Protein: Heparanase (EC 3.2.1.166) (Endo-glucoronidase) (Heparanase-1) (Hpa1) [Cleaved into: Heparanase 8 kDa subunit; Heparanase 50 kDa subunit] (Q9Y251)
Organism: Homo sapiens (Human)
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 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.
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). {ECO:0000250}.
Sequence: MLLRSKPALPPPLMLLLLGPLGPLSPGALPRPAQAQDVVDLDFFTQEPLHLVSPSFLSVTIDANLATDPRFLILLGSPKLRTLARGLSPAYLRFGGTKTDFLIFDPKKESTFEERSYWQSQVNQDICKYGSIPPDVEEKLRLEWPYQEQLLLREHYQKKFKNSTYSRSSVDVLYTFANCSGLDLIFGLNALLRTADLQWNSSNAQLLLDYCSSKGYNISWELGNEPNSFLKKADIFINGSQLGEDFIQLHKLLRKSTFKNAKLYGPDVGQPRRKTAKMLKSFLKAGGEVIDSVTWHHYYLNGRTATKEDFLNPDVLDIFISSVQKVFQVVESTRPGKKVWLGETSSAYGGGAPLLSDTFAAGFMWLDKLGLSARMGIEVVMRQVFFGAGNYHLVDENFDPLPDYWLSLLFKKLVGTKVLMASVQGSKRRKLRVYLHCTNTDNPRYKEGDLTLYAINLHNVTKYLRLPYPFSNKQVDKYLLRPLGPHGLLSKSVQLNGLTLKMVDDQTLPPLMEKPLRPGSSLGLPAFSYSFFVIRNAKVAACI
InterPro domains: - IPR017853: Glycoside hydrolase superfamily (homologous_superfamily) [77-413]
- IPR005199: Glycoside hydrolase, family 79 (family) [165-370]
Interaction partners: - Hepatocyte growth factor-regulated tyrosine kinase substrate
- Syndecan-1
- Inactive heparanase-2
- Iduronate 2-sulfatase
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0003824 (catalytic activity), GO:0016787 (hydrolase activity), GO:0016798 (hydrolase activity, acting on glycosyl bonds), GO:0004553 (hydrolase activity, hydrolyzing O-glycosyl compounds)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0051179 (localization), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0048869 (cellular developmental process), GO:0051641 (cellular localization), GO:0048856 (anatomical structure development), GO:0023056 (positive regulation of signaling), GO:0007275 (multicellular organism development), GO:0009653 (anatomical structure morphogenesis), GO:0055085 (transmembrane transport), GO:0042221 (response to chemical), GO:0048584 (positive regulation of response to stimulus), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0051234 (establishment of localization), GO:0051239 (regulation of multicellular organismal process), GO:0071704 (organic substance metabolic process), GO:0048646 (anatomical structure formation involved in morphogenesis), GO:0009056 (catabolic process), GO:0033036 (macromolecule localization), GO:0050793 (regulation of developmental process), GO:0044237 (cellular metabolic process), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0023051 (regulation of signaling), GO:0006950 (response to stress), GO:0051094 (positive regulation of developmental process), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0042634 (regulation of hair cycle), GO:0009967 (positive regulation of signal transduction), GO:1901564 (organonitrogen compound metabolic process), GO:0009611 (response to wounding), GO:0001568 (blood vessel development), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0044248 (cellular catabolic process), GO:0048731 (system development), GO:0019538 (protein metabolic process), GO:0009966 (regulation of signal transduction), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:1901135 (carbohydrate derivative metabolic process), GO:0045184 (establishment of protein localization), GO:0001525 (angiogenesis), GO:0035295 (tube development), GO:2000026 (regulation of multicellular organismal development), GO:0042127 (regulation of cell population proliferation), GO:0009888 (tissue development), GO:0010646 (regulation of cell communication), GO:0071806 (protein transmembrane transport), GO:0006810 (transport), GO:0070727 (cellular macromolecule localization), GO:0010647 (positive regulation of cell communication), GO:1901575 (organic substance catabolic process), GO:0044260 (cellular macromolecule metabolic process), GO:0006790 (sulfur compound metabolic process), GO:0008284 (positive regulation of cell population proliferation), GO:0035239 (tube morphogenesis), GO:0044273 (sulfur compound catabolic process), GO:0071705 (nitrogen compound transport), GO:1901565 (organonitrogen compound catabolic process), GO:0001944 (vasculature development), GO:0030163 (protein catabolic process), GO:0071702 (organic substance transport), GO:0030855 (epithelial cell differentiation), GO:0006022 (aminoglycan metabolic process), GO:0009057 (macromolecule catabolic process), GO:0042060 (wound healing), GO:0048514 (blood vessel morphogenesis), GO:0002064 (epithelial cell development), GO:0009100 (glycoprotein metabolic process), GO:0060055 (angiogenesis involved in wound healing), GO:1901136 (carbohydrate derivative catabolic process), GO:0044265 (cellular macromolecule catabolic process), GO:0015031 (protein transport), GO:0072359 (circulatory system development), GO:1902533 (positive regulation of intracellular signal transduction), GO:0033688 (regulation of osteoblast proliferation), GO:0008104 (protein localization), GO:0060429 (epithelium development), GO:0051797 (regulation of hair follicle development), GO:1902531 (regulation of intracellular signal transduction), GO:0006029 (proteoglycan metabolic process), GO:0051897 (positive regulation of protein kinase B signaling), GO:0045446 (endothelial cell differentiation), GO:0051896 (regulation of protein kinase B signaling), GO:0001885 (endothelial cell development), GO:0003158 (endothelium development), GO:0030203 (glycosaminoglycan metabolic process), GO:0006516 (glycoprotein catabolic process), GO:0030167 (proteoglycan catabolic process), GO:0061028 (establishment of endothelial barrier), GO:1903510 (mucopolysaccharide metabolic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0016020 (membrane), GO:0005615 (extracellular space), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0030312 (external encapsulating structure), GO:0005576 (extracellular region), GO:0005773 (vacuole), GO:0043230 (extracellular organelle), GO:0043229 (intracellular organelle), GO:0031012 (extracellular matrix), GO:0070062 (extracellular exosome), GO:0043227 (membrane-bounded organelle), GO:0065010 (extracellular membrane-bounded organelle), GO:0000323 (lytic vacuole), GO:0043231 (intracellular membrane-bounded organelle), GO:0062023 (collagen-containing extracellular matrix), GO:0031982 (vesicle), GO:0005764 (lysosome), GO:1903561 (extracellular vesicle)