Q6YGZ1 (HPSE_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Heparanase
EC=3.2.-.-

Alternative name(s):
Endo-glucoronidase

Cleaved into the following 2 chains:

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

Gene names

Name:	Hpse
Synonyms:	Hpa

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	535 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. Highly selective enzyme cleaving HSPGs at specific intrachain sites. 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.6 Ref.7 Ref.8 Ref.9
Enzyme regulation	Inhibited by EDTA and activated by calcium and magnesium By similarity. Inhibited by laminarin sulfate and, to a lower extent, by heparin and sulfamin. Ref.2 Ref.3
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 By similarity. Ref.2
Subcellular location	Lysosome membrane; Peripheral membrane protein By similarity. 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. Colocalizes with SDC1 in endosomal/lysosomal vesicles. Accumulates in perinuclear lysosomal vesicles. Heparin retains proheparanase in the extracellular medium By similarity. Associates with lipid rafts. Ref.6
Tissue specificity	Expressed in skin, mainly in the stratum granulosum and the first layer of the stratum corneum in the upper part of the epidermis. Also detected in hair follicles and in sebaceous glands. Ref.6 Ref.9
Developmental stage	In 18.5 day embryos, expressed in the peri-chondrium, periosteum and at the chondro-osseus junction of developing bone. Ref.7
Post-translational modification	Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, and the 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 By similarity. N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility. Ref.2
Sequence similarities	Belongs to the glycosyl hydrolase 79 family.
Biophysicochemical properties	pH dependence: Optimum pH is 5. Ref.2

Ontologies

Keywords
Biological process	Cell adhesion
Cellular component	Lysosome Membrane Nucleus Secreted
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 Inferred from electronic annotation. Source: InterPro cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of hair follicle development Inferred from direct assay Ref.6. Source: UniProtKB positive regulation of osteoblast proliferation Inferred from direct assay Ref.9. Source: UniProtKB positive regulation of protein kinase B signaling cascade Inferred from direct assay Ref.8. Source: UniProtKB vascular wound healing Inferred from direct assay Ref.6. Source: UniProtKB
Cellular component	lysosomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane raft Inferred from direct assay Ref.8. Source: UniProtKB nucleus Inferred from direct assay Ref.6Ref.8. Source: UniProtKB proteinaceous extracellular matrix Traceable author statement Ref.1. Source: MGI
Molecular function	cation binding Inferred from electronic annotation. Source: InterPro hydrolase activity, acting on glycosyl bonds Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 27	27	By similarity
	Chain	28 – 101	74	Heparanase 8 kDa subunit		PRO_0000042263
	Propeptide	102 – 149	48	Linker peptide By similarity		PRO_0000042264
	Chain	150 – 535	386	Heparanase 50 kDa subunit		PRO_0000042265
Regions
	Region	150 – 154	5	Heparin/HS-binding By similarity
	Region	262 – 272	11	Heparin/HS-binding By similarity
	Region	280 – 409	130	Required for heterodimerization with the heparanase 8 kDa subunit By similarity
	Region	519 – 535	17	Required for transferring proheparanase to the Golgi apparatus, secretion and subsequent enzyme activity and for enhancement of PKB/AKT1 phosphorylation By similarity
Sites
	Active site	217	1	Proton donor Potential
	Active site	335	1	Nucleophile Potential
Amino acid modifications
	Glycosylation	154	1	N-linked (GlcNAc...)
	Glycosylation	192	1	N-linked (GlcNAc...) Potential
	Glycosylation	209	1	N-linked (GlcNAc...) Potential
	Glycosylation	451	1	N-linked (GlcNAc...) Potential
Experimental info
	Sequence conflict	206	1	K → R in AAN41636. Ref.3
	Sequence conflict	212	1	W → S in AAN41636. Ref.3
	Sequence conflict	230 – 232	3	DGL → NGS in AAN41636. Ref.3
	Sequence conflict	335	1	E → K in AAN41636. Ref.3
	Sequence conflict	342	1	G → A in AAN41636. Ref.3
	Sequence conflict	455	1	H → Y in AAN41636. Ref.3
	Sequence conflict	531	1	I → V in AAN41636. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q6YGZ1 [UniParc]. Last modified July 27, 2011. Version 3. Checksum: 6E73A8302FB8A0DF	FASTA	535	60,066
	10 20 30 40 50 60 MLRLLLLWLW GPLGALAQGA PAGTAPTDDV VDLEFYTKRP LRSVSPSFLS ITIDASLATD 70 80 90 100 110 120 PRFLTFLGSP RLRALARGLS PAYLRFGGTK TDFLIFDPDK EPTSEERSYW KSQVNHDICR 130 140 150 160 170 180 SEPVSAAVLR KLQVEWPFQE LLLLREQYQK EFKNSTYSRS SVDMLYSFAK CSGLDLIFGL 190 200 210 220 230 240 NALLRTPDLR WNSSNAQLLL DYCSSKGYNI SWELGNEPNS FWKKAHILID GLQLGEDFVE 250 260 270 280 290 300 LHKLLQRSAF QNAKLYGPDI GQPRGKTVKL LRSFLKAGGE VIDSLTWHHY YLNGRIATKE 310 320 330 340 350 360 DFLSSDVLDT FILSVQKILK VTKEITPGKK VWLGETSSAY GGGAPLLSNT FAAGFMWLDK 370 380 390 400 410 420 LGLSAQMGIE VVMRQVFFGA GNYHLVDENF EPLPDYWLSL LFKKLVGPRV LLSRVKGPDR 430 440 450 460 470 480 SKLRVYLHCT NVYHPRYQEG DLTLYVLNLH NVTKHLKVPP PLFRKPVDTY LLKPSGPDGL 490 500 510 520 530 LSKSVQLNGQ ILKMVDEQTL PALTEKPLPA GSALSLPAFS YGFFVIRNAK IAACI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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: 10395326] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: SJL/J. Tissue: Spleen.
[2]	"Cloning, expression, and purification of mouse heparanase." Miao H.-Q., Navarro E., Patel S., Sargent D., Koo H., Wan H., Plata A., Zhou Q., Ludwig D., Bohlen P., Kussie P. Protein Expr. Purif. 26:425-431(2002) [PubMed: 12460766] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 28-57 AND 150-179, GLYCOSYLATION, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, SUBUNIT. Strain: FVB. Tissue: Embryo.
[3]	"Processing of macromolecular heparin by heparanase." Gong F., Jemth P., Galvis M.L.E., Vlodavsky I., Horner A., Lindahl U., Li J.-P. J. Biol. Chem. 278:35152-35158(2003) [PubMed: 12837765] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], ENZYME REGULATION.
[4]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J and NOD. Tissue: Thymus.
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[6]	"Heparanase regulates murine hair growth." Zcharia E., Philp D., Edovitsky E., Aingorn H., Metzger S., Kleinman H.K., Vlodavsky I., Elkin M. Am. J. Pathol. 166:999-1008(2005) [PubMed: 15793281] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[7]	"Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models." Zcharia E., Zilka R., Yaar A., Yacoby-Zeevi O., Zetser A., Metzger S., Sarid R., Naggi A., Casu B., Ilan N., Vlodavsky I., Abramovitch R. FASEB J. 19:211-221(2005) [PubMed: 15677344] [Abstract] Cited for: FUNCTION, ENZYMATIC ACTIVITY, DEVELOPMENTAL STAGE.
[8]	"Heparanase induces Akt phosphorylation via a lipid raft receptor." Ben-Zaken O., Gingis-Velitski S., Vlodavsky I., Ilan N. Biochem. Biophys. Res. Commun. 361:829-834(2007) [PubMed: 17689495] [Abstract] Cited for: FUNCTION.
[9]	"Heparanase expression and activity influences chondrogenic and osteogenic processes during endochondral bone formation." Brown A.J., Alicknavitch M., D'Souza S.S., Daikoku T., Kirn-Safran C.B., Marchetti D., Carson D.D., Farach-Carson M.C. Bone 43:689-699(2008) [PubMed: 18589009] [Abstract] Cited for: FUNCTION, ENZYMATIC ACTIVITY, PROTEOLYTIC PROCESSING, TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF359507 mRNA. Translation: AAQ15188.1. AY077467 mRNA. Translation: AAL76083.1. AY151051 mRNA. Translation: AAN41636.1. AK040471 mRNA. Translation: BAC30600.1. AK154628 mRNA. Translation: BAE32725.1. BC138782 mRNA. Translation: AAI38783.1. BC138784 mRNA. Translation: AAI38785.1.
IPI	IPI00170098.
RefSeq	NP_690016.1. NM_152803.4.
UniGene	Mm.265786.
3D structure databases
ProteinModelPortal	Q6YGZ1.
ModBase	Search...
Protein-protein interaction databases
STRING	Q6YGZ1.
Protein family/group databases
CAZy	GH79. Glycoside Hydrolase Family 79.
PTM databases
PhosphoSite	Q6YGZ1.
Proteomic databases
PRIDE	Q6YGZ1.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000045617; ENSMUSP00000044072; ENSMUSG00000035273.
GeneID	15442.
KEGG	mmu:15442.
Organism-specific databases
CTD	10855.
MGI	MGI:1343124. Hpse.
Phylogenomic databases
eggNOG	roNOG14199.
GeneTree	ENSGT00390000004874.
HOGENOM	HBG715522.
HOVERGEN	HBG081606.
InParanoid	Q6YGZ1.
OrthoDB	EOG45MN5C.
Gene expression databases
ArrayExpress	Q6YGZ1.
Bgee	Q6YGZ1.
CleanEx	MM_HPSE.
Genevestigator	Q6YGZ1.
GermOnline	ENSMUSG00000035273. Mus musculus.
Family and domain databases
InterPro	IPR005199. Glyco_hydro_79. IPR013781. Glyco_hydro_subgr_catalytic. IPR017853. Glycoside_hydrolase_SF. [Graphical view]
Gene3D	G3DSA:3.20.20.80. Glyco_hydro_cat. 1 hit.
KO	K07964.
PANTHER	PTHR14363. Glyco_hydro_79_N. 1 hit.
Pfam	PF03662. Glyco_hydro_79n. 1 hit. [Graphical view]
SUPFAM	SSF51445. Glyco_hydro_cat. 1 hit.
ProtoNet	Search...
Other
NextBio	288230.
SOURCE	Search...

Entry information

Entry name

HPSE_MOUSE

Accession

Primary (citable) accession number: Q6YGZ1
Secondary accession number(s): B2RS99, Q8K3K3

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	July 27, 2011
Last modified:	November 16, 2011
This is version 62 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program