Q9Y251 (HPSE_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Heparanase
EC=3.2.1.166

Alternative name(s):
Endo-glucoronidase
Heparanase-1
Short name=Hpa1

Cleaved into the following 2 chains:

1. Heparanase 8 kDa subunit
2. Heparanase 50 kDa subunit

Gene names

Name:	HPSE
Synonyms:	HEP, HPA, HPA1, HPR1, HPSE1, HSE1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	543 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Ref.16 Ref.19 Ref.21 Ref.27 Ref.29 Ref.30 Ref.31 Ref.33 Ref.35 Ref.36 Ref.38 Ref.39
Catalytic activity	Endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan. Ref.16 Ref.17 Ref.18 Ref.34 Ref.35 Ref.36
Enzyme regulation	Inhibited by EDTA, laminarin sulfate and, to a lower extent, by heparin and sulfamin and activated by calcium and magnesium By similarity.
Subunit structure	Heterodimer; heterodimer formation between the 8 kDa and the 50 kDa subunits is required for enzyme activity. Interacts with TF; the interaction, inhibited by heparin, enhances the generation of activated factor X and activates coagulation. Interacts with HRG; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts with SDC1; the interaction enhances the shedding of SDC1. Interacts with HPSE2. Ref.7 Ref.15 Ref.18 Ref.34 Ref.35 Ref.37
Subcellular location	Lysosome membrane; Peripheral membrane protein. Secreted. Nucleus. Note: Proheparanase is secreted via vesicles of the Golgi. Interacts with cell membrane heparan sulfate proteoglycans (HSPGs). Endocytosed and accumulates in endosomes. Transferred to lysosomes where it is proteolytically cleaved to produce the active enzyme. Under certain stimuli, transferred to the cell surface. Associates with lipid rafts. Colocalizes with SDC1 in endosomal/lysosomal vesicles. Accumulates in perinuclear lysosomal vesicles. Heparin retains proheparanase in the extracellular medium By similarity. Ref.6 Ref.15 Ref.17 Ref.22 Ref.23 Ref.24 Ref.25 Ref.31 Ref.38
Tissue specificity	Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Also expressed in hair follicles, specifically in both Henle's and Huxley's layers of inner the root sheath (IRS) at anagen phase. Ref.1 Ref.4 Ref.5 Ref.29 Ref.38
Post-translational modification	Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, and 8 kDa and 50 kDa products. The active form, the 8/50 kDa heterodimer, is resistant to degradation. Complete removal of the linker peptide appears to be a prerequisite to the complete activation of the enzyme. N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility. Ref.3 Ref.7 Ref.20
Sequence similarities	Belongs to the glycosyl hydrolase 79 family.
Biophysicochemical properties	pH dependence: Optimum pH is 4-6. Ref.2 Ref.5 Ref.7 Ref.24

Ontologies

Keywords
Biological process	Cell adhesion
Cellular component	Lysosome Membrane Nucleus Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal
Ligand	Calcium Magnesium
Molecular function	Hydrolase
PTM	Glycoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	carbohydrate metabolic process Traceable author statement. Source: Reactome cell-matrix adhesion Inferred from direct assay Ref.19. Source: UniProtKB glycosaminoglycan catabolic process Traceable author statement. Source: Reactome heparan sulfate proteoglycan catabolic process Inferred from direct assay Ref.16. Source: UniProtKB positive regulation of blood coagulation Inferred from direct assay Ref.34. Source: UniProtKB positive regulation of hair follicle development Inferred from electronic annotation. Source: Compara positive regulation of osteoblast proliferation Inferred from direct assay Ref.38. Source: UniProtKB positive regulation of protein kinase B signaling cascade Inferred from direct assay Ref.21. Source: UniProtKB positive regulation vascular endothelial growth factor production Inferred from direct assay Ref.27. Source: UniProtKB regulation of hair follicle development Inferred from direct assay Ref.29. Source: UniProtKB vascular wound healing Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell lysosomal lumen Traceable author statement. Source: Reactome lysosomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane raft Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.38. Source: UniProtKB
Molecular_function	beta-glucuronidase activity Traceable author statement Ref.3. Source: ProtInc heparanase activity Inferred from direct assay Ref.16. Source: UniProtKB protein dimerization activity Inferred from direct assay Ref.18. Source: UniProtKB syndecan binding Inferred from direct assay Ref.22. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9Y251-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9Y251-2)

Also known as: 55 kDa; splice 5;

The sequence of this isoform differs from the canonical sequence as follows:
     167-225: RSSVDVLYTFANCSGLDLIFGLNALLRTADLQWNSSNAQLLLDYCSSKGYNISWELGNE → K

Note: Escapes proteolytic cleavage, devoid of HS degradation activity.

Isoform 3 (identifier: Q9Y251-3)

The sequence of this isoform differs from the canonical sequence as follows:
     329-402: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 35	35	Ref.7
	Chain	36 – 109	74	Heparanase 8 kDa subunit		PRO_0000042260
	Propeptide	110 – 157	48	Linker peptide		PRO_0000042261
	Chain	158 – 543	386	Heparanase 50 kDa subunit		PRO_0000042262
Regions
	Region	158 – 162	5	Heparin/HS-binding
	Region	270 – 280	11	Heparin/HS-binding
	Region	527 – 543	17	Required for transferring proheparanase to the Golgi apparatus, secretion and subsequent enzyme activity and for enhancement of PKB/AKT1 phosphorylation
Sites
	Active site	225	1	Proton donor Potential
	Active site	343	1	Nucleophile Potential
Amino acid modifications
	Glycosylation	162	1	N-linked (GlcNAc...) Ref.20
	Glycosylation	178	1	N-linked (GlcNAc...) Ref.20
	Glycosylation	200	1	N-linked (GlcNAc...) Ref.20
	Glycosylation	217	1	N-linked (GlcNAc...) Ref.20 Ref.28 Ref.32
	Glycosylation	238	1	N-linked (GlcNAc...) Ref.20 Ref.32
	Glycosylation	459	1	N-linked (GlcNAc...) Ref.20
Natural variations
	Alternative sequence	167 – 225	59	RSSVD…ELGNE → K in isoform 2.		VSP_044537
	Alternative sequence	329 – 402	74	Missing in isoform 3.		VSP_044664
	Natural variant	260	1	N → S in some hepatocellular carcinoma. Ref.40		VAR_023600
	Natural variant	307	1	K → R. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.8 Ref.9 Ref.10 Ref.11 Ref.13 Corresponds to variant rs11099592 [ dbSNP | Ensembl ].		VAR_068907
Experimental info
	Mutagenesis	156	1	Y → A or E: Alteration of the correct processing of heparanase which results in the cleavage at an upstream site in the linker peptide and no activation of proheparanase. Ref.25
	Mutagenesis	156	1	Y → V: Normal processing. Ref.25
	Mutagenesis	158	1	K → A: No association with GS-modified heparin; when associated with K-158. Ref.26
	Mutagenesis	161	1	K → A: Two-fold increase in the level of secretion upon addition of GS-modified heparin. No association with GS-modified heparin; when associated with K-161. Ref.26
	Mutagenesis	162	1	N → Q: Faster electrophoretic migration typical of a size reduction and important decrease of secretion. Larger size reduction; when associated with Q-178; Q-200; Q-217; Q-238 and Q-459. Ref.20
	Mutagenesis	178	1	N → Q: Faster electrophoretic migration typical of a size reduction and important decrease of secretion. Larger size reduction; when associated with Q-162; Q-200; Q-217; Q-238 and Q-459. Ref.20
	Mutagenesis	200	1	N → Q: Faster electrophoretic migration typical of a size reduction and partial decrease in secretion. Larger size reduction; when associated with Q-162; Q-178; Q-217; Q-238 and Q-459. Ref.20
	Mutagenesis	217	1	N → Q: Faster electrophoretic migration typical of a size reduction and partial decrease in secretion. Larger size reduction; when associated with Q-162; Q-178; Q-200; Q-238 and Q-459. Ref.20
	Mutagenesis	225	1	E → A: Loss of heparanase activity. No effect on HPSE-mediated cell adhesion. Ref.14 Ref.19
	Mutagenesis	238	1	N → Q: Faster electrophoretic migration typical of a size reduction. Larger size reduction and important decrease of secretion; when associated with Q-162; Q-178; Q-200; Q-217 and Q-459. Ref.20
	Mutagenesis	343	1	E → A: Loss of heparanase activity. Ref.14
	Mutagenesis	367	1	D → A: Strong decrease in heparanase activity. Ref.14
	Mutagenesis	378	1	E → A: No reduction in heparanase activity.
	Mutagenesis	396	1	E → A: No reduction in heparanase activity.
	Mutagenesis	414	1	V → K: Abolishes processing, secretion and enzyme activity. Ref.31
	Mutagenesis	417	1	K → E: No effect on processing nor secretion. No enzyme activity detected. Ref.31
	Mutagenesis	459	1	N → Q: Faster electrophoretic migration typical of a size reduction. Larger size reduction and important decrease of secretion; when associated with Q-162; Q-178; Q-200; Q-217 and Q-238. Ref.20
	Mutagenesis	525	1	P → G: No effect on processing nor secretion. No enzyme activity detected. Ref.31
	Mutagenesis	527	1	F → R: No effect on processing nor secretion. No enzyme activity detected. Ref.31
	Mutagenesis	528	1	S → K: No effect on processing nor secretion. No enzyme activity detected. Ref.31
	Mutagenesis	529	1	Y → A: No effect on processing nor secretion. No enzyme activity detected. Ref.31
	Mutagenesis	531	1	F → R: Abolishes processing, secretion and enzyme activity. Ref.31
	Mutagenesis	533	1	V → R: Abolishes processing, secretion and enzyme activity. Ref.31
	Mutagenesis	534	1	I → D: Abolishes processing, secretion and enzyme activity. Ref.31
	Mutagenesis	535	1	R → A: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	536	1	N → A: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	537	1	A → K: Abolishes processing, secretion and enzyme activity. Ref.31
	Mutagenesis	538	1	K → A: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	539	1	V → A: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	540	1	A → K: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	541	1	A → K: No effect on processing, secretion nor enzyme activity. Ref.31
	Mutagenesis	542	1	C → A: Abolishes processing, secretion and enzyme activity. Ref.31
	Sequence conflict	13	1	L → LL in AAD54516. Ref.5
	Sequence conflict	36	1	Q → QQ in AAD54516. Ref.5
	Sequence conflict	291	1	D → G in BAD96706. Ref.11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 18, 2010. Version 2. Checksum: A990F5AFD639CA1A	FASTA	543	61,149
	10 20 30 40 50 60 MLLRSKPALP PPLMLLLLGP LGPLSPGALP RPAQAQDVVD LDFFTQEPLH LVSPSFLSVT 70 80 90 100 110 120 IDANLATDPR FLILLGSPKL RTLARGLSPA YLRFGGTKTD FLIFDPKKES TFEERSYWQS 130 140 150 160 170 180 QVNQDICKYG SIPPDVEEKL RLEWPYQEQL LLREHYQKKF KNSTYSRSSV DVLYTFANCS 190 200 210 220 230 240 GLDLIFGLNA LLRTADLQWN SSNAQLLLDY CSSKGYNISW ELGNEPNSFL KKADIFINGS 250 260 270 280 290 300 QLGEDFIQLH KLLRKSTFKN AKLYGPDVGQ PRRKTAKMLK SFLKAGGEVI DSVTWHHYYL 310 320 330 340 350 360 NGRTATKEDF LNPDVLDIFI SSVQKVFQVV ESTRPGKKVW LGETSSAYGG GAPLLSDTFA 370 380 390 400 410 420 AGFMWLDKLG LSARMGIEVV MRQVFFGAGN YHLVDENFDP LPDYWLSLLF KKLVGTKVLM 430 440 450 460 470 480 ASVQGSKRRK LRVYLHCTNT DNPRYKEGDL TLYAINLHNV TKYLRLPYPF SNKQVDKYLL 490 500 510 520 530 540 RPLGPHGLLS KSVQLNGLTL KMVDDQTLPP LMEKPLRPGS SLGLPAFSYS FFVIRNAKVA ACI
	Isoform 2 (55 kDa) (splice 5) [UniParc]. Checksum: DCF33CD4B2BC3A43	FASTA	485	54,734
	10 20 30 40 50 60 MLLRSKPALP PPLMLLLLGP LGPLSPGALP RPAQAQDVVD LDFFTQEPLH LVSPSFLSVT 70 80 90 100 110 120 IDANLATDPR FLILLGSPKL RTLARGLSPA YLRFGGTKTD FLIFDPKKES TFEERSYWQS 130 140 150 160 170 180 QVNQDICKYG SIPPDVEEKL RLEWPYQEQL LLREHYQKKF KNSTYSKPNS FLKKADIFIN 190 200 210 220 230 240 GSQLGEDFIQ LHKLLRKSTF KNAKLYGPDV GQPRRKTAKM LKSFLKAGGE VIDSVTWHHY 250 260 270 280 290 300 YLNGRTATKE DFLNPDVLDI FISSVQKVFQ VVESTRPGKK VWLGETSSAY GGGAPLLSDT 310 320 330 340 350 360 FAAGFMWLDK LGLSARMGIE VVMRQVFFGA GNYHLVDENF DPLPDYWLSL LFKKLVGTKV 370 380 390 400 410 420 LMASVQGSKR RKLRVYLHCT NTDNPRYKEG DLTLYAINLH NVTKYLRLPY PFSNKQVDKY 430 440 450 460 470 480 LLRPLGPHGL LSKSVQLNGL TLKMVDDQTL PPLMEKPLRP GSSLGLPAFS YSFFVIRNAK VAACI
	Isoform 3 [UniParc]. Checksum: F0E4853CC0CF0D88	FASTA	469	53,161
	10 20 30 40 50 60 MLLRSKPALP PPLMLLLLGP LGPLSPGALP RPAQAQDVVD LDFFTQEPLH LVSPSFLSVT 70 80 90 100 110 120 IDANLATDPR FLILLGSPKL RTLARGLSPA YLRFGGTKTD FLIFDPKKES TFEERSYWQS 130 140 150 160 170 180 QVNQDICKYG SIPPDVEEKL RLEWPYQEQL LLREHYQKKF KNSTYSRSSV DVLYTFANCS 190 200 210 220 230 240 GLDLIFGLNA LLRTADLQWN SSNAQLLLDY CSSKGYNISW ELGNEPNSFL KKADIFINGS 250 260 270 280 290 300 QLGEDFIQLH KLLRKSTFKN AKLYGPDVGQ PRRKTAKMLK SFLKAGGEVI DSVTWHHYYL 310 320 330 340 350 360 NGRTATKEDF LNPDVLDIFI SSVQKVFQDY WLSLLFKKLV GTKVLMASVQ GSKRRKLRVY 370 380 390 400 410 420 LHCTNTDNPR YKEGDLTLYA INLHNVTKYL RLPYPFSNKQ VDKYLLRPLG PHGLLSKSVQ 430 440 450 460 LNGLTLKMVD DQTLPPLMEK PLRPGSSLGL PAFSYSFFVI RNAKVAACI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and functional expression of a human heparanase gene." Kussie P.H., Hulmes J.D., Ludwig D.L., Patel S., Navarro E.C., Seddon A.P., Giorgio N.A., Bohlen P. Biochem. Biophys. Res. Commun. 261:183-187(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ARG-307, TISSUE SPECIFICITY. Tissue: Placenta.
[2]	"Human heparanase. Purification, characterization, cloning, and expression." Toyoshima M., Nakajima M. J. Biol. Chem. 274:24153-24160(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES, PROTEIN SEQUENCE OF 158-168; 326-337 AND 447-491, VARIANT ARG-307. Tissue: Embryonic fibroblast.
[3]	"Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis." 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. Nat. Med. 5:793-802(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, PROTEOLYTIC PROCESSING, VARIANT ARG-307.
[4]	"Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis." Hulett M.D., Freeman C., Hamdorf B.J., Baker R.T., Harris M.J., Parish C.R. Nat. Med. 5:803-809(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, PROTEIN SEQUENCE OF 158-174; 263-272; 326-337; 433-436; 438-443; 466-468 AND 478-483, VARIANT ARG-307. Tissue: Placenta.
[5]	"Heparanase expression in invasive trophoblasts and acute vascular damage." Dempsey L.A., Plummer T.B., Coombes S.L., Platt J.L. Glycobiology 10:467-475(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY, VARIANT ARG-307. Tissue: Placenta.
[6]	"Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis." Zcharia E., Metzger S., Chajek-Shaul T., Friedmann Y., Pappo O., Aviv A., Elkin M., Pecker I., Peretz T., Vlodavsky I. J. Mammary Gland Biol. Neoplasia 6:311-322(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION.
[7]	"Biochemical characterization of the active heterodimer form of human heparanase (Hpa1) protein expressed in insect cells." 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. Biochem. J. 373:423-435(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 36-41 AND 158-163, SUBUNIT, GLYCOSYLATION, BIOPHYSICOCHEMICAL PROPERTIES. Tissue: Placenta.
[8]	"Cloning, expression, and characterization of an alternatively spliced variant of human heparanase." Nasser N.J., Avivi A., Shushy M., Vlodavsky I., Nevo E. Biochem. Biophys. Res. Commun. 354:33-38(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, VARIANT ARG-307. Tissue: Kidney.
[9]	"Cloned heparanase from MCF-7 cells." Pinhal M.A., Semedo P. Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ARG-307.
[10]	"Two new transcript variants of Homo sapiens heparanase (HPSE)." Jin S., Yu L., Gong F. Submitted (JUN-2009) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT ARG-307.
[11]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ARG-307. Tissue: Small intestine.
[12]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., 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 E.A., 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 S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[13]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ARG-307. Tissue: Pancreas.
[14]	"Identification of active-site residues of the pro-metastatic endoglycosidase heparanase." Hulett M.D., Hornby J.R., Ohms S.J., Zuegg J., Freeman C., Gready J.E., Parish C.R. Biochemistry 39:15659-15667(2000) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF GLU-225; GLU-343 AND ASP-367.
[15]	"Human heparanase is localized within lysosomes in a stable form." Goldshmidt O., Nadav L., Aingorn H., Irit C., Feinstein N., Ilan N., Zamir E., Geiger B., Vlodavsky I., Katz B.Z. Exp. Cell Res. 281:50-62(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, INTERACTION WITH SDC1.
[16]	"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." Okada Y., Yamada S., Toyoshima M., Dong J., Nakajima M., Sugahara K. J. Biol. Chem. 277:42488-42495(2002) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION.
[17]	"Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts." Nadav L., Eldor A., Yacoby-Zeevi O., Zamir E., Pecker I., Ilan N., Geiger B., Vlodavsky I., Katz B.Z. J. Cell Sci. 115:2179-2187(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEOLYTIC PROCESSING, ENZYME ACTIVITY, SUBCELLULAR LOCATION.
[18]	"Heterodimer formation is essential for heparanase enzymatic activity." Levy-Adam F., Miao H.Q., Heinrikson R.L., Vlodavsky I., Ilan N. Biochem. Biophys. Res. Commun. 308:885-891(2003) [PubMed] [Europe PMC] [Abstract] Cited for: HETERODIMERIZATION, ENZYME ACTIVITY.
[19]	"Heparanase mediates cell adhesion independent of its enzymatic activity." Goldshmidt O., Zcharia E., Cohen M., Aingorn H., Cohen I., Nadav L., Katz B.Z., Geiger B., Vlodavsky I. FASEB J. 17:1015-1025(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF GLU-225.
[20]	"Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines." Simizu S., Ishida K., Wierzba M.K., Osada H. J. Biol. Chem. 279:2697-2703(2004) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459, MUTAGENESIS OF ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459.
[21]	"Heparanase induces endothelial cell migration via protein kinase B/Akt activation." Gingis-Velitski S., Zetser A., Flugelman M.Y., Vlodavsky I., Ilan N. J. Biol. Chem. 279:23536-23541(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[22]	"Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans." Gingis-Velitski S., Zetser A., Kaplan V., Ben-Zaken O., Cohen E., Levy-Adam F., Bashenko Y., Flugelman M.Y., Vlodavsky I., Ilan N. J. Biol. Chem. 279:44084-44092(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[23]	"Processing and activation of latent heparanase occurs in lysosomes." Zetser A., Levy-Adam F., Kaplan V., Gingis-Velitski S., Bashenko Y., Schubert S., Flugelman M.Y., Vlodavsky I., Ilan N. J. Cell Sci. 117:2249-2258(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION.
[24]	"Heparanase processing by lysosomal/endosomal protein preparation." Cohen E., Atzmon R., Vlodavsky I., Ilan N. FEBS Lett. 579:2334-2338(2005) [PubMed] [Europe PMC] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION.
[25]	"Site-directed mutagenesis, proteolytic cleavage, and activation of human proheparanase." Abboud-Jarrous G., Rangini-Guetta Z., Aingorn H., Atzmon R., Elgavish S., Peretz T., Vlodavsky I. J. Biol. Chem. 280:13568-13575(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, MUTAGENESIS OF TYR-156.
[26]	"Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase." Levy-Adam F., Abboud-Jarrous G., Guerrini M., Beccati D., Vlodavsky I., Ilan N. J. Biol. Chem. 280:20457-20466(2005) [PubMed] [Europe PMC] [Abstract] Cited for: HEPARIN/HS-BINDING DOMAINS, MUTAGENESIS OF LYS-158 AND LYS-161.
[27]	"Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation." Zetser A., Bashenko Y., Edovitsky E., Levy-Adam F., Vlodavsky I., Ilan N. Cancer Res. 66:1455-1463(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[28]	"Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach." Lewandrowski U., Moebius J., Walter U., Sickmann A. Mol. Cell. Proteomics 5:226-233(2006) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217, MASS SPECTROMETRY. Tissue: Platelet.
[29]	"Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis." Malgouries S., Donovan M., Thibaut S., Bernard B.A. Exp. Dermatol. 17:1017-1023(2008) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, FUNCTION.
[30]	"Heparanase induces VEGF C and facilitates tumor lymphangiogenesis." Cohen-Kaplan V., Naroditsky I., Zetser A., Ilan N., Vlodavsky I., Doweck I. Int. J. Cancer 123:2566-2573(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[31]	"Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling." Fux L., Feibish N., Cohen-Kaplan V., Gingis-Velitski S., Feld S., Geffen C., Vlodavsky I., Ilan N. Cancer Res. 69:1758-1767(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION OF THE C-TERMINAL DOMAIN, SUBCELLULAR LOCATION, MUTAGENESIS OF VAL-414; LYS-417; PRO-525; PHE-527; SER-528; TYR-529; PHE-531; VAL-533; ILE-534; ARG-535; ASN-536; ALA-537; LYS-538; VAL-539; ALA-540; ALA-541 AND CYS-542.
[32]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217 AND ASN-238, MASS SPECTROMETRY. Tissue: Liver.
[33]	"Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis." Purushothaman A., Uyama T., Kobayashi F., Yamada S., Sugahara K., Rapraeger A.C., Sanderson R.D. Blood 115:2449-2457(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[34]	"Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII." Nadir Y., Brenner B., Fux L., Shafat I., Attias J., Vlodavsky I. Haematologica 95:1927-1934(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TF, ENZYME ACTIVITY.
[35]	"Histidine-rich glycoprotein binds heparanase and regulates its enzymatic activity and cell surface interactions." Poon I.K., Yee D.Y., Jones A.L., Wood R.J., Davis D.S., Freeman C., Parish C.R., Hulett M.D. Int. J. Biochem. Cell Biol. 42:1507-1516(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HRG, ENZYME ACTIVITY, FUNCTION.
[36]	"Unraveling the specificity of heparanase utilizing synthetic substrates." Peterson S.B., Liu J. J. Biol. Chem. 285:14504-14513(2010) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION.
[37]	"Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity." Levy-Adam F., Feld S., Cohen-Kaplan V., Shteingauz A., Gross M., Arvatz G., Naroditsky I., Ilan N., Doweck I., Vlodavsky I. J. Biol. Chem. 285:28010-28019(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HPSE2.
[38]	"Heparanase in primary human osteoblasts." Smith P.N., Freeman C., Yu D., Chen M., Gatenby P.A., Parish C.R., Li R.W. J. Orthop. Res. 28:1315-1322(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[39]	"Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity." Ramani V.C., Yang Y., Ren Y., Nan L., Sanderson R.D. J. Biol. Chem. 286:6490-6499(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[40]	"Heparanase mRNA expression and point mutation in hepatocellular carcinoma." Chen X.P., Liu Y.B., Rui J., Peng S.Y., Peng C.H., Zhou Z.Y., Shi L.H., Shen H.W., Xu B. World J. Gastroenterol. 10:2795-2799(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SER-260.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF152376 mRNA. Translation: AAD45669.1. AF155510 mRNA. Translation: AAD54941.1. AF144325 mRNA. Translation: AAD41342.1. AF165154 mRNA. Translation: AAD45379.1. AF084467 mRNA. Translation: AAD54516.1. AM419200 mRNA. Translation: CAL91960.1. AY948074 mRNA. Translation: AAX47106.1. GQ337901 mRNA. Translation: ACT98237.1. AK222986 mRNA. Translation: BAD96706.1. AC114781 Genomic DNA. No translation available. BC051321 mRNA. Translation: AAH51321.1.
IPI	IPI00410297. IPI00884403. IPI00944522.
RefSeq	NP_001092010.1. NM_001098540.2. NP_001159970.1. NM_001166498.2. NP_001186759.1. NM_001199830.1. NP_006656.2. NM_006665.5.
UniGene	Hs.44227.
3D structure databases
ProteinModelPortal	Q9Y251.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000308107.
Protein family/group databases
CAZy	GH79. Glycoside Hydrolase Family 79.
PTM databases
PhosphoSite	Q9Y251.
Polymorphism databases
DMDM	296434532.
Proteomic databases
PaxDb	Q9Y251.
PRIDE	Q9Y251.
Protocols and materials databases
DNASU	10855.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000311412; ENSP00000308107; ENSG00000173083. ENST00000405413; ENSP00000384262; ENSG00000173083. ENST00000512196; ENSP00000423265; ENSG00000173083. ENST00000513463; ENSP00000421365; ENSG00000173083.
GeneID	10855.
KEGG	hsa:10855.
UCSC	uc003hoj.4. human.
Organism-specific databases
CTD	10855.
GeneCards	GC04M084213.
HGNC	HGNC:5164. HPSE.
HPA	CAB009813.
MIM	604724. gene.
neXtProt	NX_Q9Y251.
PharmGKB	PA29435.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG72789.
HOGENOM	HOG000007256.
HOVERGEN	HBG081606.
InParanoid	Q9Y251.
KO	K07964.
OMA	TWHHYYL.
OrthoDB	EOG45MN5C.
PhylomeDB	Q9Y251.
Enzyme and pathway databases
BioCyc	MetaCyc:ENSG00000173083-MONOMER.
Pathway_Interaction_DB	syndecan_1_pathway. Syndecan-1-mediated signaling events.
Reactome	REACT_111217. Metabolism. REACT_116125. Disease.
Gene expression databases
ArrayExpress	Q9Y251.
Bgee	Q9Y251.
CleanEx	HS_HPSE.
Genevestigator	Q9Y251.
GermOnline	ENSG00000173083. Homo sapiens.
Family and domain databases
Gene3D	3.20.20.80. 1 hit.
InterPro	IPR005199. Glyco_hydro_79. IPR013781. Glyco_hydro_catalytic_dom. IPR017853. Glycoside_hydrolase_SF. [Graphical view]
PANTHER	PTHR14363. PTHR14363. 1 hit.
Pfam	PF03662. Glyco_hydro_79n. 1 hit. [Graphical view]
SUPFAM	SSF51445. Glyco_hydro_cat. 1 hit.
ProtoNet	Search...
Other
ChEMBL	CHEMBL3921.
DrugBank	DB01109. Heparin.
GenomeRNAi	10855.
NextBio	41205.
SOURCE	Search...

Entry information

Entry name

HPSE_HUMAN

Accession

Primary (citable) accession number: Q9Y251
Secondary accession number(s): A9JIG7 , C7F7I3, E9PCA9, E9PGR1, Q53GE5, Q9UL39

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	May 18, 2010
Last modified:	May 1, 2013
This is version 108 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.