Top Qs
Timeline
Chat
Perspective
Glypican 3
Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Remove ads
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]
Remove ads
Structure and function
Summarize
Perspective
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]
Remove ads
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
Summarize
Perspective
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]
Remove ads
See also
References
Further reading
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.
Remove ads