Heparanase

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Heparanase
Identifiers
Symbol(s) HPSE; HPR1; HPA; HPSE1; HSE1
External IDs OMIM: 604724 MGI: 1343124 HomoloGene: 68528
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 10855 15442
Ensembl ENSG00000173083 ENSMUSG00000035273
Uniprot Q9Y251 Q6YGZ1
Refseq NM_006665 (mRNA)
NP_006656 (protein)		 XM_982223 (mRNA)
XP_987317 (protein)
Location Chr 4: 84.43 - 84.48 Mb Chr 5: 100.92 - 100.96 Mb
Pubmed search [1] [2]

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.

Contents

[edit] Synthesis 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 fragment

The 8 kDa and 50 kDa fragments form a heterodimer and it is this heterodimer that constitutes the active heparanase molecule.[1] 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.

[edit] Endoglycosidic action

Heparanase cleaves polymeric heparan sulfate molecules at sites which are internal within the polymeric chain.[2]

[edit] 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.[3][4] 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.

[edit] References

  1. ^ Vlodavsky I, Ilan N. et al. (2007). "Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate". Curr. Pharm. Des. 13 (20): 2057–2073. doi:10.2174/138161207781039742. PMID 17627539. 
  2. ^ Pikas DS, Li JP, Vlodavsky I, Lindahl U (1998). "Substrate specificity of heparanases from human hepatoma and platelets.". J. Biol. Chem. 273 (30): 18770–7. PMID 9668050. 
  3. ^ Nakajima M, Irimura T, Nicolson GL. (1988). "Heparanases and tumor metastasis". J. Cell. Biochem. 36 (2): 157–167. doi:10.1002/jcb.240360207. PMID 3281960. 
  4. ^ Vlodavsky I, Goldshmidt O, Zcharia E, et al. (2003). "Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development.". Semin. Cancer Biol. 12 (2): 121–9. doi:10.1006/scbi.2001.0420. PMID 12027584. 


[edit] Further reading

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