Heparanase: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{SIB}} + & -{{EH}} + & -{{EJ}} + & -{{Editor Help}} + & -{{Editor Join}} +))
 
m (1 revision imported)
 
(3 intermediate revisions by 3 users not shown)
Line 1: Line 1:
'''Editors-In-Chief:''' William J. Gibson, Massachusetts Institute of Technology, Cambridge MA
{{Infobox_gene}}
'''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 [[oligosaccharide]]s.<ref name="pmid10395325">{{cite journal | vauthors = 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 | title = Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis | journal = Nature Medicine | volume = 5 | issue = 7 | pages = 793–802 | date = July 1999 | pmid = 10395325 | doi = 10.1038/10518 }}</ref><ref name="pmid10395326">{{cite journal | vauthors = Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR | title = Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis | journal = Nature Medicine | volume = 5 | issue = 7 | pages = 803–9 | date = July 1999 | pmid = 10395326 | doi = 10.1038/10525 }}</ref>


== Synthesis and structure ==


<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = no
}}
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Heparanase
| HGNCid = 5164
| Symbol = HPSE
| AltSymbols =; HPR1; HPA; HPSE1; HSE1
| OMIM = 604724
| ECnumber = 
| Homologene = 68528
| MGIid = 1343124
| GeneAtlas_image1 = PBB_GE_HPSE_219403_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0004566 |text = beta-glucuronidase activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}}
| Component = {{GNF_GO|id=GO:0005764 |text = lysosome}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006029 |text = proteoglycan metabolic process}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 10855
    | Hs_Ensembl = ENSG00000173083
    | Hs_RefseqProtein = NP_006656
    | Hs_RefseqmRNA = NM_006665
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 4
    | Hs_GenLoc_start = 84432639
    | Hs_GenLoc_end = 84475329
    | Hs_Uniprot = Q9Y251
    | Mm_EntrezGene = 15442
    | Mm_Ensembl = ENSMUSG00000035273
    | Mm_RefseqmRNA = XM_982223
    | Mm_RefseqProtein = XP_987317
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 100920698
    | Mm_GenLoc_end = 100959985
    | Mm_Uniprot = Q6YGZ1
  }}
}}
{{SI}}
'''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 [[oligosaccharide]]s.
==Synthesis and structure==
The protein is originally synthesised in an inactive 65 [[kDa]] proheparanase form in the [[golgi apparatus]] and transferred to late [[endosome]]s/[[lysosome]]s for transport to the cell-surface. In the lysosome it is [[proteolysis|proteolytically processed]] into its active form. Proteolytic processing results in the production of three products,
The protein is originally synthesised in an inactive 65 [[kDa]] proheparanase form in the [[golgi apparatus]] and transferred to late [[endosome]]s/[[lysosome]]s for transport to the cell-surface. In the lysosome it is [[proteolysis|proteolytically processed]] into its active form. Proteolytic processing results in the production of three products,
* a linker peptide
* a linker peptide
* a 8 kDa proheparanase fragment and
* an 8 kDa proheparanase fragment and
* a 50 kDa proheparanase fragment
* 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.<ref>{{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 | id = PMID 17627539}}</ref> 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.
The 8 kDa and 50 kDa fragments form a [[heterodimer]] and it is this heterodimer that constitutes the active heparanase molecule.<ref>{{cite journal | vauthors = Vlodavsky I, Ilan N, Naggi A, Casu B | title = Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate | journal = Curr. Pharm. Des. | volume = 13 | issue = 20 | pages = 2057–2073 | year = 2007 | pmid = 17627539 | doi = 10.2174/138161207781039742 }}</ref> 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.


==[[Endoglycosidase|Endoglycosidic action]]==
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.<ref>{{cite journal | vauthors = Wu L, Jiang J, Jin Y, Kallemeijn WW, Kuo CL, Artola M, Dai W, van Elk C, van Eijk M, van der Marel GA, ((Codée JDC)), Florea BI, ((Aerts JMFG)), Overkleeft HS, Davies GJ | title = Activity-based probes for functional interrogation of retaining β-glucuronidases | journal = Nat. Chem. Biol. | year = 2017 | pmid = 28581485 | doi = 10.1038/nchembio.2395 | volume=13 | issue = 8 | pages=867–873| url = http://eprints.whiterose.ac.uk/117420/1/Accepted_Version.pdf }}</ref>  Removal of the linker reveals an extended cleft on the enzyme surface, which contains the heparanase [[active site]].<ref>{{cite journal | vauthors = Wu L, Viola CM, Brzozowski AM, Davies GJ | title = Structural characterization of human heparanase reveals insights into substrate recognition | journal = Nat. Struct. Mol. Biol. | volume = 22 | issue = 12 | pages = 1016–1022 | year = 2015 | pmid = 26575439 | doi = 10.1038/nsmb.3136 | pmc=5008439}}</ref>
Heparanase cleaves polymeric [[heparan sulfate]] molecules at sites which are internal within the polymeric chain.<ref>{{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=}}</ref>


==Role in [[metastasis]] and [[angiogenesis]]==
== Function ==
The successful penetration of the [[endothelium|endothelial cell layer]] that lines the interior surface of [[blood vessel]]s is an important process in the formation of blood borne tumour [[metastases]]. [[Heparan sulfate]] [[proteoglycan]]s 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 line]]s.<ref>{{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 | id = PMID 3281960}}</ref><ref>{{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}}</ref> 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.


==Heparanase Inhibitors==
Heparanase has [[endoglycosidase]] activity and cleaves polymeric [[heparan sulfate]] molecules at sites which are internal within the polymeric chain.<ref>{{cite journal | vauthors = 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 = 10.1074/jbc.273.30.18770 }}</ref> In ocular surface physiology this activity functions as an off/on switch for the prosecretory mitogen [[lacritin]].  Lacritin binds the cell surface heparan sulfate proteoglycan [[syndecan-1]] only in the presence of active heparanase.  Heparanase partially or completely cleaves [[heparan sulfate]] to expose a binding site in the N-terminal 50 amino acids of [[syndecan-1]].<ref name="pmid16982797">{{cite journal | vauthors = Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, Chirico WJ, Rapraeger AC, Laurie GW | title = Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin | journal = The Journal of Cell Biology | volume = 174 | issue = 7 | pages = 1097–106 | date = September 2006 | pmid = 16982797 | pmc = 1666580 | doi = 10.1083/jcb.200511134 }}</ref>
* Heparin and low molecular weight heparin
* Suramin
* Calcium spirulan
* Phosphomannopentaose sulfate (PI-88)
* Maltohexaose sulfate
* Laminarin sulfate
* Anti-heparanase antibodies


== Clinical significance ==
The successful penetration of the [[endothelium|endothelial cell layer]] that lines the interior surface of [[blood vessel]]s is an important process in the formation of blood borne tumour [[metastases]]. [[Heparan sulfate]] [[proteoglycan]]s 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 line]]s.<ref>{{cite journal | vauthors = Nakajima M, Irimura T, Nicolson GL | title = Heparanases and tumor metastasis | journal = J. Cell. Biochem. | volume = 36 | issue = 2 | pages = 157–167 | year = 1988 | pmid = 3281960 | doi = 10.1002/jcb.240360207 }}</ref><ref>{{cite journal | vauthors = Vlodavsky I, Goldshmidt O, Zcharia E, Atzmon R, Rangini-Guatta Z, Elkin M, Peretz T, Friedmann Y | 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 }}</ref> 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.<ref>{{Cite journal|last=Yang|first=Jian-min|last2=Wang|first2=Hui-ju|last3=Du|first3=Ling|last4=Han|first4=Xiao-mei|last5=Ye|first5=Zai-yuan|last6=Fang|first6=Yong|last7=Tao|first7=Hou-quan|last8=Zhao|first8=Zhong-sheng|last9=Zhou|first9=Yong-lie|date=2009-01-25|title=Screening and identification of novel B cell epitopes in human heparanase and their anti-invasion property for hepatocellular carcinoma|journal=Cancer Immunology, Immunotherapy|language=en|volume=58|issue=9|pages=1387–1396|doi=10.1007/s00262-008-0651-x|pmid=19169879|issn=0340-7004}}</ref><ref>{{Cite journal|url=http://www.spandidos-publications.com/ol/4/1/178|title=Overexpression of heparanase multiple antigenic peptide 2 is associated with poor prognosis in gastric cancer: Potential for therapy|journal=Oncology Letters|volume=4|pages=178–182|access-date=2016-03-29|doi=10.3892/ol.2012.703|pmid=22807984|year=2012|last1=Zhang|first1=JUN|last2=Yang|first2=Jianmin|last3=Han|first3=Xiaomei|last4=Zhao|first4=Zhongsheng|last5=Du|first5=Ling|last6=Yu|first6=Tong|last7=Wang|first7=Huiju}}</ref>
Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant [[heparan sulfate]] [[proteoglycan]]s.<ref>{{cite journal | vauthors = Baker AB, Gibson WJ, Kolachalama VB, Golomb M, Indolfi L, Spruell C, Zcharia E, Vlodavsky I, Edelman ER | title = Heparanase regulates thrombosis in vascular injury and stent-induced flow disturbance. | journal = J Am Coll Cardiol | volume = 59 | issue = 17 | pages = 1551–60 | year = 2012 | pmid = 22516446 | pmc = 4191917 | doi = 10.1016/j.jacc.2011.11.057 }}</ref>


==References==
==References==
{{reflist}}
{{reflist|35em}}
 
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text =
}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
*{{cite journal | vauthors = Zcharia E, Metzger S, Chajek-Shaul T, Friedmann Y, Pappo O, Aviv A, Elkin M, Pecker I, Peretz T, Vlodavsky I | 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 = 10.1023/A:1011375624902 }}
| citations =  
*{{cite journal | vauthors = Vlodavsky I, Abboud-Jarrous G, Elkin M, Naggi A, Casu B, Sasisekharan R, Ilan N | 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 | vauthors = van den Hoven MJ, Rops AL, Vlodavsky I, Levidiotis V, Berden JH, van der Vlag J | 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 | vauthors = 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 = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | 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 = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal | vauthors = 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 | 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 | vauthors = Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR | 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 | vauthors = Kussie PH, Hulmes JD, Ludwig DL, Patel S, Navarro EC, Seddon AP, Giorgio NA, Bohlen P | 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 | vauthors = 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 = 10.1074/jbc.274.34.24153 }}
*{{cite journal | vauthors = 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 = 10.1093/glycob/10.5.467 }}
*{{cite journal | vauthors = 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 = 10.1016/S0378-1119(00)00251-1 }}
*{{cite journal | vauthors = Hulett MD, Hornby JR, Ohms SJ, Zuegg J, Freeman C, Gready JE, Parish CR | 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 = 10.1021/bi002080p }}
*{{cite journal | vauthors = Ginath S, Menczer J, Friedmann Y, Aingorn H, Aviv A, Tajima K, Dantes A, Glezerman M, Vlodavsky I, Amsterdam A | 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 = 10.3892/ijo.18.6.1133 }}
*{{cite journal | vauthors = Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, Vlodavsky I, Zimmermann A, Büchler MW | 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 | vauthors = Sasaki M, Ito T, Kashima M, Fukui S, Izumiyama N, Watanabe A, Sano M, Fujiwara Y, Miura M | 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 | pmc = 1781717 | doi = 10.1080/09629350120093731 }}
*{{cite journal | vauthors = Jiang P, Kumar A, Parrillo JE, Dempsey LA, Platt JL, Prinz RA, Xu X | 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 | vauthors = Nadav L, Eldor A, Yacoby-Zeevi O, Zamir E, Pecker I, Ilan N, Geiger B, Vlodavsky I, Katz BZ | 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 = }}
{{refend}}


*{{cite journal  | author=Nasser NJ |title=Heparanase involvement in physiology and disease. |journal=Journal of mammary gland biology and neoplasia |volume=65 |issue= 11 |pages= 1706-15 |year= 2008 |pmid= 18425416 |doi=  }}
{{Sugar hydrolases}}
*{{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=  }}
}}
{{refend}}


[[Category:Peripheral membrane proteins]]
[[Category:Peripheral membrane proteins]]
 
[[Category:Extracellular matrix remodeling enzymes]]
{{WH}}
{{WikiDoc Sources}}

Latest revision as of 12:01, 10 January 2019

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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.[1][2]

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.[3] 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.[4] Removal of the linker reveals an extended cleft on the enzyme surface, which contains the heparanase active site.[5]

Function

Heparanase has endoglycosidase activity and cleaves polymeric heparan sulfate molecules at sites which are internal within the polymeric chain.[6] In ocular surface physiology this activity functions as an off/on switch for the prosecretory mitogen lacritin. Lacritin binds the cell surface heparan sulfate proteoglycan syndecan-1 only in the presence of active heparanase. Heparanase partially or completely cleaves heparan sulfate to expose a binding site in the N-terminal 50 amino acids of syndecan-1.[7]

Clinical significance

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.[8][9] 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.[10][11]

Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant heparan sulfate proteoglycans.[12]

References

  1. ↑ 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 (July 1999). "Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis". Nature Medicine. 5 (7): 793–802. doi:10.1038/10518. PMID 10395325.
  2. ↑ Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR (July 1999). "Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis". Nature Medicine. 5 (7): 803–9. doi:10.1038/10525. PMID 10395326.
  3. ↑ Vlodavsky I, Ilan N, Naggi A, Casu B (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.
  4. ↑ Wu L, Jiang J, Jin Y, Kallemeijn WW, Kuo CL, Artola M, Dai W, van Elk C, van Eijk M, van der Marel GA, Codée JDC, Florea BI, Aerts JMFG, Overkleeft HS, Davies GJ (2017). "Activity-based probes for functional interrogation of retaining β-glucuronidases" (PDF). Nat. Chem. Biol. 13 (8): 867–873. doi:10.1038/nchembio.2395. PMID 28581485.
  5. ↑ Wu L, Viola CM, Brzozowski AM, Davies GJ (2015). "Structural characterization of human heparanase reveals insights into substrate recognition". Nat. Struct. Mol. Biol. 22 (12): 1016–1022. doi:10.1038/nsmb.3136. PMC 5008439. PMID 26575439.
  6. ↑ 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. doi:10.1074/jbc.273.30.18770. PMID 9668050.
  7. ↑ Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, Chirico WJ, Rapraeger AC, Laurie GW (September 2006). "Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin". The Journal of Cell Biology. 174 (7): 1097–106. doi:10.1083/jcb.200511134. PMC 1666580. PMID 16982797.
  8. ↑ 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.
  9. ↑ Vlodavsky I, Goldshmidt O, Zcharia E, Atzmon R, Rangini-Guatta Z, Elkin M, Peretz T, Friedmann Y (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.
  10. ↑ Yang, Jian-min; Wang, Hui-ju; Du, Ling; Han, Xiao-mei; Ye, Zai-yuan; Fang, Yong; Tao, Hou-quan; Zhao, Zhong-sheng; Zhou, Yong-lie (2009-01-25). "Screening and identification of novel B cell epitopes in human heparanase and their anti-invasion property for hepatocellular carcinoma". Cancer Immunology, Immunotherapy. 58 (9): 1387–1396. doi:10.1007/s00262-008-0651-x. ISSN 0340-7004. PMID 19169879.
  11. ↑ Zhang, JUN; Yang, Jianmin; Han, Xiaomei; Zhao, Zhongsheng; Du, Ling; Yu, Tong; Wang, Huiju (2012). "Overexpression of heparanase multiple antigenic peptide 2 is associated with poor prognosis in gastric cancer: Potential for therapy". Oncology Letters. 4: 178–182. doi:10.3892/ol.2012.703. PMID 22807984. Retrieved 2016-03-29.
  12. ↑ Baker AB, Gibson WJ, Kolachalama VB, Golomb M, Indolfi L, Spruell C, Zcharia E, Vlodavsky I, Edelman ER (2012). "Heparanase regulates thrombosis in vascular injury and stent-induced flow disturbance". J Am Coll Cardiol. 59 (17): 1551–60. doi:10.1016/j.jacc.2011.11.057. PMC 4191917. 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. doi:10.1023/A:1011375624902. PMID 11547900.
  • 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. doi:10.1159/000093553. PMID 16855356.
  • 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. 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. doi:10.1016/0378-1119(94)90802-8. 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. doi:10.1016/S0378-1119(97)00411-3. 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. doi:10.1038/10518. PMID 10395325.
  • 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. doi:10.1038/10525. PMID 10395326.
  • 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. 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. doi:10.1074/jbc.274.34.24153. 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. doi:10.1093/glycob/10.5.467. 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. doi:10.1016/S0378-1119(00)00251-1. 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. doi:10.1021/bi002080p. 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. doi:10.3892/ijo.18.6.1133. 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. doi:10.1080/09629350120093731. PMC 1781717. 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. doi:10.1074/jbc.M105682200. 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.
Retrieved from "https://www.wikidoc.org/index.php?title=Heparanase&oldid=1526225"