Heparanase

Details

Name
Heparanase
Synonyms
  • 3.2.1.166
  • Endo-glucoronidase
  • HEP
  • Heparanase-1
  • HPA
  • HPA1
  • HPR1
  • HPSE1
  • HSE1
Gene Name
HPSE
Organism
Humans
Amino acid sequence
>lcl|BSEQ0037119|Heparanase
MLLRSKPALPPPLMLLLLGPLGPLSPGALPRPAQAQDVVDLDFFTQEPLHLVSPSFLSVT
IDANLATDPRFLILLGSPKLRTLARGLSPAYLRFGGTKTDFLIFDPKKESTFEERSYWQS
QVNQDICKYGSIPPDVEEKLRLEWPYQEQLLLREHYQKKFKNSTYSRSSVDVLYTFANCS
GLDLIFGLNALLRTADLQWNSSNAQLLLDYCSSKGYNISWELGNEPNSFLKKADIFINGS
QLGEDFIQLHKLLRKSTFKNAKLYGPDVGQPRRKTAKMLKSFLKAGGEVIDSVTWHHYYL
NGRTATKEDFLNPDVLDIFISSVQKVFQVVESTRPGKKVWLGETSSAYGGGAPLLSDTFA
AGFMWLDKLGLSARMGIEVVMRQVFFGAGNYHLVDENFDPLPDYWLSLLFKKLVGTKVLM
ASVQGSKRRKLRVYLHCTNTDNPRYKEGDLTLYAINLHNVTKYLRLPYPFSNKQVDKYLL
RPLGPHGLLSKSVQLNGLTLKMVDDQTLPPLMEKPLRPGSSLGLPAFSYSFFVIRNAKVA
ACI
Number of residues
543
Molecular Weight
61148.17
Theoretical pI
9.72
GO Classification
Functions
beta-glucuronidase activity / heparanase activity / protein dimerization activity / syndecan binding
Processes
carbohydrate metabolic process / cell-matrix adhesion / glycosaminoglycan catabolic process / glycosaminoglycan metabolic process / heparan sulfate proteoglycan catabolic process / positive regulation of blood coagulation / positive regulation of hair follicle development / positive regulation of osteoblast proliferation / positive regulation of protein kinase B signaling / positive regulation of vascular endothelial growth factor production / proteoglycan metabolic process / regulation of hair follicle development / small molecule metabolic process / vascular wound healing
Components
extracellular region / intracellular membrane-bounded organelle / lysosomal lumen / lysosomal membrane / lysosome / membrane raft / nucleoplasm / nucleus
General Function
Syndecan binding
Specific Function
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 extacellular 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.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Lysosome membrane
Gene sequence
>lcl|BSEQ0010746|Heparanase (HPSE)
ATGCTGCTGCGCTCGAAGCCTGCGCTGCCGCCGCCGCTGATGCTGCTGCTCCTGGGGCCG
CTGGGTCCCCTCTCCCCTGGCGCCCTGCCCCGACCTGCGCAAGCACAGGACGTCGTGGAC
CTGGACTTCTTCACCCAGGAGCCGCTGCACCTGGTGAGCCCCTCGTTCCTGTCCGTCACC
ATTGACGCCAACCTGGCCACGGACCCGCGGTTCCTCATCCTCCTGGGTTCTCCAAAGCTT
CGTACCTTGGCCAGAGGCTTGTCTCCTGCGTACCTGAGGTTTGGTGGCACCAAGACAGAC
TTCCTAATTTTCGATCCCAAGAAGGAATCAACCTTTGAAGAGAGAAGTTACTGGCAATCT
CAAGTCAACCAGGATATTTGCAAATATGGATCCATCCCTCCTGATGTGGAGGAGAAGTTA
CGGTTGGAATGGCCCTACCAGGAGCAATTGCTACTCCGAGAACACTACCAGAAAAAGTTC
AAGAACAGCACCTACTCAAGAAGCTCTGTAGATGTGCTATACACTTTTGCAAACTGCTCA
GGACTGGACTTGATCTTTGGCCTAAATGCGTTATTAAGAACAGCAGATTTGCAGTGGAAC
AGTTCTAATGCTCAGTTGCTCCTGGACTACTGCTCTTCCAAGGGGTATAACATTTCTTGG
GAACTAGGCAATGAACCTAACAGTTTCCTTAAGAAGGCTGATATTTTCATCAATGGGTCG
CAGTTAGGAGAAGATTTTATTCAATTGCATAAACTTCTAAGAAAGTCCACCTTCAAAAAT
GCAAAACTCTATGGTCCTGATGTTGGTCAGCCTCGAAGAAAGACGGCTAAGATGCTGAAG
AGCTTCCTGAAGGCTGGTGGAGAAGTGATTGATTCAGTTACATGGCATCACTACTATTTG
AATGGACGGACTGCTACCAAGGAAGATTTTCTAAACCCTGATGTATTGGACATTTTTATT
TCATCTGTGCAAAAAGTTTTCCAGGTGGTTGAGAGCACCAGGCCTGGCAAGAAGGTCTGG
TTAGGAGAAACAAGCTCTGCATATGGAGGCGGAGCGCCCTTGCTATCCGACACCTTTGCA
GCTGGCTTTATGTGGCTGGATAAATTGGGCCTGTCAGCCCGAATGGGAATAGAAGTGGTG
ATGAGGCAAGTATTCTTTGGAGCAGGAAACTACCATTTAGTGGATGAAAACTTCGATCCT
TTACCTGATTATTGGCTATCTCTTCTGTTCAAGAAATTGGTGGGCACCAAGGTGTTAATG
GCAAGCGTGCAAGGTTCAAAGAGAAGGAAGCTTCGAGTATACCTTCATTGCACAAACACT
GACAATCCAAGGTATAAAGAAGGAGATTTAACTCTGTATGCCATAAACCTCCATAATGTC
ACCAAGTACTTGCGGTTACCCTATCCTTTTTCTAACAAGCAAGTGGATAAATACCTTCTA
AGACCTTTGGGACCTCATGGATTACTTTCCAAATCTGTCCAACTCAATGGTCTAACTCTA
AAGATGGTGGATGATCAAACCTTGCCACCTTTAATGGAAAAACCTCTCCGGCCAGGAAGT
TCACTGGGCTTGCCAGCTTTCTCATATAGTTTTTTTGTGATAAGAAATGCCAAAGTTGCT
GCTTGCATCTGA
Chromosome Location
4
Locus
4q21.3
External Identifiers
ResourceLink
UniProtKB IDQ9Y251
UniProtKB Entry NameHPSE_HUMAN
GenBank Protein ID5616197
GenBank Gene IDAF152376
GenAtlas IDHPSE
HGNC IDHGNC:5164
General References
  1. Kussie PH, Hulmes JD, Ludwig DL, Patel S, Navarro EC, Seddon AP, Giorgio NA, Bohlen P: Cloning and functional expression of a human heparanase gene. Biochem Biophys Res Commun. 1999 Jul 22;261(1):183-7. [Article]
  2. Toyoshima M, Nakajima M: Human heparanase. Purification, characterization, cloning, and expression. J Biol Chem. 1999 Aug 20;274(34):24153-60. [Article]
  3. Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I: Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med. 1999 Jul;5(7):793-802. [Article]
  4. Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR: Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat Med. 1999 Jul;5(7):803-9. [Article]
  5. Dempsey LA, Plummer TB, Coombes SL, Platt JL: Heparanase expression in invasive trophoblasts and acute vascular damage. Glycobiology. 2000 May;10(5):467-75. [Article]
  6. Zcharia E, Metzger S, Chajek-Shaul T, Friedmann Y, Pappo O, Aviv A, Elkin M, Pecker I, Peretz T, Vlodavsky I: Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis. J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):311-22. [Article]
  7. McKenzie E, Young K, Hircock M, Bennett J, Bhaman M, Felix R, Turner P, Stamps A, McMillan D, Saville G, Ng S, Mason S, Snell D, Schofield D, Gong H, Townsend R, Gallagher J, Page M, Parekh R, Stubberfield C: Biochemical characterization of the active heterodimer form of human heparanase (Hpa1) protein expressed in insect cells. Biochem J. 2003 Jul 15;373(Pt 2):423-35. [Article]
  8. Nasser NJ, Avivi A, Shushy M, Vlodavsky I, Nevo E: Cloning, expression, and characterization of an alternatively spliced variant of human heparanase. Biochem Biophys Res Commun. 2007 Mar 2;354(1):33-8. Epub 2007 Jan 2. [Article]
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  11. Hulett MD, Hornby JR, Ohms SJ, Zuegg J, Freeman C, Gready JE, Parish CR: Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry. 2000 Dec 26;39(51):15659-67. [Article]
  12. Goldshmidt O, Nadav L, Aingorn H, Irit C, Feinstein N, Ilan N, Zamir E, Geiger B, Vlodavsky I, Katz BZ: Human heparanase is localized within lysosomes in a stable form. Exp Cell Res. 2002 Nov 15;281(1):50-62. [Article]
  13. Okada Y, Yamada S, Toyoshima M, Dong J, Nakajima M, Sugahara K: 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. Epub 2002 Sep 3. [Article]
  14. Nadav L, Eldor A, Yacoby-Zeevi O, Zamir E, Pecker I, Ilan N, Geiger B, Vlodavsky I, Katz BZ: Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts. J Cell Sci. 2002 May 15;115(Pt 10):2179-87. [Article]
  15. Levy-Adam F, Miao HQ, Heinrikson RL, Vlodavsky I, Ilan N: Heterodimer formation is essential for heparanase enzymatic activity. Biochem Biophys Res Commun. 2003 Sep 5;308(4):885-91. [Article]
  16. Goldshmidt O, Zcharia E, Cohen M, Aingorn H, Cohen I, Nadav L, Katz BZ, Geiger B, Vlodavsky I: Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J. 2003 Jun;17(9):1015-25. [Article]
  17. Simizu S, Ishida K, Wierzba MK, Osada H: Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines. J Biol Chem. 2004 Jan 23;279(4):2697-703. Epub 2003 Oct 22. [Article]
  18. Gingis-Velitski S, Zetser A, Flugelman MY, Vlodavsky I, Ilan N: Heparanase induces endothelial cell migration via protein kinase B/Akt activation. J Biol Chem. 2004 May 28;279(22):23536-41. Epub 2004 Mar 24. [Article]
  19. Gingis-Velitski S, Zetser A, Kaplan V, Ben-Zaken O, Cohen E, Levy-Adam F, Bashenko Y, Flugelman MY, Vlodavsky I, Ilan N: Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans. J Biol Chem. 2004 Oct 15;279(42):44084-92. Epub 2004 Jul 29. [Article]
  20. Zetser A, Levy-Adam F, Kaplan V, Gingis-Velitski S, Bashenko Y, Schubert S, Flugelman MY, Vlodavsky I, Ilan N: Processing and activation of latent heparanase occurs in lysosomes. J Cell Sci. 2004 May 1;117(Pt 11):2249-58. [Article]
  21. Cohen E, Atzmon R, Vlodavsky I, Ilan N: Heparanase processing by lysosomal/endosomal protein preparation. FEBS Lett. 2005 Apr 25;579(11):2334-8. [Article]
  22. Abboud-Jarrous G, Rangini-Guetta Z, Aingorn H, Atzmon R, Elgavish S, Peretz T, Vlodavsky I: Site-directed mutagenesis, proteolytic cleavage, and activation of human proheparanase. J Biol Chem. 2005 Apr 8;280(14):13568-75. Epub 2005 Jan 19. [Article]
  23. Levy-Adam F, Abboud-Jarrous G, Guerrini M, Beccati D, Vlodavsky I, Ilan N: Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase. J Biol Chem. 2005 May 27;280(21):20457-66. Epub 2005 Mar 10. [Article]
  24. Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N: Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006 Feb 1;66(3):1455-63. [Article]
  25. Lewandrowski U, Moebius J, Walter U, Sickmann A: Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach. Mol Cell Proteomics. 2006 Feb;5(2):226-33. Epub 2005 Oct 31. [Article]
  26. Malgouries S, Donovan M, Thibaut S, Bernard BA: Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis. Exp Dermatol. 2008 Dec;17(12):1017-23. doi: 10.1111/j.1600-0625.2008.00739.x. Epub 2008 Jun 14. [Article]
  27. Cohen-Kaplan V, Naroditsky I, Zetser A, Ilan N, Vlodavsky I, Doweck I: Heparanase induces VEGF C and facilitates tumor lymphangiogenesis. Int J Cancer. 2008 Dec 1;123(11):2566-73. doi: 10.1002/ijc.23898. [Article]
  28. Fux L, Feibish N, Cohen-Kaplan V, Gingis-Velitski S, Feld S, Geffen C, Vlodavsky I, Ilan N: Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling. Cancer Res. 2009 Mar 1;69(5):1758-67. doi: 10.1158/0008-5472.CAN-08-1837. Epub 2009 Feb 24. [Article]
  29. Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, Wang L, Zou H: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009 Feb;8(2):651-61. doi: 10.1021/pr8008012. [Article]
  30. Purushothaman A, Uyama T, Kobayashi F, Yamada S, Sugahara K, Rapraeger AC, Sanderson RD: Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood. 2010 Mar 25;115(12):2449-57. doi: 10.1182/blood-2009-07-234757. Epub 2010 Jan 22. [Article]
  31. Nadir Y, Brenner B, Fux L, Shafat I, Attias J, Vlodavsky I: Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII. Haematologica. 2010 Nov;95(11):1927-34. doi: 10.3324/haematol.2010.023713. Epub 2010 Jul 15. [Article]
  32. Poon IK, Yee DY, Jones AL, Wood RJ, Davis DS, Freeman C, Parish CR, Hulett MD: 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. doi: 10.1016/j.biocel.2010.05.008. Epub 2010 May 31. [Article]
  33. Peterson SB, Liu J: Unraveling the specificity of heparanase utilizing synthetic substrates. J Biol Chem. 2010 May 7;285(19):14504-13. doi: 10.1074/jbc.M110.104166. Epub 2010 Feb 24. [Article]
  34. Levy-Adam F, Feld S, Cohen-Kaplan V, Shteingauz A, Gross M, Arvatz G, Naroditsky I, Ilan N, Doweck I, Vlodavsky I: Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity. J Biol Chem. 2010 Sep 3;285(36):28010-9. doi: 10.1074/jbc.M110.116384. Epub 2010 Jun 24. [Article]
  35. Smith PN, Freeman C, Yu D, Chen M, Gatenby PA, Parish CR, Li RW: Heparanase in primary human osteoblasts. J Orthop Res. 2010 Oct;28(10):1315-22. doi: 10.1002/jor.21138. [Article]
  36. Ramani VC, Yang Y, Ren Y, Nan L, Sanderson RD: 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. doi: 10.1074/jbc.M110.183277. Epub 2010 Dec 3. [Article]
  37. Chen XP, Liu YB, Rui J, Peng SY, Peng CH, Zhou ZY, Shi LH, Shen HW, Xu B: Heparanase mRNA expression and point mutation in hepatocellular carcinoma. World J Gastroenterol. 2004 Oct 1;10(19):2795-9. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB01109Heparinapproved, investigationalunknownsubstrateDetails
DB06779DalteparinapprovedunknownsubstrateDetails