GPC5 (glypican 5)

2010-11-01   Khin Thway , Joanna Selfe , Janet Shipley 

Molecular Cytogenetics, Section of Molecular Carcinogenesis, the Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom

Identity

HGNC
LOCATION
13q31.3
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Note

The gene spans 1.47 Mb of DNA, comprising 8 exons.

Transcription

2.904 kb mRNA. 1718 bp open reading frame.

Proteins

Description

572 amino acids; 64 kDa protein (core protein). GPC5 is a heparan sulfate proteoglycan (HSPG), that is bound to the cell surface by a glycosyl-phosphatidylinositol (GPI) anchor.

Expression

GPC5 is expressed mainly in fetal tissues, including brain, lung and liver. In the adult, expression is primarily in brain tissue.

Localisation

Attached to the cell membrane by a GPI anchor.
Atlas Image
Schematic of glypican protein structure at the cell surface. The protein is held in the plasma membrane by a GPI anchor at the carboxyl terminus. Numerous glycosoaminoglycan (GAG) attachment sites close to the membrane surface allow heparin and chondroitin sulphate chains to be attached to the core protein (shown in green). The amino terminal end of the protein is a globular structure held together by a conserved set of cysteine residues forming disulphide bridges. (Picture reproduced from Filmus and Selleck, 2001).

Function

The precise functions of GPC5 have yet to be fully established. HSPGs are common constituents of cell surfaces and the extracellular matrix (ECM), with essential functions in cell growth and development (Burgess and Macaig, 1989; Andres et al., 1992). Glypicans appear to be expressed predominantly during development, with expression levels changing in a stage- and tissue-specific manner, suggesting their involvement in morphogenesis (Sing and Filmus, 2002). As they can bind numerous ligands and be associated with a variety of receptors, they act as co-receptors for a number of heparin-binding growth factors, modulating their activity. The heparan sulfate modifications of glypicans can mediate interactions with growth factors or ECM proteins, but ligands and ECM proteins can also bind through motifs in the core proteins (Mythreye and Blobe, 2009). Glypicans can be secreted from the cell surface, such soluble forms can also bind growth factors. Evidence to date suggests that glypicans can regulate Wnt, hedgehog, fibroblast growth factor and bone morphogenetic protein pathways. The effect on these pathways may be stimulatory or inhibitory depending on cellular context (Gallet et al., 2008; Capurro et al., 2008; Kreuger et al., 2004; Yan and Lin, 2007; Grisaru et al., 2001; Yan et al., 2010).
GPC5 expression has been shown in the developing central nervous system, limbs and kidneys of mice, and its expression in mammalian fetal tissues suggests roles in growth and differentiation during development (Veugelers et al., 1997; Saunders et al., 1997; Luxardi et al., 2007). Its almost exclusive expression in adult brain tissue suggests a possible role in controlling neurotropic factors and maintaining neural function.

Homology

GPC5 is a member of the glypican family of HSPGs, of which six members (GPC1, GPC2, GPC3, GPC4, GPC5, GPC6) have been identified in mammals. GPC3 is the most homologous member to GPC5 in humans. There is approximately 20-60% sequence homology between family members, including conservation of a pattern of 14 cysteine residues. Homolog glypican-like genes are also present in Drosophila (dally and dally-like).

Implicated in

Entity name
Tumourigenesis
Note
Amplification of 13q31-32 has been shown in poor prognosis liposarcomas, breast cancers and neurologic tumours (Reardon et al., 2000; Ojopi et al., 2001; Ullmann et al., 2001; Schmidt et al., 2005). Amplification of 13q31-32 has also been shown in approximately 20% of alveolar rhabdomyosarcoma, as well as gain of GPC5 copies in both alveolar and embryonal rhabdomyosarcoma (Gordon et al., 2000). GPC5 is overexpressed in the majority of rhabdomyosarcomas compared with normal skeletal muscle and has been shown to modulate responses to FGF2 in rhabdomyosarcoma cells (Williamson et al., 2007). GPC5 may also potentiate hedgehog signalling in these cells as it can bind to both Hedgehog and the Patched receptor (Li et al., 2010a). A recent genome wide association study has linked polymorphisms in GPC5 to risk of lung cancer in never-smokers (Li et al., 2010b). The high-risk allele was coincident with lower expression of GPC5, suggesting that the role of GPC5 is likely to be tumour type-specific in an analogous manner to GPC3, the closest family member to GPC5.
Entity name
Developmental disorders
Note
Studies on the role of GPC5 in disease are still relatively limited. In humans, deletions of the 13q31-32 region are associated with the 13q deletion syndrome, a developmental disorder with a wide phenotypic spectrum including mental and growth retardation, congenital defects and craniofacial dysmorphy, and GPC5 is suggested as a candidate gene for digital malformations in this syndrome (Quelin et al., 2009). Correspondingly, GPC5 is also a candidate gene for postaxial polydactyly type A2, which is associated with duplication of 13q31-32 (van der Zwaag et al., 2010).
Entity name
Multiple sclerosis
Note
Several genome wide association studies have identified GPC5 as having a potential role in Multiple Sclerosis (MS) (Baranzini et al., 2009; Lorentzen et al., 2010). Several different GPC5 polymorphisms were also highlighted in an independent study designed to determine which genes are associated with efficacy of interferon beta therapy in MS (Byun et al., 2008), this finding has subsequently been confirmed in a separate study (Cenit et al., 2009). HSPGs are found in dense networks in active MS plaques, where they may sequester pro-inflammatory cytokines.

Bibliography

Pubmed IDLast YearTitleAuthors
15561061992Binding of two growth factor families to separate domains of the proteoglycan betaglycan.Andres JL et al
190107932009Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.Baranzini SE et al
25498571989The heparin-binding (fibroblast) growth factor family of proteins.Burgess WH et al
181951342008Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis.Byun E et al
184774532008Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding.Capurro MI et al
195563172009Glypican 5 is an interferon-beta response gene: a replication study.Cénit MD et al
115187202001Glypicans: proteoglycans with a surprise.Filmus J et al
184774542008Cellular trafficking of the glypican Dally-like is required for full-strength Hedgehog signaling and wingless transcytosis.Gallet A et al
108250072000A novel and consistent amplicon at 13q31 associated with alveolar rhabdomyosarcoma.Gordon AT et al
111809502001Glypican-3 modulates BMP- and FGF-mediated effects during renal branching morphogenesis.Grisaru S et al
154698392004Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity.Kreuger J et al
203047032010Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.Li Y et al
206920502010Association to the Glypican-5 gene in multiple sclerosis.Lorentzen AR et al
171076642007Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain.Luxardi G et al
194279002009Proteoglycan signaling co-receptors: roles in cell adhesion, migration and invasion.Mythreye K et al
111071722001Comparative genomic hybridization detects novel amplifications in fibroadenomas of the breast.Ojopi EP et al
190224132009Twelve new patients with 13q deletion syndrome: genotype-phenotype analyses in progress.Quélin C et al
109407692000Multiple genomic alterations including N-myc amplification in a primary large cell medulloblastoma.Reardon DA et al
93313331997Expression of the cell surface proteoglycan glypican-5 is developmentally regulated in kidney, limb, and brain.Saunders S et al
155401192005Gains of 13q are correlated with a poor prognosis in liposarcoma.Schmidt H et al
124174062002The role of glypicans in mammalian development.Song HH et al
116799392001Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: unexpected divergence from small-cell carcinoma of the lung.Ullmann R et al
90709151997Characterization of glypican-5 and chromosomal localization of human GPC5, a new member of the glypican gene family.Veugelers M et al
172106832007Role for amplification and expression of glypican-5 in rhabdomyosarcoma.Williamson D et al
179591662007Drosophila glypican Dally-like acts in FGF-receiving cells to modulate FGF signaling during tracheal morphogenesis.Yan D et al
205015922010The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development.Yan D et al
199419832010An interstitial duplication of chromosome 13q31.3q32.1 further delineates the critical region for postaxial polydactyly type A2.van der Zwaag PA et al

Other Information

Locus ID:

NCBI: 2262
MIM: 602446
HGNC: 4453
Ensembl: ENSG00000179399

Variants:

dbSNP: 2262
ClinVar: 2262
TCGA: ENSG00000179399
COSMIC: GPC5

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000179399ENST00000377067P78333
ENSG00000179399ENST00000618283A0A087WX13
ENSG00000179399ENST00000618596A0A087WX91

Expression (GTEx)

0
5
10
15

Pathways

PathwaySourceExternal ID
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Diseases associated with glycosaminoglycan metabolismREACTOMER-HSA-3560782
Defective B4GALT7 causes EDS, progeroid typeREACTOMER-HSA-3560783
Defective B3GAT3 causes JDSSDHDREACTOMER-HSA-3560801
Defective EXT1 causes exostoses 1, TRPS2 and CHDSREACTOMER-HSA-3656253
Defective EXT2 causes exostoses 2REACTOMER-HSA-3656237
Signal TransductionREACTOMER-HSA-162582
Visual phototransductionREACTOMER-HSA-2187338
Retinoid metabolism and transportREACTOMER-HSA-975634
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog ligand biogenesisREACTOMER-HSA-5358346
Release of Hh-Np from the secreting cellREACTOMER-HSA-5362798
MetabolismREACTOMER-HSA-1430728
Metabolism of carbohydratesREACTOMER-HSA-71387
Glycosaminoglycan metabolismREACTOMER-HSA-1630316
Heparan sulfate/heparin (HS-GAG) metabolismREACTOMER-HSA-1638091
A tetrasaccharide linker sequence is required for GAG synthesisREACTOMER-HSA-1971475
HS-GAG biosynthesisREACTOMER-HSA-2022928
HS-GAG degradationREACTOMER-HSA-2024096
Chondroitin sulfate/dermatan sulfate metabolismREACTOMER-HSA-1793185
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Defective B3GALT6 causes EDSP2 and SEMDJL1REACTOMER-HSA-4420332
Metabolism of fat-soluble vitaminsREACTOMER-HSA-6806667

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
190107932009Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.155
190107932009Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.155
203047032010Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.83
203047032010Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.83
178461262007Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations.68
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
191747802009Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort.52
213393342011Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating Hedgehog signaling.40
198651022010Multiple sclerosis susceptibility alleles in African Americans.35
194229352009Genetic risk profiling and prediction of disease course in Crohn's disease patients.33

Citation

Khin Thway ; Joanna Selfe ; Janet Shipley

GPC5 (glypican 5)

Atlas Genet Cytogenet Oncol Haematol. 2010-11-01

Online version: http://atlasgeneticsoncology.org/gene/45705/gpc5