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{{Infobox_gene}}
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'''Glypican-3''' is a [[protein]] that in humans is encoded by the ''GPC3'' [[gene]].<ref name="pmid8589713">{{cite journal | vauthors = Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D | title = Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome | journal = Nature Genetics | volume = 12 | issue = 3 | pages = 241–7 | date = March 1996 | pmid = 8589713 | pmc =  | doi = 10.1038/ng0396-241 }}</ref><ref name="pmid9787072">{{cite journal | vauthors = Veugelers M, Vermeesch J, Watanabe K, Yamaguchi Y, Marynen P, David G | title = GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome | journal = Genomics | volume = 53 | issue = 1 | pages = 1–11 | date = October 1998 | pmid = 9787072 | pmc =  | doi = 10.1006/geno.1998.5465 }}</ref><ref name="entrez_2719">{{cite web | title = Entrez Gene: GPC3 glypican 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2719| access-date = }}</ref><ref name="pmid17258707">{{cite journal | vauthors = Jakubovic BD, Jothy S | title = Glypican-3: from the mutations of Simpson-Golabi-Behmel genetic syndrome to a tumor marker for hepatocellular carcinoma | journal = Experimental and Molecular Pathology | volume = 82 | issue = 2 | pages = 184–9 | date = April 2007 | pmid = 17258707 | doi = 10.1016/j.yexmp.2006.10.010 }}</ref> The ''GPC3'' gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids.<ref name = "Ho_2011">{{cite journal | vauthors = Ho M, Kim H | title = Glypican-3: a new target for cancer immunotherapy | journal = European Journal of Cancer | volume = 47 | issue = 3 | pages = 333–8 | date = February 2011 | pmid = 21112773 | pmc = 3031711 | doi = 10.1016/j.ejca.2010.10.024 }}</ref> Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).<ref name = "Ho_2011" />
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


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==Structure and function==
{{GNF_Protein_box
The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa.<ref name = "Ho_2011" /> Six glypicans (GPC1-6) have been identified in mammals. Cell surface [[heparan sulfate]] [[proteoglycan]]s are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a [[glycosyl]] [[phosphatidylinositol]] linkage. These proteins may play a role in the control of [[cell division]] and growth regulation.<ref name="entrez_2719"/> GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.<ref name="Gao W 2018">{{cite journal | vauthors = Li N, Gao W, Zhang YF, Ho M | title = Glypicans as Cancer Therapeutic Targets | journal = Trends in Cancer | volume = 4 | issue = 11 | pages = 741–754 | date = November 2018 | pmid = 30352677 | pmc = 6209326 | doi = 10.1016/j.trecan.2018.09.004 }}</ref> A biochemical study has revealed that Wnt recognizes a heparan sulfate structure on GPC3 containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the glypican.<ref>{{cite journal | vauthors = Gao W, Xu Y, Liu J, Ho M | title = Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate | journal = Scientific Reports | volume = 6 | pages = 26245 | date = May 2016 | pmid = 27185050 | pmc = 4869111 | doi = 10.1038/srep26245 }}</ref>
| image = 
| image_source =
| PDB =  
| Name = Glypican 3
| HGNCid = 4451
| Symbol = GPC3
| AltSymbols =; DGSX; OCI-5; SDYS; SGB; SGBS; SGBS1
| OMIM = 300037
| ECnumber = 
| Homologene = 20944
| MGIid = 104903
| GeneAtlas_image1 = PBB_GE_GPC3_209220_at_tn.png
| Function = {{GNF_GO|id=GO:0048503 |text = GPI anchor binding}}
| Component = {{GNF_GO|id=GO:0005578 |text = proteinaceous extracellular matrix}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0001658 |text = ureteric bud branching}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0030513 |text = positive regulation of BMP signaling pathway}} {{GNF_GO|id=GO:0045926 |text = negative regulation of growth}}  
  | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2719
    | Hs_Ensembl = ENSG00000147257
    | Hs_RefseqProtein = NP_004475
    | Hs_RefseqmRNA = NM_004484
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = X
    | Hs_GenLoc_start = 132497439
    | Hs_GenLoc_end = 132947588
    | Hs_Uniprot = P51654
    | Mm_EntrezGene = 14734
    | Mm_Ensembl = ENSMUSG00000055653
    | Mm_RefseqmRNA = NM_016697
    | Mm_RefseqProtein = NP_057906
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = X
    | Mm_GenLoc_start = 48517053
    | Mm_GenLoc_end = 48858548
    | Mm_Uniprot = Q3TWB2
  }}
}}
'''Glypican 3''', also known as '''GPC3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GPC3 glypican 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2719| accessdate = }}</ref>


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==Disease linkage==
{{PBB_Summary
Deletion mutations in this gene are associated with [[Simpson-Golabi-Behmel syndrome]].<ref name="pmid17549790">{{cite journal | vauthors = Davoodi J, Kelly J, Gendron NH, MacKenzie AE | title = The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26 | journal = Proteomics | volume = 7 | issue = 13 | pages = 2300–10 | date = June 2007 | pmid = 17549790 | doi = 10.1002/pmic.200600654 }}</ref>
| section_title =  
| summary_text = Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.<ref name="entrez">{{cite web | title = Entrez Gene: GPC3 glypican 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2719| accessdate = }}</ref>
}}


==References==
==Diagnostic utility==
{{reflist|2}}
Glypican 3 [[immunostaining]] has utility for differentiating [[hepatocellular carcinoma]] (HCC) and dysplastic changes in [[cirrhosis|cirrhotic]] [[liver]]s; HCC stains with glypican 3, while liver with dysplastic changes and/or [[cirrhosis|cirrhotic changes]] does not.<ref>{{cite journal | vauthors = Anatelli F, Chuang ST, Yang XJ, Wang HL | title = Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy | journal = American Journal of Clinical Pathology | volume = 130 | issue = 2 | pages = 219–23 | date = August 2008 | pmid = 18628090 | doi = 10.1309/WMB5PX57Y4P8QCTY }}</ref>  Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in cholangiocarcinoma.<ref name = "Phung_2012">{{cite journal | vauthors = Phung Y, Gao W, Man YG, Nagata S, Ho M | title = High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening | journal = mAbs | volume = 4 | issue = 5 | pages = 592–9 | date = September 2012 | pmid = 22820551 | pmc = 3499300 | doi = 10.4161/mabs.20933 }}</ref> The YP7 murine antibody has been humanized and named as 'hYP7'. <ref>{{Cite journal|last=Zhang|first=Yi-Fan|last2=Ho|first2=Mitchell|date=2016-09-26|title=Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma|url=https://www.ncbi.nlm.nih.gov/pubmed/27667400|journal=Scientific Reports|volume=6|pages=33878|doi=10.1038/srep33878|issn=2045-2322|pmc=PMC5036187|pmid=27667400}}</ref> GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors.<ref name = "Ho_2011" /> However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.
==Further reading==
 
== Therapeutic potential ==
Glypican 3 is a potential therapeutic target for treating liver cancer and other cancers.<ref name="Ho_2011"/><ref name="Gao W 2018"/> Several therapeutic anti-GPC3 antibodies have been developed. Humanized monoclonal antibodies (GC33,<ref>{{cite journal | vauthors = Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, Sugo I, Ohizumi I, Aburatani H, Hamakubo T, Kodama T, Tsuchiya M, Yamada-Okabe H | title = Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer | journal = Cancer Research | volume = 68 | issue = 23 | pages = 9832–8 | date = December 2008 | pmid = 19047163 | doi = 10.1158/0008-5472.CAN-08-1973 }}</ref> hYP7<ref name = "Phung_2012" /> ) recognize the C-lobe of GPC3. The laboratory of Dr. Mitchell Ho at the National Cancer Institute reported the human single-domain antibody HN3<ref>{{cite journal | vauthors = Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M | title = Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 12 | pages = E1083-91 | date = March 2013 | pmid = 23471984 | pmc = 3607002 | doi = 10.1073/pnas.1217868110 }}</ref> targeting the N-lobe of GPC3 and the human monoclonal antibody HS20<ref>{{cite journal | vauthors = Gao W, Kim H, Feng M, Phung Y, Xavier CP, Rubin JS, Ho M | title = Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy | journal = Hepatology | volume = 60 | issue = 2 | pages = 576–87 | date = August 2014 | pmid = 24492943 | pmc = 4083010 | doi = 10.1002/hep.26996 }}</ref><ref>{{cite journal | vauthors = Kim H, Ho M | title = Isolation of Antibodies to Heparan Sulfate on Glypicans by Phage Display | journal = Current Protocols in Protein Science | volume = 94 | issue = 1 | pages = e66 | date = November 2018 | pmid = 30091851 | pmc = 6205898 | doi = 10.1002/cpps.66 }}</ref> targeting the heparan sulfate chains of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3 <ref>{{cite journal | vauthors = Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M | title = Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis | journal = Nature Communications | volume = 6 | pages = 6536 | date = March 2015 | pmid = 25758784 | pmc = 4357278 | doi = 10.1038/ncomms7536 }}</ref><ref>{{cite journal | vauthors = Wang C, Gao W, Feng M, Pastan I, Ho M | title = Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy | journal = Oncotarget | volume = 8 | issue = 20 | pages = 32450–32460 | date = May 2017 | pmid = 27419635 | pmc = 5464801 | doi = 10.18632/oncotarget.10592 }}</ref> and antibody-drug conjugates based on hYP7 <ref>{{cite journal | vauthors = Fu Y, Urban DJ, Nani RR, Zhang YF, Li N, Fu H, Shah H, Gorka AP, Guha R, Chen L, Hall MD, Schnermann MJ, Ho M | title = Glypican-3 Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma | journal = Hepatology | date = October 2018 | pmid = 30353932 | doi = 10.1002/hep.30326 }}</ref> have been developed for treating liver cancer.
 
== See also ==
* [[Glypican]]
{{clear}}
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Li M, Squire JA, Weksberg R | title = Overgrowth syndromes and genomic imprinting: from mouse to man | journal = Clinical Genetics | volume = 53 | issue = 3 | pages = 165–70 | date = March 1998 | pmid = 9630066 | doi = 10.1111/j.1399-0004.1998.tb02668.x }}
| citations =
* {{cite journal | vauthors = Filmus J | title = Glypicans in growth control and cancer | journal = Glycobiology | volume = 11 | issue = 3 | pages = 19R-23R | date = March 2001 | pmid = 11320054 | doi = 10.1093/glycob/11.3.19R }}
*{{cite journal | author=Li M, Squire JA, Weksberg R |title=Overgrowth syndromes and genomic imprinting: from mouse to man. |journal=Clin. Genet. |volume=53 |issue= 3 |pages= 165-70 |year= 1998 |pmid= 9630066 |doi= }}
* {{cite journal | vauthors = Filmus J, Shi W, Wong ZM, Wong MJ | title = Identification of a new membrane-bound heparan sulphate proteoglycan | journal = The Biochemical Journal | volume = 311 ( Pt 2) | issue = Pt 2 | pages = 561–5 | date = October 1995 | pmid = 7487896 | pmc = 1136036 | doi =  }}
*{{cite journal | author=Filmus J |title=Glypicans in growth control and cancer. |journal=Glycobiology |volume=11 |issue= 3 |pages= 19R-23R |year= 2001 |pmid= 11320054 |doi= }}
* {{cite journal | vauthors = Watanabe K, Yamada H, Yamaguchi Y | title = K-glypican: a novel GPI-anchored heparan sulfate proteoglycan that is highly expressed in developing brain and kidney | journal = The Journal of Cell Biology | volume = 130 | issue = 5 | pages = 1207–18 | date = September 1995 | pmid = 7657705 | pmc = 2120559 | doi = 10.1083/jcb.130.5.1207 }}
*{{cite journal | author=Filmus J, Shi W, Wong ZM, Wong MJ |title=Identification of a new membrane-bound heparan sulphate proteoglycan. |journal=Biochem. J. |volume=311 ( Pt 2) |issue= |pages= 561-5 |year= 1995 |pmid= 7487896 |doi=  }}
* {{cite journal | vauthors = Xuan JY, Besner A, Ireland M, Hughes-Benzie RM, MacKenzie AE | title = Mapping of Simpson-Golabi-Behmel syndrome to Xq25-q27 | journal = Human Molecular Genetics | volume = 3 | issue = 1 | pages = 133–7 | date = January 1994 | pmid = 7909248 | doi = 10.1093/hmg/3.1.133 }}
*{{cite journal | author=Watanabe K, Yamada H, Yamaguchi Y |title=K-glypican: a novel GPI-anchored heparan sulfate proteoglycan that is highly expressed in developing brain and kidney. |journal=J. Cell Biol. |volume=130 |issue= 5 |pages= 1207-18 |year= 1995 |pmid= 7657705 |doi= }}
* {{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 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | author=Xuan JY, Besner A, Ireland M, ''et al.'' |title=Mapping of Simpson-Golabi-Behmel syndrome to Xq25-q27. |journal=Hum. Mol. Genet. |volume=3 |issue= 1 |pages= 133-7 |year= 1994 |pmid= 7909248 |doi= }}
* {{cite journal | vauthors = Shen T, Sonoda G, Hamid J, Li M, Filmus J, Buick RN, Testa JR | title = Mapping of the Simpson-Golabi-Behmel overgrowth syndrome gene (GPC3) to chromosome X in human and rat by fluorescence in situ hybridization | journal = Mammalian Genome | volume = 8 | issue = 1 | pages = 72 | date = January 1997 | pmid = 9021160 | doi = 10.1007/s003359900357 }}
*{{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 | vauthors = Lage H, Dietel M | title = Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5 | journal = Gene | volume = 188 | issue = 2 | pages = 151–6 | date = April 1997 | pmid = 9133586 | doi = 10.1016/S0378-1119(96)00689-0 }}
*{{cite journal  | author=Pilia G, Hughes-Benzie RM, MacKenzie A, ''et al.'' |title=Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. |journal=Nat. Genet. |volume=12 |issue= 3 |pages= 241-7 |year= 1996 |pmid= 8589713 |doi= 10.1038/ng0396-241 }}
* {{cite journal | vauthors = Huber R, Crisponi L, Mazzarella R, Chen CN, Su Y, Shizuya H, Chen EY, Cao A, Pilia G | title = Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene | journal = Genomics | volume = 45 | issue = 1 | pages = 48–58 | date = October 1997 | pmid = 9339360 | doi = 10.1006/geno.1997.4916 }}
*{{cite journal | author=Shen T, Sonoda G, Hamid J, ''et al.'' |title=Mapping of the Simpson-Golabi-Behmel overgrowth syndrome gene (GPC3) to chromosome X in human and rat by fluorescence in situ hybridization. |journal=Mamm. Genome |volume=8 |issue= 1 |pages= 72 |year= 1997 |pmid= 9021160 |doi= }}
* {{cite journal | vauthors = Hsu HC, Cheng W, Lai PL | title = Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution | journal = Cancer Research | volume = 57 | issue = 22 | pages = 5179–84 | date = November 1997 | pmid = 9371521 | doi =  }}
*{{cite journal | author=Lage H, Dietel M |title=Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5. |journal=Gene |volume=188 |issue= 2 |pages= 151-6 |year= 1997 |pmid= 9133586 |doi= }}
* {{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 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal | author=Huber R, Crisponi L, Mazzarella R, ''et al.'' |title=Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene. |journal=Genomics |volume=45 |issue= 1 |pages= 48-58 |year= 1997 |pmid= 9339360 |doi= 10.1006/geno.1997.4916 }}
* {{cite journal | vauthors = Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A | title = Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome | journal = Developmental Dynamics | volume = 213 | issue = 4 | pages = 431–9 | date = December 1998 | pmid = 9853964 | doi = 10.1002/(SICI)1097-0177(199812)213:4<431::AID-AJA8>3.0.CO;2-7 }}
*{{cite journal | author=Hsu HC, Cheng W, Lai PL |title=Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. |journal=Cancer Res. |volume=57 |issue= 22 |pages= 5179-84 |year= 1997 |pmid= 9371521 |doi=  }}
* {{cite journal | vauthors = Huber R, Mazzarella R, Chen CN, Chen E, Ireland M, Lindsay S, Pilia G, Crisponi L | title = Glypican 3 and glypican 4 are juxtaposed in Xq26.1 | journal = Gene | volume = 225 | issue = 1-2 | pages = 9–16 | date = December 1998 | pmid = 9931407 | doi = 10.1016/S0378-1119(98)00549-6 | url = https://zenodo.org/record/1260055 }}
*{{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 | vauthors = Xuan JY, Hughes-Benzie RM, MacKenzie AE | title = A small interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family | journal = Journal of Medical Genetics | volume = 36 | issue = 1 | pages = 57–8 | date = January 1999 | pmid = 9950367 | pmc = 1762951 | doi = 10.1136/jmg.36.1.57 | doi-broken-date = 2018-09-05 }}
*{{cite journal  | author=Veugelers M, Vermeesch J, Watanabe K, ''et al.'' |title=GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome. |journal=Genomics |volume=53 |issue= 1 |pages= 1-11 |year= 1998 |pmid= 9787072 |doi= 10.1006/geno.1998.5465 }}
* {{cite journal | vauthors = Veugelers M, Cat BD, Muyldermans SY, Reekmans G, Delande N, Frints S, Legius E, Fryns JP, Schrander-Stumpel C, Weidle B, Magdalena N, David G | title = Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene | journal = Human Molecular Genetics | volume = 9 | issue = 9 | pages = 1321–8 | date = May 2000 | pmid = 10814714 | doi = 10.1093/hmg/9.9.1321 }}
*{{cite journal | author=Pellegrini M, Pilia G, Pantano S, ''et al.'' |title=Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome. |journal=Dev. Dyn. |volume=213 |issue= 4 |pages= 431-9 |year= 1999 |pmid= 9853964 |doi= 10.1002/(SICI)1097-0177(199812)213:4<431::AID-AJA8>3.0.CO;2-7 }}
* {{cite journal | vauthors = Khan S, Blackburn M, Mao DL, Huber R, Schlessinger D, Fant M | title = Glypican-3 (GPC3) expression in human placenta: localization to the differentiated syncytiotrophoblast | journal = Histology and Histopathology | volume = 16 | issue = 1 | pages = 71–8 | date = January 2001 | pmid = 11193214 | doi = 10.14670/HH-16.71 }}
*{{cite journal | author=Huber R, Mazzarella R, Chen CN, ''et al.'' |title=Glypican 3 and glypican 4 are juxtaposed in Xq26.1. |journal=Gene |volume=225 |issue= 1-2 |pages= 9-16 |year= 1999 |pmid= 9931407 |doi= }}
*{{cite journal | author=Xuan JY, Hughes-Benzie RM, MacKenzie AE |title=A small interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family. |journal=J. Med. Genet. |volume=36 |issue= 1 |pages= 57-8 |year= 1999 |pmid= 9950367 |doi= }}
*{{cite journal | author=Veugelers M, Cat BD, Muyldermans SY, ''et al.'' |title=Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. |journal=Hum. Mol. Genet. |volume=9 |issue= 9 |pages= 1321-8 |year= 2000 |pmid= 10814714 |doi= }}
*{{cite journal | author=Khan S, Blackburn M, Mao DL, ''et al.'' |title=Glypican-3 (GPC3) expression in human placenta: localization to the differentiated syncytiotrophoblast. |journal=Histol. Histopathol. |volume=16 |issue= 1 |pages= 71-8 |year= 2001 |pmid= 11193214 |doi= }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
== External links ==
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sgbs  GeneReviews/NIH/NCBI/UW entry on Simpson-Golabi-Behmel Syndrome]
 
[[Category:Immunologic tests]]

Latest revision as of 16:28, 18 January 2019

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Wikidata
View/Edit Human

Glypican-3 is a protein that in humans is encoded by the GPC3 gene.[1][2][3][4] The GPC3 gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids.[5] Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).[5]

Structure and function

The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa.[5] Six glypicans (GPC1-6) have been identified in mammals. Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.[3] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[6] A biochemical study has revealed that Wnt recognizes a heparan sulfate structure on GPC3 containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the glypican.[7]

Disease linkage

Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[8]

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[9] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in cholangiocarcinoma.[10] The YP7 murine antibody has been humanized and named as 'hYP7'. [11] GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors.[5] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.

Therapeutic potential

Glypican 3 is a potential therapeutic target for treating liver cancer and other cancers.[5][6] Several therapeutic anti-GPC3 antibodies have been developed. Humanized monoclonal antibodies (GC33,[12] hYP7[10] ) recognize the C-lobe of GPC3. The laboratory of Dr. Mitchell Ho at the National Cancer Institute reported the human single-domain antibody HN3[13] targeting the N-lobe of GPC3 and the human monoclonal antibody HS20[14][15] targeting the heparan sulfate chains of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3 [16][17] and antibody-drug conjugates based on hYP7 [18] have been developed for treating liver cancer.

See also

References

  1. ↑ Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D (March 1996). "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome". Nature Genetics. 12 (3): 241–7. doi:10.1038/ng0396-241. PMID 8589713.
  2. ↑ Veugelers M, Vermeesch J, Watanabe K, Yamaguchi Y, Marynen P, David G (October 1998). "GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome". Genomics. 53 (1): 1–11. doi:10.1006/geno.1998.5465. PMID 9787072.
  3. ↑ 3.0 3.1 "Entrez Gene: GPC3 glypican 3".
  4. ↑ Jakubovic BD, Jothy S (April 2007). "Glypican-3: from the mutations of Simpson-Golabi-Behmel genetic syndrome to a tumor marker for hepatocellular carcinoma". Experimental and Molecular Pathology. 82 (2): 184–9. doi:10.1016/j.yexmp.2006.10.010. PMID 17258707.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Ho M, Kim H (February 2011). "Glypican-3: a new target for cancer immunotherapy". European Journal of Cancer. 47 (3): 333–8. doi:10.1016/j.ejca.2010.10.024. PMC 3031711. PMID 21112773.
  6. ↑ 6.0 6.1 Li N, Gao W, Zhang YF, Ho M (November 2018). "Glypicans as Cancer Therapeutic Targets". Trends in Cancer. 4 (11): 741–754. doi:10.1016/j.trecan.2018.09.004. PMC 6209326. PMID 30352677.
  7. ↑ Gao W, Xu Y, Liu J, Ho M (May 2016). "Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate". Scientific Reports. 6: 26245. doi:10.1038/srep26245. PMC 4869111. PMID 27185050.
  8. ↑ Davoodi J, Kelly J, Gendron NH, MacKenzie AE (June 2007). "The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26". Proteomics. 7 (13): 2300–10. doi:10.1002/pmic.200600654. PMID 17549790.
  9. ↑ Anatelli F, Chuang ST, Yang XJ, Wang HL (August 2008). "Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy". American Journal of Clinical Pathology. 130 (2): 219–23. doi:10.1309/WMB5PX57Y4P8QCTY. PMID 18628090.
  10. ↑ 10.0 10.1 Phung Y, Gao W, Man YG, Nagata S, Ho M (September 2012). "High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening". mAbs. 4 (5): 592–9. doi:10.4161/mabs.20933. PMC 3499300. PMID 22820551.
  11. ↑ Zhang, Yi-Fan; Ho, Mitchell (2016-09-26). "Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma". Scientific Reports. 6: 33878. doi:10.1038/srep33878. ISSN 2045-2322. PMC 5036187. PMID 27667400.
  12. ↑ Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, Sugo I, Ohizumi I, Aburatani H, Hamakubo T, Kodama T, Tsuchiya M, Yamada-Okabe H (December 2008). "Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer". Cancer Research. 68 (23): 9832–8. doi:10.1158/0008-5472.CAN-08-1973. PMID 19047163.
  13. ↑ Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M (March 2013). "Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 110 (12): E1083–91. doi:10.1073/pnas.1217868110. PMC 3607002. PMID 23471984.
  14. ↑ Gao W, Kim H, Feng M, Phung Y, Xavier CP, Rubin JS, Ho M (August 2014). "Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy". Hepatology. 60 (2): 576–87. doi:10.1002/hep.26996. PMC 4083010. PMID 24492943.
  15. ↑ Kim H, Ho M (November 2018). "Isolation of Antibodies to Heparan Sulfate on Glypicans by Phage Display". Current Protocols in Protein Science. 94 (1): e66. doi:10.1002/cpps.66. PMC 6205898. PMID 30091851.
  16. ↑ Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M (March 2015). "Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis". Nature Communications. 6: 6536. doi:10.1038/ncomms7536. PMC 4357278. PMID 25758784.
  17. ↑ Wang C, Gao W, Feng M, Pastan I, Ho M (May 2017). "Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy". Oncotarget. 8 (20): 32450–32460. doi:10.18632/oncotarget.10592. PMC 5464801. PMID 27419635.
  18. ↑ Fu Y, Urban DJ, Nani RR, Zhang YF, Li N, Fu H, Shah H, Gorka AP, Guha R, Chen L, Hall MD, Schnermann MJ, Ho M (October 2018). "Glypican-3 Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma". Hepatology. doi:10.1002/hep.30326. PMID 30353932.

Further reading

External links

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