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Heparanase

Definition:

Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extracellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.

References:

[1]. Yukihiko Okada, et al. Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence. J Biol Chem. 2002 Nov 8;277(45):42488-95. [Content Brief]

[2]. Paul N Smith, et al. Heparanase in primary human osteoblasts. J Orthop Res. 2010 Oct;28(10):1315-22. [Content Brief]

[3]. Orit Goldshmidt, et al. Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J. 2003 Jun;17(9):1015-25. [Content Brief]

[4]. Victoria Cohen-Kaplan, et al. Heparanase induces VEGF C and facilitates tumor lymphangiogenesis. Int J Cancer. 2008 Dec 1;123(11):2566-73. [Content Brief]

[5]. Sherket B Peterson, et al. Unraveling the specificity of heparanase utilizing synthetic substrates. J Biol Chem. 2010 May 7;285(19):14504-13. [Content Brief]

[6]. Liat Fux, et al. Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling. Cancer Res. 2009 Mar 1;69(5):1758-67. [Content Brief]

[7]. Svetlana Gingis-Velitski, et al. Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J Biol Chem. 2004 May 28;279(22):23536-41. [Content Brief]

[8]. Anurag Purushothaman, et al. Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood. 2010 Mar 25;115(12):2449-57. [Content Brief]

[9]. Sylvain Malgouries, et al. Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol. 2008 Dec;17(12):1017-23. [Content Brief]

[10]. Ivan K H Poon, et al. Histidine-rich glycoprotein binds heparanase and regulates its enzymatic activity and cell surface interactions. Int J Biochem Cell Biol. 2010 Sep;42(9):1507-16. [Content Brief]

[11]. Vishnu C Ramani, et al. Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity. J Biol Chem. 2011 Feb 25;286(8):6490-9. [Content Brief]

[12]. Anna Zetser, et al. Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006 Feb 1;66(3):1455-63. [Content Brief]

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