Glypican

Last updated
Glypican
4acr.png
C-terminally truncated human glypican-1. PDB 4acr
Identifiers
SymbolGlypican
Pfam PF01153
InterPro IPR001863
PROSITE PDOC00927
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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. [1] [2] In Drosophila two glypicans have been identified, and these are referred to as dally (division abnormally delayed) and dally-like. One glypican has been identified in C. elegans. [3] Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt [4] [5] [6] and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling. [2]

Contents

Structure

While six glypicans have been identified in mammals, several characteristics remain consistent between these different proteins. First, the core protein of all glypicans is similar in size, approximately ranging between 60 and 70 kDa. [7] Additionally, in terms of amino acid sequence, the location of fourteen cysteine residues is conserved; however, researchers describe glypicans as having moderate similarity in amino acid sequence overall. [3] Nevertheless, it is thought that the fourteen conserved cysteine residues play a vital role in determining three-dimensional shape, thus suggesting the existence of a highly similar three-dimensional structure. [7] Overall, GPC3 and GPC5 have very similar primary structures with 43% sequence similarity. On the other hand, GPC1, GPC2, GPC4, and GPC6 have between 35% and 63% sequence similarity. Thus, GPC3 and GPC5 are often referred to as one subfamily of glypicans, with GPC1, GPC2, GPC4, and GPC6 constituting the other group. [3] Between the subfamilies of glypicans, there is about 25% sequence similarity. [2] Furthermore, the amino acid sequence and structure of each glypican is well-conserved between species; all vertebrate glypicans are more than 90% similar regardless of the species. [3]

For all members of the glypican family, the C-terminus of the protein is attached to the cell membrane covalently via a glycosylphosphatidylinositol (GPI) anchor. To allow for the addition of the GPI anchor, glypicans have a hydrophobic domain at the C-terminus of the protein. Within 50 amino acids of this GPI anchor, the heparan sulfate chains attach to the protein core. Therefore, unlike syndecans the heparan sulfate glycosaminoglycan chains attached to glypicans are located rather close to the cell-membrane. [7] The glypicans found in vertebrates, Drosophila, and C. elegans all have an N-terminal signal sequence. [3]

Function

Glypicans are critically involved in developmental morphogenesis, and have been implicated as regulators in several cell signaling pathways. [3] These include the Wnt and Hedgehog signaling pathways, as well as signaling of fibroblast growth factors and bone morphogenic proteins. The regulating processes performed by glypicans can either stimulate or inhibit specific cellular processes. [2] The mechanisms by which glypicans regulate cellular pathways are not entirely clear. One commonly proposed mechanism suggests that glypicans behave as co-receptors which bind both the ligand and the receptor. Wnt recognizes a heparan sulfate structure on GPC3, which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S enhances the binding of Wnt to the heparan sulfate glypican. [5] A cysteine-rich domain at the N-lobe of GPC3 has been identified to form a Wnt-binding hydrophobic groove including phenylalanine-41 that interacts with Wnt. [6] Glypicans are expressed in various different amounts depending on the tissue, and they also are expressed to different degrees during the different stages of development. [8] Drosophila Dally mutants have irregular wing, antenna, genitalia, and brain development. [2]

Location

GPC5 and GPC6 are next to one another on chromosome 13q32 (in humans). GPC3 and GPC4 are also found next to one another, and are located on the human chromosome Xq26. [3] Some suggest that this implies that these glypicans arose because of a gene duplication event. [8] The gene for GPC1 is found on chromosome 2q36. Nearby genes include ZIC2, ZIC3, COL4A1/2, and COL4A3/4. [3]

Simpson-Golabi-Behmel Syndrome

Since 1996, it has been known that patients with Simpson–Golabi–Behmel syndrome (SGBS) have mutations in GPC3. Because this is an X-linked syndrome, it appears to affect males more significantly than females. While the phenotype associated with this condition can vary from mild to lethal, common symptoms include macroglossia, cleft palate, syndactyly, polydactyly, cystic and dysplastic kidneys, congenital heart defects, and a distinct facial appearance. Additional symptoms/characteristics have also been noted. Overall, these symptoms/characteristics are distinguished by prenatal and post-natal overgrowth. Typically, patients identified with SGBS have point mutations or microdeletions in the gene encoding GPC3, and the mutations can occur in multiple different locations of the gene. No correlation has been noticed between the location of the GPC3 mutation and the phenotypic manifestation of this disease. therefore, it is inferred that SGBS results due to a nonfunctional GPC3 protein. Researchers currently speculate that GPC3 is a negative regulator of cell proliferation, and this would explain why patients with SGBS experience overgrowth. [2]

Implications in cancer

Abnormal expression of glypicans has been noted in multiple types of cancer, including human hepatocellular carcinoma, ovarian cancer, mesothelioma, pancreatic cancer, glioma, breast cancer and recently GPC2 in neuroblastoma. [9] Most research involving the relationship between glypicans and cancer has focused on GPC1 [10] [11] and GPC3. [1]

A correlation between GPC3 expression levels and various types of cancer. [1] To summarize these findings, it can be generally said that tissues which normally express GPC3 exhibit down-regulation of GPC3 expression during tumor progression. Similarly, the corresponding cancers of tissues which normally do not exhibit GPC3 expression often express GPC3. Furthermore, oftentimes GPC3 expression occurs during embryonic development in these tissues, and is subsequently re-expressed during tumor progression. [8] GPC3 expression can be detected in normal ovarian cells; however, several ovarian cancer cell lines do not express GPC3. [12] [13] On the other hand, GPC3 expression is undetectable in healthy adult liver cells, while GPC3 expression occurs in the majority of human hepatocellular carcinomas. [1] A similar correlation has been found in colorectal tumors. GPC3 is an oncofetal protein in both liver and intestine, as GPC3 is typically only expressed during embryonic development but also found in cancerous tumors. [8]

GPC3 mutations do not occur in the coding sequence of this protein. Ovarian cancer cell lines do not express GPC3 due to hypermethylation of the GPC3 promoter. After removing these methyl groups, the authors restored expression of GPC3. [12] Mesothelioma cell lines contain a GPC3 promoter which is incorrectly methylated. [13] Re-establishing expression of GPC3 prevented colony-forming by cancerous cells. [12] [13]

GPC1 implications in cancer

In addition to GPC3, GPC1 has also been implicated in tumor progression, especially in pancreatic cancer, glioma, and breast cancer. [2] GPC1 expression is severely high in pancreatic ductal adenocarcinoma cells, and results indicate that GPC1 expression is linked to cancer progression, including tumor growth, angiogenesis and metastasis. In addition to overexpression of GPC1 on the plasma membrane of pancreatic ductal adenocarcinoma cells. GPC1 is released into the tumor microenvironment by these cells. Because glypicans play a role in growth factor binding, researchers have speculated that increased levels of GPC1 in the tumor microenvironment may function to store growth factors for cancerous cells. [2] By reducing the level of GCP1 in pancreatic adenocarcinoma cells, the growth of these cells was hindered. By reducing the levels of expressed GCP1 immunocompromised mice, slowed the growth tumors and reduced angiogenesis and metastases when compared with control GCP1 mice. GPC1 is highly expressed in human glioma blood vessel endothelial cells. Furthermore, increasing the level of GPC1 in mouse brain endothelial cells results in cell growth and stimulates mitosis in response to the angiogenic factor, FGF2. This suggests that GPC1 acts as a regulator for cell cycle progression. [14] GPC1 expression is well-above normal in human breast cancers, while expression of GPC1 is low in healthy breast tissue. Furthermore, expression was not significantly increased for any other glypican. GPC1 plays a role in heparin-binding and cell cycle progression in the breast tissue. [15]

GPC2 implications in cancer

Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression, suggesting GPC2 as a therapeutic target in neuroblastoma. [9] [16] Silencing of GPC2 by CRISPR/Cas9 results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. [9] Immunotoxins and chimeric antigen receptor (CAR) T cells targeting GPC2 have been developed for treating neuroblastoma and other GPC2-positive cancers. Immunotoxin treatment inhibits neuroblastoma growth in mice. CAR T cells targeting GPC2 can eliminate tumors in a metastatic neuroblastoma mouse model. [9] A GPC2-directed antibody-drug conjugate (ADC) is capable of killing GPC2-expressing neuroblastoma cells. [16]

Molecular biology

Glypicans can modify cell signaling pathways and contribute to cellular proliferation and tissue growth. In Drosophila, the glypican dally assists diffusion of the BMP-family growth-promoting morphogen Decapentaplegic in the developing wing, while the developing haltere lacks dally and remains small. [17] Extracellular localization of the other glypican in Drosophila, dally-like, is also required for the proper level of Hedgehog signaling in the developing wing. [18]

Clinical

In humans, glypican-1 is overexpressed in breast [15] and brain cancers (gliomas), [19] while glypican-3 is overexpressed in liver cancers. [20] [1] Glypican-2 is overexpressed in neuroblastoma. [9]

Mutations in this gene have also been associated with biliary atresia. [21]

Related Research Articles

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Simpson–Golabi–Behmel syndrome</span> Congenital disorder

Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with sgbs which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.

<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.

Zbtb7, whose protein product is also known as Pokemon, is a gene that functions as a regulator of cellular growth and a proto oncogene.

<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">CYR61</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

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

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

<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">WNT1-inducible-signaling pathway protein 1</span> Protein-coding gene in the species Homo sapiens

WNT1-inducible-signaling pathway protein 1 (WISP-1), also known as CCN4, is a matricellular protein that in humans is encoded by the WISP1 gene.

<span class="mw-page-title-main">EMP3</span> Protein-coding gene in the species Homo sapiens

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.

<span class="mw-page-title-main">FAT1</span> Protein-coding gene in the species Homo sapiens

Protocadherin FAT1 is a protein that in humans is encoded by the FAT1 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 2</span> Protein-coding gene in the species Homo sapiens

Glypican 2 (GPC2), 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.

<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">WNT7B</span> Protein-coding gene in the species Homo sapiens

Wnt7b is a signaling protein that plays a crucial role for many developmental processes including placental, lung, eye, dendrite, and bone formation along with kidney development. The primary role of Wnt7b is to establish the cortico-medullary axis of epithelial organization.

hPG80 refers to the extracellular and oncogenic version of progastrin. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention 'progastrin', without necessarily explicitly specifying whether it is intracellular or extracellular in the tumor pathological setting.

References

  1. 1 2 3 4 5 Ho M, Kim H (February 2011). "Glypican-3: a new target for cancer immunotherapy". European Journal of Cancer. 47 (3): 333–8. doi:10.1016/j.ejca.2010.10.024. PMC   3031711 . PMID   21112773.
  2. 1 2 3 4 5 6 7 8 Filmus J, Capurro M, Rast J (2008). "Glypicans". Genome Biology. 9 (5): 224. doi: 10.1186/gb-2008-9-5-224 . PMC   2441458 . PMID   18505598.
  3. 1 2 3 4 5 6 7 8 De Cat B, David G (April 2001). "Developmental roles of the glypicans". Seminars in Cell & Developmental Biology. 12 (2): 117–25. doi:10.1006/scdb.2000.0240. PMID   11292377.
  4. ↑ Gao, Wei; Ho, Mitchell (2011). "The role of glypican-3 in regulating Wnt in hepatocellular carcinomas". Cancer Reports. 1 (1): 14–19. PMC   3343874 . PMID   22563565.
  5. 1 2 Gao, Wei; Xu, Yongmei; Liu, Jian; Ho, Mitchell (May 17, 2016). "Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate". Scientific Reports. 6: 26245. Bibcode:2016NatSR...626245G. doi:10.1038/srep26245. ISSN   2045-2322. PMC   4869111 . PMID   27185050.
  6. 1 2 Li, Na; Wei, Liwen; Liu, Xiaoyu; Bai, Hongjun; Ye, Yvonne; Li, Dan; Li, Nan; Baxa, Ulrich; Wang, Qun; Lv, Ling; Chen, Yun (October 2019). "A Frizzled-Like Cysteine-Rich Domain in Glypican-3 Mediates Wnt Binding and Regulates Hepatocellular Carcinoma Tumor Growth in Mice". Hepatology. 70 (4): 1231–1245. doi:10.1002/hep.30646. ISSN   1527-3350. PMC   6783318 . PMID   30963603.
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  8. 1 2 3 4 Filmus J (March 2001). "Glypicans in growth control and cancer". Glycobiology. 11 (3): 19R–23R. doi: 10.1093/glycob/11.3.19r . PMID   11320054.
  9. 1 2 3 4 5 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.
  10. ↑ Pan, Jiajia; Ho, Mitchell (2021-11-01). "Role of glypican-1 in regulating multiple cellular signaling pathways". American Journal of Physiology. Cell Physiology. 321 (5): C846–C858. doi:10.1152/ajpcell.00290.2021. ISSN   1522-1563. PMC   8616591 . PMID   34550795.
  11. ↑ Pan, Jiajia; Li, Nan; Renn, Alex; Zhu, Hu; Chen, Lu; Shen, Min; Hall, Matthew D.; Qian, Min; Pastan, Ira; Ho, Mitchell (2022-06-01). "GPC1-Targeted Immunotoxins Inhibit Pancreatic Tumor Growth in Mice via Depletion of Short-lived GPC1 and Downregulation of Wnt Signaling". Molecular Cancer Therapeutics. 21 (6): 960–973. doi:10.1158/1535-7163.MCT-21-0778. ISSN   1538-8514. PMC   9167738 . PMID   35312769.
  12. 1 2 3 Lin H, Huber R, Schlessinger D, Morin PJ (February 1999). "Frequent silencing of the GPC3 gene in ovarian cancer cell lines". Cancer Research. 59 (4): 807–10. PMID   10029067.
  13. 1 2 3 Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC, Jhanwar SC, Mossman BT, Filmus J, Testa JR (January 2000). "Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma". Oncogene. 19 (3): 410–6. doi: 10.1038/sj.onc.1203322 . PMID   10656689.
  14. ↑ Qiao D, Yang X, Meyer K, Friedl A (July 2008). "Glypican-1 regulates anaphase promoting complex/cyclosome substrates and cell cycle progression in endothelial cells". Molecular Biology of the Cell. 19 (7): 2789–801. doi:10.1091/mbc.E07-10-1025. PMC   2441674 . PMID   18417614.
  15. 1 2 Matsuda K, Maruyama H, Guo F, Kleeff J, Itakura J, Matsumoto Y, Lander AD, Korc M (July 2001). "Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells". Cancer Research. 61 (14): 5562–9. PMID   11454708.
  16. 1 2 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 (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.
  17. ↑ Crickmore MA, Mann RS (January 2007). "Hox control of morphogen mobility and organ development through regulation of glypican expression". Development. 134 (2): 327–34. doi: 10.1242/dev.02737 . PMID   17166918.
  18. ↑ Gallet A, Staccini-Lavenant L, Thérond PP (May 2008). "Cellular trafficking of the glypican Dally-like is required for full-strength Hedgehog signaling and wingless transcytosis". Developmental Cell. 14 (5): 712–25. doi: 10.1016/j.devcel.2008.03.001 . PMID   18477454.
  19. ↑ Su G, Meyer K, Nandini CD, Qiao D, Salamat S, Friedl A (June 2006). "Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells". The American Journal of Pathology. 168 (6): 2014–26. doi:10.2353/ajpath.2006.050800. PMC   1606624 . PMID   16723715.
  20. ↑ Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Poon RT (April 2008). "Biology of hepatocellular carcinoma". Annals of Surgical Oncology. 15 (4): 962–71. doi:10.1245/s10434-007-9730-z. PMID   18236113. S2CID   20684585.
  21. ↑ Cui S, Leyva-Vega M, Tsai EA, EauClaire SF, Glessner JT, Hakonarson H, Devoto M, Haber BA, Spinner NB, Matthews RP (May 2013). "Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene". Gastroenterology. 144 (5): 1107–1115.e3. doi:10.1053/j.gastro.2013.01.022. PMC   3736559 . PMID   23336978.
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