Glypican-3 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that, in humans, is encoded by the ''GPC3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
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.
Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).
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.
Six glypicans (GPC1-6) have been identified in mammals. Cell surface
heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
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
A glycosyl group is a univalent free radical or substituent structure obtained by removing the hemiacetal hydroxyl group from the cyclic form of a monosaccharide and, by extension, of a lower oligosaccharide.
Glycosyl also reacts with inorganic a ...
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
linkage. These proteins may play a role in the control of
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
and growth regulation.
GPC3 has been found to regulate Wnt/β-catenin and Yap signaling pathways.
GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.
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.
Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.
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.
GPC3 also modulates
Yap signaling.
It might interact with
FAT1
Protocadherin FAT1 is a protein that in humans is encoded by the ''FAT1'' gene.
Function
This gene is an ortholog of the ''Drosophila'' fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila d ...
on the cell surface.
Disease linkage
Deletion mutations in this gene are associated with
Simpson–Golabi–Behmel syndrome
Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, cardiac, and renal abnormalities.
The syndrome is inherited in an X-linked recessive fashion, where males express the phenoty ...
.
Diagnostic utility
Glypican 3
immunostaining
In biochemistry, immunostaining is any use of an antibody-based method to detect a specific protein in a sample. The term "immunostaining" was originally used to refer to the immunohistochemical staining of tissue sections, as first described by A ...
has utility for differentiating
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
(HCC)
and dysplastic changes in
cirrhotic liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
s; HCC stains with glypican 3, while liver with dysplastic changes and/or
cirrhotic changes does not. Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.
The YP7 murine antibody has been humanized and named as 'hYP7'.
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.
However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.
Therapeutic potential
To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33,
YP7,
HN3
and HS20
have been made and widely tested. The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 and other murine monoclonal antibodies that recognize the C-lobe of GPC3 by hybridoma technology.
These antibodies have been humanized (e.g. hYP7) via antibody engineering for clinical applications.
The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3
targeting the N-lobe of GPC3
and the human monoclonal antibody HS20
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,
the antibody-drug conjugates based on hYP7 and the T-cell engaging bispecific antibodies derived from YP7 and GC33, have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33, hYP7
and HN3
are being developed 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.
CAR (hYP7) T cells are being evaluated at a clinical trial
NCT05003895 at the NIH.
See also
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Glypican
Glypicans constitute one of the two major families of heparan sulfate proteoglycans, with the other major family being syndecans. Six glypicans have been identified in mammals, and are referred to as GPC1 through GPC6. In ''Drosophila'' two gly ...
References
Further reading
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External links
GeneReviews/NIH/NCBI/UW entry on Simpson-Golabi-Behmel Syndrome
Immunologic tests