoforms are maternally expressed; (2) XHpaS is a developmental variant; (3) in the early embryo, heparanase is localized to both the plasma membrane and the nucleus; (4) several tissues express heparanase, but expression in the developing nervous system is most evident; (5) two promoters with distinct activities in different tissues drive heparanase expression; (6) Oct binding transcription factors may modulate heparanase promoter activity in the early embryo. These data argue that heparanase is expressed widely during development, but localization and levels are finely regulated.

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Section: Developmental Expression Of Heparanase 2667supporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Bertolesi

Michaiel

et al. 2011

Developmental Dynamics

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“…Recently, we have demonstrated that exogenous addition of the latent 65 kDa heparanase stimulates Akt-dependent endothelial cell invasion and migration, 33 presumably independent of heparanase enzymatic activity. Nonenzymatic activities of heparanase also include enhanced adhesion of tumor-derived cells 32,45 and primary T cells, 46 mediated by b1-integrin activation and correlated with Akt, Pyk2 and ERK activation. 32,46 More recently, we have demonstrated that heparanase is intimately involved in the regulation of vascular endothelial growth factor expression, thus contributing to tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 90%

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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Heparanase is a mammalian endo-b-D-glucuronidase that cleaves heparan sulfate side chains at a limited number of sites. Such enzymatic activity is thought to participate in degradation and remodeling of the extracellular matrix and to facilitate cell invasion associated with tumor metastasis, angiogenesis and inflammation. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase upregulation has been documented in an increasing number of primary human tumors, correlating with poor postoperative survival and increased tumor vascularity. Here, we employed antiheparanase 733 polyclonal antibody that preferentially recognizes the 50 kDa active heparanase subunit over the 65 kDa proenzyme, as well as anti-heparanase 92.4 monoclonal antibody that recognizes both the latent and the active enzyme, to follow heparanase expression, processing and localization throughout the adenoma-carcinoma transition of the colon epithelium. Normal (nondysplastic) mucosa of the large bowel near epithelial neoplasms, as well as areas of mild dysplasia in adenomas, exhibited a strong reactivity with antibody 733 that became even stronger in foci of moderate dysplasia. Interestingly, although reactivity with antibody 733 was markedly reduced in severe dysplasia and in colorectal carcinoma, response to antibody 92.4 exhibited the opposite trend and staining intensities increased in parallel with tumor stage, the highest being in carcinoma cells. Involvement of latent heparanase (detected by 92.4, but not by 733 antibody) in tumor progression was suggested by activation of the Akt/PKB signal transduction pathway upon heparanase overexpression or exogenous addition to HT29 human colon carcinoma cells. These results suggest that heparanase expression is induced during colon carcinogenesis, and that its processing, conformation and localization are tightly regulated during the course of colon adenoma-carcinoma progression. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 Heparan sulfate proteoglycans consist of a protein core to which several heparan sulfate side chains are covalently attached. These complex macromolecules are highly abundant in the extracellular matrix and are thought to play an important structural role, contributing to extracellular matrix integrity and insolubility. 3 In addition, heparan sulfate side chains can bind to a variety of biological mediators such as growth factors, cytokines and chemokines, 4,5 thus functioning as a readily available reservoir that can be liberated upon local or systemic cues. Moreover, heparan sulfate proteoglycans on the cell surface participates directly in signal-transduction cascades by potentiating the interaction between certain growth factors and their receptors. 6-9 Heparan sulfate-degrading activity is thus expected to affect several fundamental aspects of cell behavior under normal and clinical settings. 1,2 Tr...

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“…Interestingly, heparanase expressed on the surface of dendritic cells and macrophages has been shown to promote migration of these cells, by degrading ECM barriers (Benhamron et al, 2006;Sasaki et al, 2004). Moreover, heparanase can enhance cell adhesion independent of its enzymatic activity, and thereby contribute to cell motility (Goldshmidt et al, 2003;Sotnikov et al, 2004). These findings suggest a role for heparanase in regulating leukocyte migration processes.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Waern

Jia

Pejler

et al. 2010

Molecular Immunology

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Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse -/-) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse-/-mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes fromHpse -/-mice displayed normal morphology, Hpse -/-alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm.Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular

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Heparanase mediates cell adhesion independent of its enzymatic activity

Cited by 173 publications

References 52 publications

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

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