Glypican 2

Last updated
GPC2
Identifiers
Aliases GPC2 , Glypican 2
External IDs OMIM: 618446 MGI: 1919201 HomoloGene: 17657 GeneCards: GPC2
Orthologs
SpeciesHumanMouse
Entrez

221914

71951

Ensembl

ENSG00000213420

ENSMUSG00000029510

UniProt

Q8N158

Q8BKV1

RefSeq (mRNA)

NM_152742

NM_172412

RefSeq (protein)

NP_689955

NP_766000

Location (UCSC) Chr 7: 100.17 – 100.18 Mb Chr 5: 138.27 – 138.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glypican 2 (GPC2), also known cerebroglycan, is a protein which in humans is encoded by the GPC2 gene. [5] [6] The GPC2 gene is at locus 7q22.1 and encodes for a 579 amino acid protein. [7] 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. [8] 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. [8]

Contents

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. [9] Cerebroglycan has especially high affinity for laminin-1. [10]

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. [11] [12] GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival. [11] [13] GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. [11] Chimeric antigen receptor (CAR) T cells and Immunotoxins (antibody-cytotoxin fusion proteins) targeting GPC2 inhibit neuroblastoma growth in mouse models. [11] The Ho lab at the National Cancer Institute generated a mouse monoclonal antibody called CT3 targeting human GPC2. [8] The CT3 antibody has been shown to recognize a tumor-associated isoform (isoform 201) of GPC2 with high affinity. [8] Immunohistochemistry using CT3 shows that the antibody has high binding signals on neuroblastoma, medulloblastoma, and retinoblastoma. [8] CT3 does not bind human normal tissues except the testis. [8] CT3-derived CAR T cells regress neuroblastoma in mice. [8] [14] 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. [12] [15]

See also

Related Research Articles

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

<span class="mw-page-title-main">Neural cell adhesion molecule</span> Mammalian protein found in Homo sapiens

Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.

<span class="mw-page-title-main">Single-domain antibody</span> Antibody fragment

A single-domain antibody (sdAb), also known as a Nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies are much smaller than common antibodies which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments and single-chain variable fragments.

<span class="mw-page-title-main">Versican</span> Protein-coding gene in the species Homo sapiens

Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Syndecan 1</span> Protein which in humans is encoded by the SDC1 gene

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

<span class="mw-page-title-main">Syndecan</span>

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

<span class="mw-page-title-main">Glypican</span>

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 glypicans have been identified, and these are referred to as dally and dally-like. One glypican has been identified in C. elegans. Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling.

<span class="mw-page-title-main">Heparin-binding EGF-like growth factor</span> Protein-coding gene in the species Homo sapiens

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

<span class="mw-page-title-main">Heparanase</span> Mammalian protein found in Homo sapiens

Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.

<span class="mw-page-title-main">Glypican 3</span> Protein-coding gene in the species Homo sapiens

Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene 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).

<span class="mw-page-title-main">Glypican 1</span> Protein-coding gene in the species Homo sapiens

Glypican-1 (GPC1) is a protein that in humans is encoded by the GPC1 gene. GPC1 is encoded by human GPC1 gene located at 2q37.3. GPC1 contains 558 amino acids with three predicted heparan sulfate chains.

<span class="mw-page-title-main">CD276</span> Protein-coding gene in the species Homo sapiens

Cluster of Differentiation 276 (CD276) or B7 Homolog 3 (B7-H3) is a human protein encoded by the CD276 gene.

<span class="mw-page-title-main">Glypican 4</span> Protein-coding gene in the species Homo sapiens

Glypican-4 is a protein that in humans is encoded by the GPC4 gene.

<span class="mw-page-title-main">SULF1</span> Protein-coding gene in the species Homo sapiens

Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.

<span class="mw-page-title-main">Glypican 5</span> Protein-coding gene in the species Homo sapiens

Glypican-5 is a protein that in humans is encoded by the GPC5 gene.

<span class="mw-page-title-main">HS3ST2</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate glucosamine 3-O-sulfotransferase 2 is an enzyme that in humans is encoded by the HS3ST2 gene.

<span class="mw-page-title-main">Glypican 6</span> Protein-coding gene in the species Homo sapiens

Glypican-6 is a protein that in humans is encoded by the GPC6 gene.

<span class="mw-page-title-main">HS6ST2</span> Protein-coding gene in the species Homo sapiens

Heparan sulfate 6-O-sulfotransferase 2 is a protein that in humans is encoded by the HS6ST2 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000213420 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029510 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Stipp CS, Litwack ED, Lander AD (January 1994). "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. doi:10.1083/jcb.124.1.149. PMC   2119891 . PMID   8294498.
  6. ↑ "Entrez Gene: GPC2 glypican 2".
  7. ↑ Li N, Spetz MR, Li D, Ho M (July 2021). "Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3". Pharmacology & Therapeutics. 223: 107892. doi:10.1016/j.pharmthera.2021.107892. PMC   8202769 . PMID   33992682.
  8. 1 2 3 4 5 6 7 Li N, Torres MB, Spetz MR, Wang R, Peng L, Tian M, et al. (June 2021). "CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice". Cell Reports. Medicine. 2 (6): 100297. doi:10.1016/j.xcrm.2021.100297. PMC   8233664 . PMID   34195677.
  9. ↑ Ivins JK, Litwack ED, Kumbasar A, Stipp CS, Lander AD (April 1997). "Cerebroglycan, a developmentally regulated cell-surface heparan sulfate proteoglycan, is expressed on developing axons and growth cones". Developmental Biology. 184 (2): 320–332. doi: 10.1006/dbio.1997.8532 . PMID   9133438. S2CID   23283933.
  10. ↑ Herndon ME, Stipp CS, Lander AD (February 1999). "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. doi: 10.1093/glycob/9.2.143 . PMID   9949192.
  11. 1 2 3 4 Li N, Fu H, Hewitt SM, Dimitrov DS, Ho M (August 2017). "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. Bibcode:2017PNAS..114E6623L. doi: 10.1073/pnas.1706055114 . PMC   5559039 . PMID   28739923.
  12. 1 2 Bosse KR, Raman P, Zhu Z, Lane M, Martinez D, Heitzeneder S, et al. (September 2017). "Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma". Cancer Cell. 32 (3): 295–309.e12. doi:10.1016/j.ccell.2017.08.003. PMC   5600520 . PMID   28898695.
  13. ↑ Li N, Spetz MR, Ho M (December 2020). "The Role of Glypicans in Cancer Progression and Therapy". The Journal of Histochemistry and Cytochemistry. 68 (12): 841–862. doi:10.1369/0022155420933709. PMC   7711243 . PMID   32623934.
  14. ↑ Sun M, Cao Y, Okada R, Reyes-González JM, Stack HG, Qin H, et al. (January 2023). "Preclinical optimization of a GPC2-targeting CAR T-cell therapy for neuroblastoma". Journal for Immunotherapy of Cancer. 11 (1): e005881. doi:10.1136/jitc-2022-005881. PMC   9835961 . PMID   36631162.
  15. ↑ Raman S, Buongervino SN, Lane MV, Zhelev DV, Zhu Z, Cui H, et al. (July 2021). "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. doi:10.1016/j.xcrm.2021.100344. PMC   8324494 . PMID   34337560.
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