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GPC3 (glypican 3)

Identity

Other namesGlypican-3 (GPC3)
MXR7
OCI-5
GTR2-2
HGNC (Hugo) GPC3
LocusID (NCBI) 2719
Location Xq26.2
Location_base_pair Starts at 132669776 and ends at 133119673 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The gene spans more than 500 kb of DNA consisting of 8 exons.
Transcription 2.2kb mRNA; 1740 bp open reading frame.

Protein

Description 580 amino acids; 65 kDa protein. GPC3 is a heparan sulfate proteoglycan (HSPG) that is attached to the cell surface via a glycosyl-phosphatidylinositol (GPI) anchor.
Expression GPC3 is highly expressed in embryonal tissues such as the developing intestine and the mesoderm-derived tissues, and its expression is downregulated in most adult tissue.
Localisation Attached to the membrane by a GPI anchor.
Function The biochemical function of GPC3 has yet to be established. HSPG may be involved in the suppression/modulation of growth in the predominantly mesodermal tissues and organs; may play a role in the modulation of IGF-II interactions with its receptor and thereby modulate its function; can have a potential role as a regulator of growth and tumor predisposition. Therefore it is likely that GPC3 is able not only to bind more than one growth factor, but also to functionally affect the signalling of different growth factors. A role for GPC3 in the regulation of insulin-like growth (IGF) factors has been proposed. IGF-II is a growth factor that can act as a survival factor in the early stages of tumourigenesis. The co-expression of GPC3 and IGF-II has been observed in embryonal tumors as well as in mouse foetal tissues; GPC3 expression is able to induce apoptosis in a cell-specific manner, but this effect could be reversed by the addition of IGF peptides; IGFs could be needed to prevent GPC3-induced apoptosis in any cell, allowing cellular responses to other factors to take place and be mediated, enhanced or inhibited by GPC3; GPC3 mutations lead to SGBS (see below), a syndrome that shares significant similarities with the Beckwith-Wiedemann syndrome that is an overgrowth syndrome that is thought to be associated with increased expression of IGF2.
Homology Belongs to the glypican family; six members, glypican-1 to 6, have been identified in mammalians; the protein core of glypicans are 20-50% identical; The glypican family is represented by at least two known members in Drosophila, dally and dally-like.

Mutations

Germinal Most known mutations are deletions involving different exons of GPC3; missense, nonsense as well as splicing site mutations.
Somatic The expression of GPC3 is altered in cancer cells. GPC3 is upregulated in hepatocellular carcinoma, in Wilm's tumor and in metastatics colorectal malignancie. With regard to tumours with neuronal phenotype, GPC3 was detected at variable levels in a neurofibrosarcoma and in most neuroblastomas, but was absent from medulloblastomas. These findings suggest that GPC3 expression is differentially regulated in the various cell lineages giving rise to pediatric tumours of the peripheral and central nervous systems. On the other hand, GPC3 is frequently silenced in mesotheliomas, in ovarian cancer cell lines and in breast cancer, often due to hypermethylation of the GPC3 promoter.

Implicated in

Entity Simpson-Golabi-Behmel Syndrome (SGBS)
Disease X-linked disease characterized by a wide variety of clinical manifestations, including pre- and post-natal overgrowth, tissue dysplasia, in particular of the kidneys, and cardiac anomalies; associated with a greater risk of developing embryonal cancers; caused by loss-of-function mutation in the GPC3 gene ; the abnormalities found in SGBS patients suggest that GPC3 might be involved in the regulation of growth and/or apoptosis during development.
  

To be noted

The ability of GPC3 to bind various growth factors or morphogens, including IGF-II, Fibroblast Growth Factor 2 as well as the tissue factor pathway inhibitor, is supported by evidence from other members of the glypican family and HSPGs in general. HSPGs of the cell surface are highly interactive macromolecules playing various roles in cell migration, proliferation, differentiation and adhesion, and participating in many developmental and pathological processes. HSPGs consist of two major families: syndecans and glypicans. Syndecans are attached to the cell membrane by a transmembrane domain while glypicans are attached through a GPI anchor. To date six members of the glypican family, glypican-1 to 6, have been identified in mammalians ; the glypican family is represented by at least two known members in Drosophila, dally and dally-like. Dally is now known to act as a co-receptor that controls signalling by morphogens and growth factors such as decapentaplegic (dpp) and wingless. Although GPC3 cannot as yet be thought of as the strict orthologue of dally, this information strengthens the notion that it may have growth factor binding and regulatory properties.

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

External links

Nomenclature
HGNC (Hugo)GPC3   4451
Cards
AtlasGPC3ID156
Entrez_Gene (NCBI)GPC3  2719  glypican 3
GeneCards (Weizmann)GPC3
Ensembl (Hinxton)ENSG00000147257 [Gene_View]  chrX:132669776-133119673 [Contig_View]  GPC3 [Vega]
ICGC DataPortalENSG00000147257
AceView (NCBI)GPC3
Genatlas (Paris)GPC3
WikiGenes2719
SOURCE (Princeton)NM_001164617 NM_001164618 NM_001164619 NM_004484
Genomic and cartography
GoldenPath (UCSC)GPC3  -  Xq26.2   chrX:132669776-133119673 -  Xq26   [Description]    (hg19-Feb_2009)
EnsemblGPC3 - Xq26 [CytoView]
Mapping of homologs : NCBIGPC3 [Mapview]
OMIM194070   300037   312870   
Gene and transcription
Genbank (Entrez)AK222761 AK222766 AK300168 AK310196 AK310689
RefSeq transcript (Entrez)NM_001164617 NM_001164618 NM_001164619 NM_004484
RefSeq genomic (Entrez)AC_000155 NC_000023 NC_018934 NG_009286 NT_011786 NW_001842400 NW_004929446
Consensus coding sequences : CCDS (NCBI)GPC3
Cluster EST : UnigeneHs.644108 [ NCBI ]
CGAP (NCI)Hs.644108
Alternative Splicing : Fast-db (Paris)GSHG0032344
Alternative Splicing GalleryENSG00000147257
Gene ExpressionGPC3 [ NCBI-GEO ]     GPC3 [ SEEK ]   GPC3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP51654 (Uniprot)
NextProtP51654  [Medical]
With graphics : InterProP51654
Splice isoforms : SwissVarP51654 (Swissvar)
Domaine pattern : Prosite (Expaxy)GLYPICAN (PS01207)   
Domains : Interpro (EBI)Glypican    Glypican-3    Glypican_CS   
Related proteins : CluSTrP51654
Domain families : Pfam (Sanger)Glypican (PF01153)   
Domain families : Pfam (NCBI)pfam01153   
DMDM Disease mutations2719
Blocks (Seattle)P51654
Human Protein AtlasENSG00000147257
Peptide AtlasP51654
HPRD02074
IPIIPI00019907   IPI00719135   IPI00944529   IPI00646987   
Protein Interaction databases
DIP (DOE-UCLA)P51654
IntAct (EBI)P51654
FunCoupENSG00000147257
BioGRIDGPC3
IntegromeDBGPC3
STRING (EMBL)GPC3
Ontologies - Pathways
QuickGOP51654
Ontology : AmiGOretinoid metabolic process  branching involved in ureteric bud morphogenesis  protein binding  proteinaceous extracellular matrix  extracellular space  Golgi lumen  plasma membrane  integral component of plasma membrane  carbohydrate metabolic process  glycosaminoglycan biosynthetic process  glycosaminoglycan catabolic process  phototransduction, visible light  anatomical structure morphogenesis  anterior/posterior axis specification  body morphogenesis  negative regulation of peptidase activity  glycosaminoglycan metabolic process  chondroitin sulfate metabolic process  bone mineralization  osteoclast differentiation  lung development  positive regulation of BMP signaling pathway  embryonic hindlimb morphogenesis  lysosomal lumen  heparan sulfate proteoglycan binding  small molecule metabolic process  positive regulation of protein catabolic process  positive regulation of endocytosis  negative regulation of smoothened signaling pathway  positive regulation of smoothened signaling pathway  negative regulation of growth  positive regulation of glucose import  anchored component of plasma membrane  negative regulation of epithelial cell proliferation  peptidyl-dipeptidase inhibitor activity  coronary vasculature development  extracellular vesicular exosome  mesenchymal cell proliferation involved in ureteric bud development  mesonephric duct morphogenesis  cell proliferation involved in metanephros development  negative regulation of canonical Wnt signaling pathway  positive regulation of Wnt signaling pathway, planar cell polarity pathway  
Ontology : EGO-EBIretinoid metabolic process  branching involved in ureteric bud morphogenesis  protein binding  proteinaceous extracellular matrix  extracellular space  Golgi lumen  plasma membrane  integral component of plasma membrane  carbohydrate metabolic process  glycosaminoglycan biosynthetic process  glycosaminoglycan catabolic process  phototransduction, visible light  anatomical structure morphogenesis  anterior/posterior axis specification  body morphogenesis  negative regulation of peptidase activity  glycosaminoglycan metabolic process  chondroitin sulfate metabolic process  bone mineralization  osteoclast differentiation  lung development  positive regulation of BMP signaling pathway  embryonic hindlimb morphogenesis  lysosomal lumen  heparan sulfate proteoglycan binding  small molecule metabolic process  positive regulation of protein catabolic process  positive regulation of endocytosis  negative regulation of smoothened signaling pathway  positive regulation of smoothened signaling pathway  negative regulation of growth  positive regulation of glucose import  anchored component of plasma membrane  negative regulation of epithelial cell proliferation  peptidyl-dipeptidase inhibitor activity  coronary vasculature development  extracellular vesicular exosome  mesenchymal cell proliferation involved in ureteric bud development  mesonephric duct morphogenesis  cell proliferation involved in metanephros development  negative regulation of canonical Wnt signaling pathway  positive regulation of Wnt signaling pathway, planar cell polarity pathway  
Pathways : KEGGProteoglycans in cancer   
REACTOMEP51654 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseGPC3
Wikipedia pathwaysGPC3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GPC3
SNP (GeneSNP Utah)GPC3
SNP : HGBaseGPC3
Genetic variants : HAPMAPGPC3
1000_GenomesGPC3 
ICGC programENSG00000147257 
Cancer Gene: CensusGPC3 
CONAN: Copy Number AnalysisGPC3 
Somatic Mutations in Cancer : COSMICGPC3 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)X:132669776-133119673
Mutations and Diseases : HGMDGPC3
OMIM194070    300037    312870   
MedgenGPC3
GENETestsGPC3
Disease Genetic AssociationGPC3
Huge Navigator GPC3 [HugePedia]  GPC3 [HugeCancerGEM]
Genomic VariantsGPC3  GPC3 [DGVbeta]
Exome VariantGPC3
dbVarGPC3
ClinVarGPC3
snp3D : Map Gene to Disease2719
General knowledge
Homologs : HomoloGeneGPC3
Homology/Alignments : Family Browser (UCSC)GPC3
Phylogenetic Trees/Animal Genes : TreeFamGPC3
Chemical/Protein Interactions : CTD2719
Chemical/Pharm GKB GenePA28832
Clinical trialGPC3
Cancer Resource (Charite)ENSG00000147257
Other databases
Probes
Litterature
PubMed121 Pubmed reference(s) in Entrez
CoreMineGPC3
GoPubMedGPC3
iHOPGPC3

Bibliography

Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine.
Filmus J, Church JG, Buick RN
Molecular and cellular biology. 1988 ; 8 (10) : 4243-4249.
PMID 3185547
 
Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21.
Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE
American journal of medical genetics. 1992 ; 43 (1-2) : 428-435.
PMID 1605222
 
The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila.
Nakato H, Futch TA, Selleck SB
Development (Cambridge, England). 1995 ; 121 (11) : 3687-3702.
PMID 8582281
 
Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.
Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D
Nature genetics. 1996 ; 12 (3) : 241-247.
PMID 8589713
 
Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution.
Hsu HC, Cheng W, Lai PL
Cancer research. 1997 ; 57 (22) : 5179-5184.
PMID 9371521
 
dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp.
Jackson SM, Nakato H, Sugiura M, Jannuzi A, Oakes R, Kaluza V, Golden C, Selleck SB
Development (Cambridge, England). 1997 ; 124 (20) : 4113-4120.
PMID 9374407
 
Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor.
Mast AE, Higuchi DA, Huang ZF, Warshawsky I, Schwartz AL, Broze GJ Jr
The Biochemical journal. 1997 ; 327 ( Pt 2) : 577-583.
PMID 9359432
 
OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2.
Song HH, Shi W, Filmus J
The Journal of biological chemistry. 1997 ; 272 (12) : 7574-7577.
PMID 9065409
 
Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies.
Lage H, Dietel M, Frˆschle G, Reymann A
International journal of clinical pharmacology and therapeutics. 1998 ; 36 (1) : 58-60.
PMID 9476151
 
Overgrowth syndromes and genomic imprinting: from mouse to man.
Li M, Squire JA, Weksberg R
Clinical genetics. 1998 ; 53 (3) : 165-170.
PMID 9630066
 
Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome.
Neri G, Gurrieri F, Zanni G, Lin A
American journal of medical genetics. 1998 ; 79 (4) : 279-283.
PMID 9781908
 
Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome.
Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A
Developmental dynamics : an official publication of the American Association of Anatomists. 1998 ; 213 (4) : 431-439.
PMID 9853964
 
Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling.
Lin X, Perrimon N
Nature. 1999 ; 400 (6741) : 281-284.
PMID 10421372
 
Frequent silencing of the GPC3 gene in ovarian cancer cell lines.
Lin H, Huber R, Schlessinger D, Morin PJ
Cancer research. 1999 ; 59 (4) : 807-810.
PMID 10029067
 
The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila.
Tsuda M, Kamimura K, Nakato H, Archer M, Staatz W, Fox B, Humphrey M, Olson S, Futch T, Kaluza V, Siegfried E, Stam L, Selleck SB
Nature. 1999 ; 400 (6741) : 276-280.
PMID 10421371
 
Dally-like protein, a new Drosophila glypican with expression overlapping with wingless.
Khare N, Baumgartner S
Mechanisms of development. 2000 ; 99 (1-2) : 199-202.
PMID 11091094
 
Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma.
Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC, Jhanwar SC, Mossman BT, Filmus J, Testa JR
Oncogene. 2000 ; 19 (3) : 410-416.
PMID 10656689
 
Expression of glypican 3 (GPC3) in embryonal tumors.
Saikali Z, Sinnett D
International journal of cancer. Journal international du cancer. 2000 ; 89 (5) : 418-422.
PMID 11008203
 
Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions.
Tumova S, Woods A, Couchman JR
The international journal of biochemistry & cell biology. 2000 ; 32 (3) : 269-288.
PMID 10716625
 
Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene.
Veugelers M, Cat BD, Muyldermans SY, Reekmans G, Delande N, Frints S, Legius E, Fryns JP, Schrander-Stumpel C, Weidle B, Magdalena N, David G
Human molecular genetics. 2000 ; 9 (9) : 1321-1328.
PMID 10814714
 
Glypicans in growth control and cancer.
Filmus J
Glycobiology. 2001 ; 11 (3) : 19R-23R.
PMID 11320054
 
Glypican-3 expression is silenced in human breast cancer.
Xiang YY, Ladeda V, Filmus J
Oncogene. 2001 ; 20 (50) : 7408-7412.
PMID 11704870
 
Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition.
DeBaun MR, Ess J, Saunders S
Molecular genetics and metabolism. 2001 ; 72 (4) : 279-286.
PMID 11286501
 
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Contributor(s)

Written05-2002Daniel Sinnett
Division of Hematology-oncology, Research Centre, Sainte-Justine Hospital, 3175 Côte Sainte-Catherine, Montreal, H3T 1C5, Québec, Canada

Citation

This paper should be referenced as such :
Sinnett, D
Glypican-3 (GPC3)
Atlas Genet Cytogenet Oncol Haematol. 2002;6(3):206-208.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/GPC3ID156.html

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