Glypican 2 Explained

Glypican 2 (GPC2), also known cerebroglycan, is a protein which in humans is encoded by the GPC2 gene.[1] [2] The GPC2 gene is at locus 7q22.1 and encodes for a 579 amino acid protein.[3] 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.[4] 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.[5] Cerebroglycan has especially high affinity for laminin-1.[6]

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.[7] [8] GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival.[9] GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. Chimeric antigen receptor (CAR) T cells and Immunotoxins (antibody-cytotoxin fusion proteins) 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 (isoform 201) 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.[10] The CT3 mAb is commercially available for Western blot, flow cytometry, immunohistochemistry, and immunofluorescence. A GPC2 specific antibody-drug conjugate (ADC) can inhibit neuroblastoma and small-cell lung cancer cell proliferation and tumor growth in mice.[11]

See also

Notes and References

  1. Stipp CS, Litwack ED, Lander AD . Cerebroglycan: an integral membrane heparan sulfate proteoglycan that is unique to the developing nervous system and expressed specifically during neuronal differentiation . The Journal of Cell Biology . 124 . 1–2 . 149–160 . January 1994 . 8294498 . 2119891 . 10.1083/jcb.124.1.149 .
  2. Web site: Entrez Gene: GPC2 glypican 2.
  3. Li N, Spetz MR, Li D, Ho M . Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3 . Pharmacology & Therapeutics . 223 . 107892 . July 2021 . 33992682 . 8202769 . 10.1016/j.pharmthera.2021.107892 .
  4. Li N, Torres MB, Spetz MR, Wang R, Peng L, Tian M, Dower CM, Nguyen R, Sun M, Tai CH, de Val N, Cachau R, Wu X, Hewitt SM, Kaplan RN, Khan J, St Croix B, Thiele CJ, Ho M . 6 . CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice . Cell Reports. Medicine . 2 . 6 . 100297 . June 2021 . 34195677 . 8233664 . 10.1016/j.xcrm.2021.100297 .
  5. Ivins JK, Litwack ED, Kumbasar A, Stipp CS, Lander AD . Cerebroglycan, a developmentally regulated cell-surface heparan sulfate proteoglycan, is expressed on developing axons and growth cones . Developmental Biology . 184 . 2 . 320–332 . April 1997 . 9133438 . 10.1006/dbio.1997.8532 . 23283933 . free .
  6. Herndon ME, Stipp CS, Lander AD . Interactions of neural glycosaminoglycans and proteoglycans with protein ligands: assessment of selectivity, heterogeneity and the participation of core proteins in binding . Glycobiology . 9 . 2 . 143–155 . February 1999 . 9949192 . 10.1093/glycob/9.2.143 . free .
  7. Li N, Fu H, Hewitt SM, Dimitrov DS, Ho M . Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma . Proceedings of the National Academy of Sciences of the United States of America . 114 . 32 . E6623–E6631 . August 2017 . 28739923 . 5559039 . 10.1073/pnas.1706055114 . free . 2017PNAS..114E6623L .
  8. Bosse KR, Raman P, Zhu Z, Lane M, Martinez D, Heitzeneder S, Rathi KS, Kendsersky NM, Randall M, Donovan L, Morrissy S, Sussman RT, Zhelev DV, Feng Y, Wang Y, Hwang J, Lopez G, Harenza JL, Wei JS, Pawel B, Bhatti T, Santi M, Ganguly A, Khan J, Marra MA, Taylor MD, Dimitrov DS, Mackall CL, Maris JM . 6 . Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma . Cancer Cell . 32 . 3 . 295–309.e12 . September 2017 . 28898695 . 5600520 . 10.1016/j.ccell.2017.08.003 .
  9. Li N, Spetz MR, Ho M . The Role of Glypicans in Cancer Progression and Therapy . The Journal of Histochemistry and Cytochemistry . 68 . 12 . 841–862 . December 2020 . 32623934 . 7711243 . 10.1369/0022155420933709 .
  10. Sun M, Cao Y, Okada R, Reyes-González JM, Stack HG, Qin H, Li N, Seibert C, Kelly MC, Ruppin E, Ho M, Thiele CJ, Nguyen R . 6 . Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma . Journal for Immunotherapy of Cancer . 11 . 1 . e005881 . January 2023 . 36631162 . 9835961 . 10.1136/jitc-2022-005881 .
  11. Raman S, Buongervino SN, Lane MV, Zhelev DV, Zhu Z, Cui H, Martinez B, Martinez D, Wang Y, Upton K, Patel K, Rathi KS, Navia CT, Harmon DB, Li Y, Pawel B, Dimitrov DS, Maris JM, Julien JP, Bosse KR . 6 . A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope . Cell Reports. Medicine . 2 . 7 . 100344 . July 2021 . 34337560 . 8324494 . 10.1016/j.xcrm.2021.100344 .

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