Glypican 3

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GPC3
Identifiers
AliasesGPC3, DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, SGBS1, Glypican 3
External IDsOMIM: 300037 MGI: 104903 HomoloGene: 20944 GeneCards: GPC3
Gene location (Human)
X chromosome (human)
Chr.X chromosome (human)[1]
X chromosome (human)
Genomic location for GPC3
Genomic location for GPC3
BandXq26.2Start133,535,745 bp[1]
End133,985,895 bp[1]
RNA expression pattern
PBB GE GPC3 209220 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_004484
NM_001164617
NM_001164618
NM_001164619

NM_016697

RefSeq (protein)

NP_001158089
NP_001158090
NP_001158091
NP_004475
NP_004475.1

NP_057906

Location (UCSC)Chr X: 133.54 – 133.99 MbChr X: 52.27 – 52.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene.[5][6][7][8] 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.[9] Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).[9]

Structure and function[edit]

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.[9] 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.[7] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[10][11] Wnt recognizes a heparan sulfate structure on GPC3 , which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the heparan sulfate glypican.[12] The core protein of GPC3 may serve as a co-receptor for Wnt. A cysteine-rich domain at the N-lobe of GPC3 has been identified as a hydrophobic groove that interacts with Wnt3a.[11] Blocking the Wnt binding domain on GPC3 using the HN3 nanobody can inhibit Wnt activation. [11]

Disease linkage[edit]

Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[13]

Diagnostic utility[edit]

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.[14] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[15] The YP7 murine antibody has been humanized and named as 'hYP7'.[16] 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.[9] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.

Therapeutic potential[edit]

GPC3 is a promising therapeutic target for treating liver cancer and other cancers.[9][10] Several therapeutic anti-GPC3 antibodies have been developed, including GC33[17] and YP7[15][16]. The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has isolated YP7 and other murine monoclonal antibodies that recognize the C-lobe of GPC3 by hybridoma technology.[15] These antibodies have been humanized (e.g. hYP7) for clinical applications. [16] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[18] targeting the N-lobe of GPC3 [11] and the human monoclonal antibody HS20[19][20] targeting the heparan sulfate moiety of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3, [21][22] the antibody-drug conjugates based on hYP7 [23] and the T-cell engaging bispecific antibodies derived from YP7[24] and GC33[25] have been developed for treating liver cancer.

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000147257 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055653 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ 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.
  6. ^ 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.
  7. ^ a b "Entrez Gene: GPC3 glypican 3".
  8. ^ 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.
  9. ^ a b c d e 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.
  10. ^ a b 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.
  11. ^ a b c d Li, Na; Wei, Liwen; Liu, Xiaoyu; Bai, Hongjun; Ye, Yvonne; Li, Dan; Li, Nan; Baxa, Ulrich; Wang, Qun (2019-04-09). "A frizzled-like cysteine rich domain in glypican-3 mediates Wnt binding and regulates hepatocellular carcinoma tumor growth in mice". Hepatology (Baltimore, Md.). doi:10.1002/hep.30646. ISSN 1527-3350. PMID 30963603.
  12. ^ 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. Bibcode:2016NatSR...626245G. doi:10.1038/srep26245. PMC 4869111. PMID 27185050.
  13. ^ 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.
  14. ^ 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.
  15. ^ a b c 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.
  16. ^ a b c Zhang YF, Ho M (September 2016). "Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma". Scientific Reports. 6: 33878. Bibcode:2016NatSR...633878Z. doi:10.1038/srep33878. PMC 5036187. PMID 27667400.
  17. ^ 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.
  18. ^ 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. Bibcode:2013PNAS..110E1083F. doi:10.1073/pnas.1217868110. PMC 3607002. PMID 23471984.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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. Bibcode:2015NatCo...6.6536G. doi:10.1038/ncomms7536. PMC 4357278. PMID 25758784.
  22. ^ 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.
  23. ^ 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. 70 (2): 563–576. doi:10.1002/hep.30326. PMC 6482108. PMID 30353932.
  24. ^ "Federal Register /Vol. 82, No. 96 / Friday, May 19, 2017" (PDF).
  25. ^ Ishiguro, Takahiro; Sano, Yuji; Komatsu, Shun-Ichiro; Kamata-Sakurai, Mika; Kaneko, Akihisa; Kinoshita, Yasuko; Shiraiwa, Hirotake; Azuma, Yumiko; Tsunenari, Toshiaki (2017-10-04). "An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors". Science Translational Medicine. 9 (410): eaal4291. doi:10.1126/scitranslmed.aal4291. ISSN 1946-6242. PMID 28978751.

Further reading[edit]

External links[edit]