Heparanase
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Heparanase, also known as HPSE, is an
cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.[5][6]
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
- an 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.[7]
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.
Crystal structures of both proheparanase and mature heparanase are available, showing that the linker peptide forms a large helical domain which blocks heparan sulfate molecules from interacting with heparanase.[8] Removal of the linker reveals an extended cleft on the enzyme surface, which contains the heparanase active site.[9]
Function
Heparanase has
syndecan-1.[12]
Clinical significance
The successful penetration of the
cell lines.[13][14] Due to the contribution of heparanase activity to metastasis and also to angiogenesis, the inhibition of heparanase activity it is considered to be a potential target for anti-cancer therapies.[15][16]
Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant heparan sulfate proteoglycans.[17]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000173083 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035273 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 38895589.
- S2CID 20125382.
- PMID 17627539.
- PMID 28581485.
- PMID 26575439.
- PMID 9668050.
- S2CID 46339755.
- PMID 16982797.
- S2CID 9743270.
- PMID 12027584.
- S2CID 19074169.
- PMID 22807984. Retrieved 2016-03-29.
- PMID 22516446.
Further reading
- Zcharia E, Metzger S, Chajek-Shaul T, Friedmann Y, Pappo O, Aviv A, Elkin M, Pecker I, Peretz T, Vlodavsky I (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. S2CID 13292455.
- Vlodavsky I, Abboud-Jarrous G, Elkin M, Naggi A, Casu B, Sasisekharan R, Ilan N (2006). "The impact of heparanese and heparin on cancer metastasis and angiogenesis". Pathophysiol. Haemost. Thromb. 35 (1–2): 116–27. S2CID 25204783.
- van den Hoven MJ, Rops AL, Vlodavsky I, Levidiotis V, Berden JH, van der Vlag J (2007). "Heparanase in glomerular diseases". Kidney Int. 72 (5): 543–8. 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, Suyama A, Sugano S (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, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I (1999). "Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis". Nat. Med. 5 (7): 793–802. S2CID 38895589.
- Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR (1999). "Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis". Nat. Med. 5 (7): 803–9. S2CID 20125382.
- Kussie PH, Hulmes JD, Ludwig DL, Patel S, Navarro EC, Seddon AP, Giorgio NA, Bohlen P (1999). "Cloning and functional expression of a human heparanase gene". Biochem. Biophys. Res. Commun. 261 (1): 183–7. 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, Zuegg J, Freeman C, Gready JE, Parish CR (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, Aingorn H, Aviv A, Tajima K, Dantes A, Glezerman M, Vlodavsky I, Amsterdam A (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, Shi X, Liao Q, Pecker I, Vlodavsky I, Zimmermann A, Büchler MW (2001). "Heparanase expression in primary and metastatic pancreatic cancer". Cancer Res. 61 (12): 4655–9. PMID 11406531.
- Sasaki M, Ito T, Kashima M, Fukui S, Izumiyama N, Watanabe A, Sano M, Fujiwara Y, Miura M (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, Dempsey LA, Platt JL, Prinz RA, Xu X (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. PMID 11779847.
- Nadav L, Eldor A, Yacoby-Zeevi O, Zamir E, Pecker I, Ilan N, Geiger B, Vlodavsky I, Katz BZ (2003). "Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts". J. Cell Sci. 115 (Pt 10): 2179–87. PMID 11973358.