Glypican 3

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Template:Short description Template:Cs1 config Template:Infobox gene 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

File:Schematic of the glypican-3 protein..tif
Schematic of the glypican-3 (GPC3) protein[5]

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 has been found to regulate Wnt/β-catenin and Yap signaling pathways.[5][6][7][8][9][10][11][12] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[7][13] 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.[13] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.[13] 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.[6] GPC3 also modulates Yap signaling.[8] It interacts with FAT1, a potential upstream cell surface receptor of YAP1 in human cells.[11] GPC3 is also found to bind Alpha-fetoprotein in liver cancer.[14]

Disease linkage

Deletion mutations in this gene are associated with Simpson–Golabi–Behmel syndrome.[1]

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[15] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[16] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[17] The YP7 murine antibody has been humanized and named as 'hYP7'.[18] 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.[5]

Therapeutic potential

To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33,[19] YP7,[17] HN3[8] and HS20[9][20] 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.[17] The antibody has been humanized (named hYP7) via antibody engineering for clinical applications.[18] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[8] targeting the N-lobe of GPC3 [13] and the human monoclonal antibody HS20[9][20] 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,[10][21][22] the antibody-drug conjugates based on hYP7[23] and the T-cell engaging bispecific antibodies derived from YP7[24][25] and GC33,[26] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33,[27] hYP7[28][29] and HN3[30] 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.[29] CAR (hYP7) T cells are being evaluated at a clinical trial at the NIH.[31]

See also

References

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  31. ↑ NCT05003895

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Further reading

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External links

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