3.2.1.166: heparanase
This is an abbreviated version!
For detailed information about heparanase, go to the full flat file.
Word Map on EC 3.2.1.166
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3.2.1.166
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metastasis
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proteoglycans
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angiogenesis
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endothelial
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heparin
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endoglycosidase
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basement
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glycosaminoglycans
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melanoma
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vessel
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oligosaccharide
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platelet
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syndecan-1
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hspgs
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node
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angiogenic
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myeloma
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nephropathy
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anticoagulant
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glycocalyx
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clinicopathological
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metalloproteinases
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glomerular
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procoagulant
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heparin-binding
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antimetastatic
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heparinase
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neovascularization
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fgf-2
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extravasation
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bfgf
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perlecan
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subendothelial
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matrigel
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microvessel
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chondroitin
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pro-tumorigenic
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o-sulfation
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matrix-degrading
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vegf-c
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pharmacology
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glypicans
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diagnostics
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proangiogenic
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medicine
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non-anticoagulant
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iduronic
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sdc1
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prometastatic
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chondroitinase
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intrachain
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drug development
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tfpi-2
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analysis
- 3.2.1.166
- metastasis
- proteoglycans
- angiogenesis
- endothelial
- heparin
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endoglycosidase
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basement
- glycosaminoglycans
- melanoma
- vessel
- oligosaccharide
- platelet
- syndecan-1
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hspgs
- node
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angiogenic
- myeloma
- nephropathy
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anticoagulant
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glycocalyx
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clinicopathological
- metalloproteinases
- glomerular
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procoagulant
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heparin-binding
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antimetastatic
- heparinase
- neovascularization
- fgf-2
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extravasation
- bfgf
- perlecan
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subendothelial
- matrigel
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microvessel
- chondroitin
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pro-tumorigenic
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o-sulfation
-
matrix-degrading
- vegf-c
- pharmacology
-
glypicans
- diagnostics
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proangiogenic
- medicine
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non-anticoagulant
-
iduronic
- sdc1
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prometastatic
- chondroitinase
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intrachain
- drug development
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tfpi-2
- analysis
Reaction
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan =
Synonyms
BpHep, C1A heparanase, endo-beta-D-glucuronidase, endo-beta-glucuronidase, heparan sulfate glycosidase, heparanase, heparanase 1, heparanase-1, HPA, Hpa1, Hpa1 heparanase, HPSE, T5
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General Information
General Information on EC 3.2.1.166 - heparanase
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evolution
malfunction
metabolism
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key enzymes sulfatases and heparanase of the pathway actively influence cancer cell proliferation, signaling, invasion, and metastasis
physiological function
additional information
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the enzyme belongs to the clan A glycoside hydrolase family 79, GH79
evolution
the enzyme belongs to the glycoxadside hydrolase family 79, GH79
evolution
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the enzyme belongs to the glycoxadside hydrolase family 79, GH79, from GH clan A
stable knockdown of HPA expression decreases the in vitro invasive, metastatic and angiogenetic capabilities of gastric cancer cells
malfunction
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heparanase knockdown impairs neurite outgrowth induced by nerve growth factor
malfunction
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heparanase variant T5 overexpression results in increased cell proliferation and larger colonies in soft agar, mediated by Src activation
malfunction
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enhanced growth/aggressiveness of numerous cancer cell types following overexpression of heparanase and inhibition of the tumorigenic/metastatic abilities of cancer cells following heparanase gene silencing
malfunction
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enzymatically inactive heparanase: mutated heparanase designated M343 fails to stimulate exosome secretion, whereas mutant M225 has a mild stimulatory effect
malfunction
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enzyme inhibition decreases the release of IL-1beta and TNF-alpha significantly, but does not change the mRNA levels of IL-1beta and TNF-alpha significantly in Astragalus membranaceus extract-treated macrophages
malfunction
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in siRNA treated T-cells, the repressing H3K9ac activation mark is reduced, with transcriptional repression of the CD69, IFNalpha and IL-2 genes and a concomitant decrease in H3K4me1 levels, accumulation of H3K4m2, not H3K4m3
malfunction
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the lack of heparanase or its inhibition prevents the increased synthesis of TGF-beta by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products and albumin overload. TGF-beta induces an autocrine loop to sustain its signal, whereas the lack of the enzyme partially interferes with this autocrine loop
malfunction
knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination. This is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. Heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance. Blocking heparanase diminishes drug resistance in myeloma
malfunction
macrophages from heparanase-knockout (Hpa-KO) mice express lower levels of cytokines (e.g. TNFalpha, interleukin 1-beta) and exhibit lower motility and phagocytic capacities. Inoculation of control monocytes togetherwith Lewis lung carcinoma (LLC) cells into Hpa-KO mice results in nearly complete inhibition of tumor growth. In striking contrast, inoculating LLC cells together with monocytes isolated from Hpa-KO mice does not affect tumor growth, indicating that heparanase is critically required for activation and function of macrophages
malfunction
whilst controlled HPSE activity plays an important role in physiological processing of the extracellular matrix, aberrant HPSE expression is associated with inflammation and cancerous growth. The proliferative advantages conferred by HPSE lead to its upregulation by tumors in a variety of tissues, and HPSE overexpression correlates strongly with metastasis and worsened clinical prognoses
histidine-rich glycoprotein interferes with heparanase binding to cell surface receptors, particularly heparan sulfate proteoglycans. Thus, the interaction between histidine-rich glycoprotein and heparanase can potentially regulate the role of heparanase in a variety of physiological and pathological conditions
physiological function
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biologically active interleukin-2 is released from the surface of endothelial cells and smooth muscle cells lining blood vessels by heparanase
physiological function
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heparanase activity correlates with the metastatic potential of tumor-derived cells. Heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving the migration of vascular endothelial cells and activated cells of the immune system. Heparan sulfate cleavage by heparanase is required for structural remodeling of the extracellular matrix. Inactive heparanase facilitates adhesion and migration of primary endothelial cells and promotes phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. vascular endothelial growth factor) and phosphorylation of selected Src substrates (i.e. endothelial growth factor receptor). Heparanase upregulates both the expression and shedding of syndecan-1 from the surface of myeloma cells
physiological function
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heparanase is constantly overexpressed and activated throughout ulcerative colitis. Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis. Heparanase overexpression markedly increases the incidence and severity of colitis-associated colonic tumors. Heparanase overexpression directly affects macrophage recruitment and activation
physiological function
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heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta
physiological function
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heparanase plays a dual role in driving hepatocyte growth factor signaling by enhancing hepatocyte growth factor expression and activity. Heparanase mediates enhanced syndecan-1 shedding. Although heparanase enzyme activity is required for enhanced syndecan-1 shedding, the active enzyme is not required for enhanced hepatocyte growth factor synthesis
physiological function
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heparanase promotes the nerve growth factor-induced neuritogenesis via MAPK p38 pathway
physiological function
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heparanase upregulates Th2 cytokines resulting in inhibition of the inflammatory lesion of experimental autoimmune encephalitis. Heparanase inhibits mitogen-induced splenocyte proliferation and mixed lymophocyte reaction through modulation of their repertoire of cytokines indicated by a marked increase in the levels of interleukin-4, interleukin-6 and interleukin-10, and a parallel decrease in interleukin-12 and tissue necrosis factor-alpha
physiological function
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heparanase variant T5 activates Src and facilitates cell proliferation and enhances myeloma xenograft development
physiological function
heparanase/MAPK1 signaling up regulates MMP9 and uPAR causing temporary loss of cell surface syndecan-1. Heparanase also activates AKT, P38, RAC1, PKC, and Src, thereby stimulating syndecan clustering, cell adhesion and tumorigenicity. Chronically elevated heparanase augments heparan sulfate 6-O-sulfation of syndecan-1, increases affinity for FGF1 and 2, and associates with tumor angiogenesis and metastatic potential
physiological function
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over-expression of heparanase is responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate-proteoglycans core protein. Heparanase regulates the gene expression of syndecan-1. The enzyme is relevant to the progression of diabetic nephropathytake and takes part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1
physiological function
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each cell has a dynamic control over the exact sequence of heparan sulfate and can change the way they respond to growth factors by altering the structure of the heparan sulfate on their surfaces. To accommodate those structural variations in heparan sulfate, heparanase adapts itself to recognize the overall structure of heparan sulfate, especially those highly sulfated domains in heparan sulfate.The substrate specificity plays a critical role in dissecting the biological functions of heparanase and heparan sulfate. Heparanase is capable of varying its substrate specificities depending on the saccharide structures around the cleavage site, overview. Potential regulating role of the surrounding saccharide sequences in controlling the cleavage site and the degradation extent by the enzyme
physiological function
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heparanase is a key enzyme involved in the dissemination of metastatic cancer cells
physiological function
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heparanase is a key player in renal fibrosis by regulating TGF-beta expression and activity, overview. Heparanase is an endo-beta-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-beta). The enzyme controls FGF-2-induced epithelial-mesenchymal transition in tubular cells and is necessary for the development of diabetic nephropathy in mice.
physiological function
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heparanase is an endoglycosidase that specifically degrades heparan sulfate, one of the main components of the extracellular matrix. Heparanase is implicated in cancer processes such as tumour formation, angiogenesis and metastasis
physiological function
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heparanase is the only known mammalian glycosidase capable of cleaving heparan sulfate chains. The expression of this enzyme is associated with tumor development because of its ability to degrade extracellular matrix and promote cell invasion
physiological function
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heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the ECM and basement membranes. Heparan sulfate is a ubiquitous macromolecule associated with the cell surface and extracellular matrix of a wide range of tissues and organs. Heparanase is preferentially expressed in human psoriatic lesions. The enzyme has the capacity to promote cancer progression. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
physiological function
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heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. The enzyme expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. Exosomes from heparanase-high cells stimulate spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than do exosomes secreted by heparanase-low cells
physiological function
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heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Involvement of heparanase in atherosclerosis and other vessel wall pathologies, overview. Heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications. The enzyme plays a direct role of heparanase in tumor metastasis. heparanase promotes gene expression (i.e., VEGF, tissue factor, HGF, RANKL, TNFalpha) and signaling pathways (i.e., phosphorylation of Akt, Src, Erk, EGF-receptor, insulin receptor) of which some are mediated by its C-terminus domain, devoid of heparanase enzymatic activity. Heparanase activates macrophages via Toll-like receptor similar to the marked increase of TNFalpha and IL-1 following addition of heparanase to monocytes isolated from human peripheral blood. Molecular mechanism underlying cytokine induction by heparanase, overview. Heparanase alters arterial structure and repair following endovascular stenting. The enzyme is a potent regulator of vascular remodeling, both on the level of paracrine regulation of vascular homeostasis and as an effector molecule in vascular response to injury
physiological function
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human heparanase is a heparan sulfate degrading enzyme located in the extracellular matrix playing a decisive role in angiogenesis and tumor metastasis
physiological function
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nuclear heparanase controls transcription of a distinct cohort of T-cell inducible genes. Since heparanase associates with active chromatin marks and RNAP II, the activated enzyme plays a role in gene transcription. The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes. Chromatin-bound heparanase is a prerequisite for the transcription of a subset of inducible immune response genes in activated T-cells. The actions of heparanase seem to influence gene transcription by associating with the demethylase LSD1, preventing recruitment of the methylase MLL and thereby modifying histone H3 methylation patterns. Heparanase belongs to an emerging class of proteins that play an important role in regulating transcription in addition to their well-recognized extra-nuclear functions
physiological function
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role of heparanase in the modification of heparan sulfate proteoglycans within the tumour microenvironment, overview. Involvement of heparanase in the metastatic extravasation of tumor cells and invasion of immune cells
physiological function
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the enzyme degrades side chains of heparan sulfate. Versatile role of heparanase in inflammation, detailed overview. In light of the potential tissue damage as a consequence of inappropriate cleavage of heparan sulfate, under physiological conditions heparanase is tightly regulated. Along with posttranslational proteolytic processing regulation of heparanase gene transcription represents an important control mechanism. Role for heparanase located within the cell nuclei in regulating expression of genes involved in shaping of inflammatory phenotype in endothelial and T cells. Key role of heparan sulfate in glycocalyx structure during acute inflammatory lung injury heparanase-mediated degradation and loss of pulmonary endothelial glycocalyx facilitating neutrophil recruitment. The enzyme is involved in colon inflammatory bowel disease through exposure of the endothelial surface and increased availability of adhesion molecules
physiological function
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the enzyme induces development of psoriasiform skin inflammation in mice. Enzymatic cleavage of heparan sulfate by heparanase profoundly affects a variety of pathophysiological processes, including inflammation, where heparanase activity is often associated with extracellular matrix remodeling, immunocyte activation,and release of chemokines anchored within the extracellular matrix network and cell surface. Heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT 3, enhanced NF-kappaB signaling, elevated expression of TNF-alpha and increased vascularization. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
physiological function
the enzyme is an endo-beta-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Cleaving heparan sulfate and releasing heparin/heparan sulfate oligosaccharides, the enzyme causes the release of growth factors, which accelerate tumor growth and metastasis
physiological function
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the enzyme is implicated in several diverse pathological processes associated with extracellular matrix degradation such as metastasis, inflammation and angiogenesis
physiological function
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the enzyme is involved in the process of tumor metastasis
physiological function
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the enzyme may be a key regulator of migration and immune response mediator in macrophages. The enzyme is an endo-beta-glucuronidase that cleaves heparan sulfate at specific intra-chain sites, is strongly implicated in dissemination of metastatic tumor cells. When mouse macrophages are stimulated with lipopolysaccharide in the absence or presence of active enzyme, the enzyme strongly sensitizes macrophages activated by lipopolysaccharide in vitro, as indicated by a marked increase in TNF-alpha, IL-6, and IL-12 p35 [5,6]. Furthermore, induction of the enzyme in several inflammatory conditions occurs and is associated with degradation of heparan sulfate, remodeling of the extracellular matrix, facilitating the inflammatory cell migration towards the injury sites and releasing of chemokines anchored within the extracellular matrix network and cell surfaces
physiological function
enzyme HPSE present in late endosomes and lysosomes performs an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HSPGs). HPSE mediated breakdown of heparan sulfate in the extracellular matrix has several effects on the behavior of nearby cells. Weakening of structural heparan sulfate networks in the extracellular matrix and basement membranes directly facilitates cell motility and extravasation into surrounding tissues. Latent pools of growth factors stored by heparan sulfate are released upon breakdown by HPSE, promoting increased cell proliferation, motility and angiogenesis. Heparan sulfate fragments generated by HPSE activity can also activate downstream signaling cascades. Whilst controlled HPSE activity plays an important role in physiological processing of the extracellular matrix, aberrant HPSE expression is associated with inflammation and cancerous growth. The proliferative advantages conferred by HPSE lead to its upregulation by tumors in a variety of tissues, and HPSE overexpression correlates strongly with metastasis and worsened clinical prognoses
physiological function
heparanase is a mammalian endo-beta-glucuronidase with importance in various pathological, e.g. carcinogenesis, and non-pathological events. Despite tumor development heparanase can also modulate inflammatory processes, scarring, tissue repair, and tissue regeneration
physiological function
heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate (HS) side chains presumably at sites of low sulfation. Heparanase is critically required for activation and function of macrophages. Heparanase activates Erk, p38, and JNK signaling in macrophages by a linear cascade, leading to increased c-Fos levels and induction of cytokine expression in a manner that apparently does not require heparanase enzymatic activity. Heparanase is a key mediator of macrophage activation and function in tumorigenesis and cross-talk with the tumor microenvironment. Heparanase from the tumor microenvironment supports tumor growth. Mutant Hpa-KO macrophages do not attenuate tumor growth
physiological function
heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is overexpressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Heparanase activates antithrombin through the binding to its heparin binding site. Activation of antithrombin, which is the most important endogenous anticoagulant, mainly accelerates factor Xa inhibition, supporting an allosteric activation effect. Heparanase may exert a non-enzymatic function interaction
physiological function
heparanase is an enzyme which cleaves heparan sulfate (HS) polysaccharides of the extracellular matrix. It is a regulator of tumor behavior, plays a key role in kidney related diseases and autoimmune diabetes
physiological function
heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance, but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic lysosomal-based secretion, stress response, and heparan sulfate turnover. Upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. Heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance, but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer. Heparanase present in late endosomes and lysosomes plays an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HSPGs), which contribute to the structural integrity, self-assembly and insolubility of the extracellular matrix (ECM) and basement membrane, thus intimately modulating cell-ECM interactions. The enzyme is involved in hematologic malignancies, e.g. multiple myeloma, overview. Heparanase enhances myeloma progression via CXCL10 down regulation. Heparan sulfate-rich glycocalyx has to be removed by lung expressed heparanase in order for neutrophils to entrap in the pulmonary vasculature in response to lipopolysacchride (LPS) septic signals. Heparanase is critical for neutrophil entry to lungs exposed to tobacco smoke. No role for lung heparanase in neutrophil infiltration to lungs exposed to intranasal LPS or in neutrophil emigration from blood to the inflamed skin or peritoneal cavity. Heparanase effects on macrophages in chronic inflammation, inflammation-associated cancer, and anti-inflammatory activity, as well as coupling aseptic inflammation and tumorigenesis. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. Recombinant heparanase promotes TNFalpha production by macrophages. Impact of heparanase on gene expression, cell signaling and angiogenesis
physiological function
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the enzyme degrades heparan sulfate (HS), a glycosaminoglycan (GAG), by hydrolysis of the beta-1,4-glycosidic linkage between glucuronic acid (GlcUA, G) and alpha-D-glucosamine (GlcN, N) residues. The overexpression of heparanase in cancers is well known and is associated with angiogenesis, inflammation and increased metastatic potential
physiological function
the upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field
physiological function
the enzyme is involved in heparan sulfate biosynthesis
physiological function
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the enzyme induces development of psoriasiform skin inflammation in mice. Enzymatic cleavage of heparan sulfate by heparanase profoundly affects a variety of pathophysiological processes, including inflammation, where heparanase activity is often associated with extracellular matrix remodeling, immunocyte activation,and release of chemokines anchored within the extracellular matrix network and cell surface. Heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT 3, enhanced NF-kappaB signaling, elevated expression of TNF-alpha and increased vascularization. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
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endogenous heparanase forms a complex with RNAP II, histone H3 (a key nucleosome component) and the H3K9ac activation mark, in resting and activated T cells and with euchromatin
additional information
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heparanase overexpressing transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecularcellular characteristics
additional information
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residues Glu225 and Glu343 are critical in its catalytic mechanism. Two heparan sulfate binding sites are formed by Lys158-Asp171 and Gln270-Lys280
additional information
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sequence homology modeling indicates that heparanase contains a TIM barrel fold, which incorporates the two heparan sulfate-binding regions (residues 158-162 and 270-280) and the catalytic residues (Glu225 and Glu343) of the active site. The C-terminus of the protein forms a discrete domain, which has non-catalytic properties and is involved in a heparanase-mediated signaling function that is distinct from its enzymatic activity
additional information
the enzyme contains two glycosaminoglycan-binding domains. Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans, docked structures are used to propose a model for substrates and conformer selectivity based on the dimensions of the active site, homology modelling, overview. Molecular dynamics simulations. Conformations of docked pentasaccharides in the binding site of heparanase
additional information
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the enzyme contains two glycosaminoglycan-binding domains. Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans, docked structures are used to propose a model for substrates and conformer selectivity based on the dimensions of the active site, homology modelling, overview. Molecular dynamics simulations. Conformations of docked pentasaccharides in the binding site of heparanase
additional information
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three-dimensional sequence homology modelling, overview. Two essential acidic residues are Glu225 and Glu343, which are involved in the catalytic mechanism, acting as a proton donor and a nucleophile, respectively
additional information
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NMR study of the endo cleavage mechanism of the heparanase, overview. Conserved active site regions, including a His-His-Tyr sequence. The BpHep residues Glu144 and Glu255 are predicted to be located at similar positions postulated for BhHep and are within loops between the beta-strands and alpha-helices, which is typical of TIM-barrel glycoside hydrolases, comparison to the human enzyme
additional information
processing of heparanase is mediated by syndecan 1 cytoplasmic domain and involves syntenin and alpha-actinin. Heparanase interacts with syndecans by virtue of the typical high affinity that exists between an enzyme and its substrate. This high affinity interaction directs rapid and efficient cellular uptake of the heparanase-syndecan complex
additional information
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processing of heparanase is mediated by syndecan 1 cytoplasmic domain and involves syntenin and alpha-actinin. Heparanase interacts with syndecans by virtue of the typical high affinity that exists between an enzyme and its substrate. This high affinity interaction directs rapid and efficient cellular uptake of the heparanase-syndecan complex
additional information
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heparanase overexpressing transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecularcellular characteristics
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