HPSE_RAT
ID HPSE_RAT Reviewed; 536 AA.
AC Q71RP1; Q9QZF8;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 103.
DE RecName: Full=Heparanase;
DE EC=3.2.1.166;
DE AltName: Full=Endo-glucoronidase;
DE Contains:
DE RecName: Full=Heparanase 8 kDa subunit;
DE Contains:
DE RecName: Full=Heparanase 50 kDa subunit;
DE Flags: Precursor;
GN Name=Hpse; Synonyms=Hep;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=10395326; DOI=10.1038/10525;
RA Hulett M.D., Freeman C., Hamdorf B.J., Baker R.T., Harris M.J.,
RA Parish C.R.;
RT "Cloning of mammalian heparanase, an important enzyme in tumor invasion and
RT metastasis.";
RL Nat. Med. 5:803-809(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ACTIVITY REGULATION.
RX PubMed=12077130; DOI=10.1074/jbc.m203282200;
RA Podyma-Inoue K.A., Yokote H., Sakaguchi K., Ikuta M., Yanagishita M.;
RT "Characterization of heparanase from a rat parathyroid cell line.";
RL J. Biol. Chem. 277:32459-32465(2002).
RN [3]
RP FUNCTION.
RX PubMed=15677344; DOI=10.1096/fj.04-1970com;
RA Zcharia E., Zilka R., Yaar A., Yacoby-Zeevi O., Zetser A., Metzger S.,
RA Sarid R., Naggi A., Casu B., Ilan N., Vlodavsky I., Abramovitch R.;
RT "Heparanase accelerates wound angiogenesis and wound healing in mouse and
RT rat models.";
RL FASEB J. 19:211-221(2005).
CC -!- FUNCTION: Endoglycosidase that cleaves heparan sulfate proteoglycans
CC (HSPGs) into heparan sulfate side chains and core proteoglycans.
CC Participates in extracellular matrix (ECM) degradation and remodeling.
CC Selectively cleaves the linkage between a glucuronic acid unit and an
CC N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo
CC group. Can also cleave the linkage between a glucuronic acid unit and
CC an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not
CC linkages between a glucuronic acid unit and a 2-O-sulfated iduronic
CC acid moiety. It is essentially inactive at neutral pH but becomes
CC active under acidic conditions such as during tumor invasion and in
CC inflammatory processes. Facilitates cell migration associated with
CC metastasis, wound healing and inflammation. Enhances shedding of
CC syndecans, and increases endothelial invasion and angiogenesis in
CC myelomas. Acts as procoagulant by increasing the generation of
CC activation factor X in the presence of tissue factor and activation
CC factor VII. Increases cell adhesion to the extracellular matrix (ECM),
CC independent of its enzymatic activity. Induces AKT1/PKB phosphorylation
CC via lipid rafts increasing cell mobility and invasion. Heparin
CC increases this AKT1/PKB activation. Regulates osteogenesis. Enhances
CC angiogenesis through up-regulation of SRC-mediated activation of VEGF.
CC Implicated in hair follicle inner root sheath differentiation and hair
CC homeostasis (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:15677344}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan
CC sulfate chains in heparan sulfate proteoglycan.; EC=3.2.1.166;
CC -!- ACTIVITY REGULATION: Inhibited by laminarin sulfate and, to a lower
CC extent, by heparin and sulfamin (By similarity). Activated by calcium
CC and magnesium. Inhibited by EDTA. {ECO:0000250,
CC ECO:0000269|PubMed:12077130}.
CC -!- SUBUNIT: Heterodimer; heterodimer formation between the 8 kDa and the
CC 50 kDa subunits is required for enzyme activity (By similarity).
CC Interacts with TF; the interaction, inhibited by heparin, enhances the
CC generation of activated factor X and activates coagulation. Interacts
CC with HRG; the interaction is enhanced at acidic pH, partially inhibits
CC binding of HPSE to cell surface receptors and modulates its enzymatic
CC activity. Interacts with SDC1; the interaction enhances the shedding of
CC SDC1. Interacts with HPSE2 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250}; Peripheral
CC membrane protein {ECO:0000250}. Secreted {ECO:0000250}. Nucleus
CC {ECO:0000250}. Note=Proheparanase is secreted via vesicles of the
CC Golgi. Interacts with cell membrane heparan sulfate proteoglycans
CC (HSPGs). Endocytosed and accumulates in endosomes. Transferred to
CC lysosomes where it is proteolytically cleaved to produce the active
CC enzyme. Under certain stimuli, transferred to the cell surface.
CC Colocalizes with SDC1 in endosomal/lysosomal vesicles. Accumulates in
CC perinuclear lysosomal vesicles. Heparin retains proheparanase in the
CC extracellular medium. Associates with lipid rafts (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Proteolytically processed. The cleavage of the 65 kDa form leads
CC to the generation of a linker peptide, and the 8 kDa and 50 kDa
CC products. The active form, the 8/50 kDa heterodimer, is resistant to
CC degradation. Complete removal of the linker peptide appears to be a
CC prerequisite to the complete activation of the enzyme (By similarity).
CC {ECO:0000250}.
CC -!- PTM: N-glycosylated. Glycosylation of the 50 kDa subunit appears to be
CC essential for its solubility (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 79 family. {ECO:0000305}.
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DR EMBL; AF359508; AAQ15189.1; -; mRNA.
DR EMBL; AF184967; AAF04563.1; -; mRNA.
DR RefSeq; NP_072127.1; NM_022605.1.
DR AlphaFoldDB; Q71RP1; -.
DR SMR; Q71RP1; -.
DR STRING; 10116.ENSRNOP00000002983; -.
DR CAZy; GH79; Glycoside Hydrolase Family 79.
DR GlyGen; Q71RP1; 4 sites.
DR GeneID; 64537; -.
DR KEGG; rno:64537; -.
DR CTD; 10855; -.
DR RGD; 61969; Hpse.
DR eggNOG; ENOG502QQST; Eukaryota.
DR InParanoid; Q71RP1; -.
DR OrthoDB; 1132327at2759; -.
DR PhylomeDB; Q71RP1; -.
DR Reactome; R-RNO-2024096; HS-GAG degradation.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:Q71RP1; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005768; C:endosome; ISO:RGD.
DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; ISO:RGD.
DR GO; GO:1904974; C:heparanase complex; ISO:RGD.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0030305; F:heparanase activity; IDA:RGD.
DR GO; GO:0045545; F:syndecan binding; ISO:RGD.
DR GO; GO:0060055; P:angiogenesis involved in wound healing; ISO:RGD.
DR GO; GO:0007160; P:cell-matrix adhesion; ISO:RGD.
DR GO; GO:0061028; P:establishment of endothelial barrier; ISO:RGD.
DR GO; GO:0002542; P:Factor XII activation; ISO:RGD.
DR GO; GO:0030200; P:heparan sulfate proteoglycan catabolic process; ISS:UniProtKB.
DR GO; GO:0030202; P:heparin metabolic process; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; ISO:RGD.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:RGD.
DR GO; GO:0010508; P:positive regulation of autophagy; ISO:RGD.
DR GO; GO:0030194; P:positive regulation of blood coagulation; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0001954; P:positive regulation of cell-matrix adhesion; ISO:RGD.
DR GO; GO:0051798; P:positive regulation of hair follicle development; ISO:RGD.
DR GO; GO:0033690; P:positive regulation of osteoblast proliferation; ISO:RGD.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISO:RGD.
DR GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; ISO:RGD.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISO:RGD.
DR GO; GO:0071806; P:protein transmembrane transport; ISO:RGD.
DR GO; GO:0051797; P:regulation of hair follicle development; ISO:RGD.
DR GO; GO:0010033; P:response to organic substance; ISO:RGD.
DR GO; GO:0061042; P:vascular wound healing; ISO:RGD.
DR GO; GO:0042060; P:wound healing; ISO:RGD.
DR InterPro; IPR005199; Glyco_hydro_79.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR Pfam; PF03662; Glyco_hydro_79n; 1.
DR SUPFAM; SSF51445; SSF51445; 1.
PE 2: Evidence at transcript level;
KW Calcium; Cell adhesion; Disulfide bond; Glycoprotein; Hydrolase; Lysosome;
KW Magnesium; Membrane; Nucleus; Reference proteome; Secreted; Signal.
FT SIGNAL 1..28
FT /evidence="ECO:0000250"
FT CHAIN 29..102
FT /note="Heparanase 8 kDa subunit"
FT /id="PRO_0000042266"
FT PROPEP 103..150
FT /note="Linker peptide"
FT /evidence="ECO:0000250"
FT /id="PRO_0000042267"
FT CHAIN 151..536
FT /note="Heparanase 50 kDa subunit"
FT /id="PRO_0000042268"
FT REGION 281..410
FT /note="Required for heterodimerization with the heparanase
FT 8 kDa subunit"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT REGION 520..536
FT /note="Required for transferring proheparanase to the Golgi
FT apparatus, secretion and subsequent enzyme activity and for
FT enhancement of PKB/AKT1 phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT ACT_SITE 218
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT ACT_SITE 336
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 55..57
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 90
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 151..155
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 263..273
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 289
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 296
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 341..343
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT BINDING 382..384
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT CARBOHYD 155
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT CARBOHYD 193
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT CARBOHYD 210
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT CARBOHYD 452
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT DISULFID 120..172
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT DISULFID 430..535
FT /evidence="ECO:0000250|UniProtKB:Q9Y251"
FT CONFLICT 15
FT /note="G -> R (in Ref. 2; AAF04563)"
FT /evidence="ECO:0000305"
FT CONFLICT 227
FT /note="H -> Q (in Ref. 2; AAF04563)"
FT /evidence="ECO:0000305"
FT CONFLICT 350
FT /note="D -> N (in Ref. 2; AAF04563)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 536 AA; 60480 MW; C434E04CF536EA4D CRC64;
MLRPLLLLWL WGRLGALTQG TPAGTAPTKD VVDLEFYTKR LFQSVSPSFL SITIDASLAT
DPRFLTFLGS PRLRALARGL SPAYLRFGGT KTDFLIFDPN KEPTSEERSY WQSQDNNDIC
GSERVSADVL RKLQMEWPFQ ELLLLREQYQ REFKNSTYSR SSVDMLYSFA KCSRLDLIFG
LNALLRTPDL RWNSSNAQLL LNYCSSKGYN ISWELGNEPN SFWKKAHISI DGLQLGEDFV
ELHKLLQKSA FQNAKLYGPD IGQPRGKTVK LLRSFLKAGG EVIDSLTWHH YYLNGRVATK
EDFLSSDVLD TFILSVQKIL KVTKEMTPGK KVWLGETSSA YGGGAPLLSD TFAAGFMWLD
KLGLSAQLGI EVVMRQVFFG AGNYHLVDEN FEPLPDYWLS LLFKKLVGPK VLMSRVKGPD
RSKLRVYLHC TNVYHPRYRE GDLTLYVLNL HNVTKHLKLP PPMFSRPVDK YLLKPFGSDG
LLSKSVQLNG QTLKMVDEQT LPALTEKPLP AGSSLSVPAF SYGFFVIRNA KIAACI
