Glypican 2
Glypican 2, also known cerebroglycan, is a protein which in humans is encoded by the GPC2 gene. The GPC2 gene is at locus 7q22.1 and encodes for a 579 amino acid protein. The C-terminus of GPC2 has the GPI attachment site, at G554, and the N-terminus encodes a signal peptide, from M1 to S24. Multiple GPC2 mRNA transcripts have been identified. GPC2-201 is the isoform overexpressed in pediatric cancers. Tumor-associated exon 3 of GPC2 shows the lowest expression in normal tissues compared with other exons.
Function
Cerebroglycan is a glycophosphatidylinositol-linked integral membrane heparan sulfate proteoglycan found in the
developing nervous system. Cerebroglycan participates in cell adhesion and is thought to regulate the growth and guidance of axons. Cerebroglycan has especially high affinity for laminin-1.
Implications in cancer
GPC2 has been identified as a therapeutic target in neuroblastoma in two independent studies published by Mitchell Ho's lab at the NCI and John Maris's lab at the University of Pennsylvania in 2017. GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. Chimeric antigen receptor T cells and Immunotoxins targeting GPC2 inhibit neuroblastoma growth in mouse models. The Ho lab at the National Cancer Institute generated a mouse monoclonal antibody called CT3 targeting human GPC2. The CT3 antibody has been shown to recognize a tumor-associated isoform of GPC2 with high affinity. Immunohistochemistry using CT3 shows that the antibody has high binding signals on neuroblastoma, medulloblastoma, and retinoblastoma. CT3 does not bind human normal tissues except the testis. CT3-derived CAR T cells regress neuroblastoma in mice. The CT3 mAb is commercially available for Western blot, flow cytometry, immunohistochemistry, and immunofluorescence. A GPC2 specific antibody-drug conjugate can inhibit neuroblastoma and small-cell lung cancer cell proliferation and tumor growth in mice.