Glypican 3

Last updated

GPC3
Identifiers
Aliases GPC3 , DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, SGBS1, Glypican 3
External IDs OMIM: 300037; MGI: 104903; HomoloGene: 20944; GeneCards: GPC3; OMA:GPC3 - orthologs
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

Contents

NP_057906

Location (UCSC) Chr X: 133.54 – 133.99 Mb Chr X: 51.36 – 51.7 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

Schematic of the glypican-3 (GPC3) protein Schematic of the glypican-3 protein..tif
Schematic of the glypican-3 (GPC3) protein

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 has been found to regulate Wnt/β-catenin and Yap signaling pathways. [9] [10] [11] [12] [13] [14] [15] [16] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling. [11] [17] The core protein of GPC3 may serve as a co-receptor or a receiver for Wnt. A cysteine-rich domain at the N-lobe of GPC3 has been identified as a hydrophobic groove that interacts with Wnt3a. [17] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation. [17] Wnt also 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 heparan sulfate. [10] GPC3 also modulates Yap signaling. [12] It interacts with FAT1, a potential upstream cell surface receptor of YAP1 in human cells. [15] GPC3 is also found to bind Alpha-fetoprotein in liver cancer. [18]

Disease linkage

Deletion mutations in this gene are associated with Simpson–Golabi–Behmel syndrome. [5]

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) [19] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not. [20] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma. [21] The YP7 murine antibody has been humanized and named as 'hYP7'. [22] 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. [9]

Therapeutic potential

To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33, [23] YP7, [21] HN3 [12] and HS20 [13] [24] have been made and widely tested. The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 murine monoclonal antibody that recognizes the C-lobe of GPC3 by hybridoma technology. [21] The antibody has been humanized (named hYP7) via antibody engineering for clinical applications. [22] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3 [12] targeting the N-lobe of GPC3 [17] and the human monoclonal antibody HS20 [13] [24] targeting the heparan sulfate chains on GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3, [14] [25] [26] the antibody-drug conjugates based on hYP7 [27] and the T-cell engaging bispecific antibodies derived from YP7 [28] [29] and GC33, [30] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33, [31] hYP7 [32] [33] and HN3 [34] are being reported at various stages for treating liver cancer. In mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells can eliminate GPC3-positive cancer cells, by inducing perforin- and granzyme-mediated cell death and reducing Wnt signaling in tumor cells. [33] CAR (hYP7) T cells are being evaluated at a clinical trial at the NIH. [35]

See also

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000055653 Ensembl, May 2017
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  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  21. 1 2 3 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): 592–599. doi:10.4161/mabs.20933. PMC   3499300 . PMID   22820551.
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  33. 1 2 Li D, Li N, Zhang YF, Fu H, Feng M, Schneider D, et al. (June 2020). "Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice". Gastroenterology. 158 (8): 2250–2265.e20. doi:10.1053/j.gastro.2020.02.011. PMC   7282931 . PMID   32060001.
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  35. NCT05003895

Further reading