Heparanase

Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.

ynthesis and structure

The protein is originally synthesised in an inactive 65 kDa proheparanase form in the golgi apparatus and transferred to late endosomes/lysosomes for transport to the cell-surface. In the lysosome it is proteolytically processed into its active form. Proteolytic processing results in the production of three products,
* a linker peptide
* a 8 kDa proheparanase fragment and
* a 50 kDa proheparanase fragmentThe 8 kDa and 50 kDa fragments form a heterodimer and it is this heterodimer that constitutes the active heparanase molecule. [cite journal | author = Vlodavsky I, Ilan N. "et al". | title = Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate | journal = Curr. Pharm. Des. | year=2007 | volume=13 | issue=20 | pages=2057–2073 | pmid = 17627539 | doi = 10.2174/138161207781039742] The linker protein is so called because prior to its excision it physically links the 8 kDa and 50 kDa proheparanase fragments. Complete excision of the linker peptide appears to be a prerequisite to the complete activation of the heparanase enzyme.

=Endoglycosidic action=

Heparanase cleaves polymeric heparan sulfate molecules at sites which are internal within the polymeric chain. [cite journal | author=Pikas DS, Li JP, Vlodavsky I, Lindahl U |title=Substrate specificity of heparanases from human hepatoma and platelets. |journal=J. Biol. Chem. |volume=273 |issue= 30 |pages= 18770–7 |year= 1998 |pmid= 9668050 |doi=]

Role in metastasis and angiogenesis

The successful penetration of the endothelial cell layer that lines the interior surface of blood vessels is an important process in the formation of blood borne tumour metastases. Heparan sulfate proteoglycans are major constituents of this layer and it has been shown that increased metastatic potential corresponds with increased heparanase activity for a number of cell lines. [cite journal | author = Nakajima M, Irimura T, Nicolson GL. | title = Heparanases and tumor metastasis | journal = J. Cell. Biochem. | year=1988 | volume=36 | issue=2 | pages=157–167 | pmid = 3281960 | doi = 10.1002/jcb.240360207] [cite journal | author=Vlodavsky I, Goldshmidt O, Zcharia E, "et al." |title=Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. |journal=Semin. Cancer Biol. |volume=12 |issue= 2 |pages= 121–9 |year= 2003 |pmid= 12027584 |doi= 10.1006/scbi.2001.0420] Due to the contribution of heparinase activity to metastasis and also to angiogenesis, the inhibition of heparinase activity it is considered to be a potential target for anti-cancer therapies.

References

PBB_Summary
section_title =
summary_text =

Further reading

PBB_Further_reading
citations =
*cite journal | author=Zcharia E, Metzger S, Chajek-Shaul T, "et al." |title=Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis. |journal=Journal of mammary gland biology and neoplasia |volume=6 |issue= 3 |pages= 311–22 |year= 2002 |pmid= 11547900 |doi=
*cite journal | author=Vlodavsky I, Abboud-Jarrous G, Elkin M, "et al." |title=The impact of heparanese and heparin on cancer metastasis and angiogenesis. |journal=Pathophysiol. Haemost. Thromb. |volume=35 |issue= 1-2 |pages= 116–27 |year= 2006 |pmid= 16855356 |doi= 10.1159/000093553
*cite journal | author=van den Hoven MJ, Rops AL, Vlodavsky I, "et al." |title=Heparanase in glomerular diseases. |journal=Kidney Int. |volume=72 |issue= 5 |pages= 543–8 |year= 2007 |pmid= 17519955 |doi= 10.1038/sj.ki.5002337
*cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=
*cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, "et al." |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=
*cite journal | author=Vlodavsky I, Friedmann Y, Elkin M, "et al." |title=Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. |journal=Nat. Med. |volume=5 |issue= 7 |pages= 793–802 |year= 1999 |pmid= 10395325 |doi= 10.1038/10518
*cite journal | author=Hulett MD, Freeman C, Hamdorf BJ, "et al." |title=Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. |journal=Nat. Med. |volume=5 |issue= 7 |pages= 803–9 |year= 1999 |pmid= 10395326 |doi= 10.1038/10525
*cite journal | author=Kussie PH, Hulmes JD, Ludwig DL, "et al." |title=Cloning and functional expression of a human heparanase gene. |journal=Biochem. Biophys. Res. Commun. |volume=261 |issue= 1 |pages= 183–7 |year= 1999 |pmid= 10405343 |doi= 10.1006/bbrc.1999.0962
*cite journal | author=Toyoshima M, Nakajima M |title=Human heparanase. Purification, characterization, cloning, and expression. |journal=J. Biol. Chem. |volume=274 |issue= 34 |pages= 24153–60 |year= 1999 |pmid= 10446189 |doi=
*cite journal | author=Dempsey LA, Plummer TB, Coombes SL, Platt JL |title=Heparanase expression in invasive trophoblasts and acute vascular damage. |journal=Glycobiology |volume=10 |issue= 5 |pages= 467–75 |year= 2000 |pmid= 10764835 |doi=
*cite journal | author=Dong J, Kukula AK, Toyoshima M, Nakajima M |title=Genomic organization and chromosome localization of the newly identified human heparanase gene. |journal=Gene |volume=253 |issue= 2 |pages= 171–8 |year= 2000 |pmid= 10940554 |doi=
*cite journal | author=Hulett MD, Hornby JR, Ohms SJ, "et al." |title=Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. |journal=Biochemistry |volume=39 |issue= 51 |pages= 15659–67 |year= 2001 |pmid= 11123890 |doi=
*cite journal | author=Ginath S, Menczer J, Friedmann Y, "et al." |title=Expression of heparanase, Mdm2, and erbB2 in ovarian cancer. |journal=Int. J. Oncol. |volume=18 |issue= 6 |pages= 1133–44 |year= 2001 |pmid= 11351242 |doi=
*cite journal | author=Koliopanos A, Friess H, Kleeff J, "et al." |title=Heparanase expression in primary and metastatic pancreatic cancer. |journal=Cancer Res. |volume=61 |issue= 12 |pages= 4655–9 |year= 2001 |pmid= 11406531 |doi=
*cite journal | author=Sasaki M, Ito T, Kashima M, "et al." |title=Erythromycin and clarithromycin modulation of growth factor-induced expression of heparanase mRNA on human lung cancer cells in vitro. |journal=Mediators Inflamm. |volume=10 |issue= 5 |pages= 259–67 |year= 2002 |pmid= 11759110 |doi=
*cite journal | author=Jiang P, Kumar A, Parrillo JE, "et al." |title=Cloning and characterization of the human heparanase-1 (HPR1) gene promoter: role of GA-binding protein and Sp1 in regulating HPR1 basal promoter activity. |journal=J. Biol. Chem. |volume=277 |issue= 11 |pages= 8989–98 |year= 2002 |pmid= 11779847 |doi= 10.1074/jbc.M105682200
*cite journal | author=Nadav L, Eldor A, Yacoby-Zeevi O, "et al." |title=Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts. |journal=J. Cell. Sci. |volume=115 |issue= Pt 10 |pages= 2179–87 |year= 2003 |pmid= 11973358 |doi=

PBB_Controls
update_page = yes
require_manual_inspection = no
update_protein_box = yes
update_summary = yes
update_citations = no