Heparanase

Details

Name

Heparanase

Kind

protein

Synonyms

• 3.2.1.166
• Endo-glucoronidase
• HEP
• Heparanase-1
• HPA
• HPA1
• HPR1
• HPSE1
• HSE1

Gene Name

HPSE

UniProtKB Entry

Q9Y251Swiss-Prot

Organism

Humans

NCBI Taxonomy ID

9606

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

Processes

angiogenesis involved in wound healing / establishment of endothelial barrier / heparin metabolic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein transmembrane transport

Components

extracellular matrix / extracellular space / specific granule lumen

General 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 a 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

Specific Function

beta-glucuronidase activity

Pfam Domain Function

• Glyco_hydro_79n (PF03662)

Signal Regions

1-35

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

4q21.23

External Identifiers

Resource	Link
UniProtKB ID	Q9Y251
UniProtKB Entry Name	HPSE_HUMAN
GenBank Protein ID	5616197
GenBank Gene ID	AF152376
GeneCard ID	HPSE
GenAtlas ID	HPSE
HGNC ID	HGNC:5164
PDB ID(s)	5E8M, 5E97, 5E98, 5E9B, 5E9C, 5L9Y, 5L9Z, 5LA4, 5LA7, 6ZDM, 7PR7, 7PR8, 7PRT, 7RG8, 7YI7, 7YJC, 8B0B, 8B0C, 8BAC, 8CQI, 8E07, 8E08, 8JYG, 8OHQ, 8OHR
KEGG ID	hsa:10855
IUPHAR/Guide To Pharmacology ID	2996
NCBI Gene ID	10855

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]
9. Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. [Article]
10. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
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]

Associated Data

Drug Relations

Drug	Drug group	Pharmacological action?	Type	Actions	Details
Heparin	approved, investigational	unknown	enzyme	substrate	Details
Dalteparin	approved	unknown	enzyme	substrate	Details
Suramin	investigational	yes	target	inhibitor	Details