GPC1 (glypican 1)

2013-11-01   Wael Awad , Derek T Logan , Katrin Mani 

Dept. of Biochemistry & Structural Biology, Lund University, Box 124, S-221 00 Lund, Sweden (WA,DTL); Glycobiology, Dept. of Experimental Medical Science, BMC A13, S-221 84 Lund, Sweden (KM)





The gene spans 32381 pb of DNA, comprising 9 exons.


1676 bp open reading frame.


Atlas Image
Crystal structure of the N-glycosylated human Gpc-1 core protein (PDB entry 4ACR). Cartoon diagram of Gpc-1 in which the body of the structure is coloured light blue, the N-terminal helix and loop in dark blue and the C-terminal helix in red. Important loops (L1:L3) and all of the α-helices (α1:α14) are labelled. The seven disulphide bonds common to all glypicans are indicated in yellow. The assignment of different lobes in the Gpc-1 structure (Svensson et al., 2011) is displayed on the bottom line.


The glypican-1 gene codes for a protein of 558 amino acids with a predicted molecular weight of 62 kDa. It is a cell surface, lipid-raft-associated heparan sulfate proteoglycan (HSPG), composed of a glycosylphosphatidylinositol (GPI)-anchored core protein substituted with a three chains of heparan sulfate near its C-terminus. It shares, along with all other glypicans, an N-terminal secretory signal, heparan sulfate attachment sites, 14 evolutionary conserved cysteine residues and hydrophobic domain near the C-terminus for the addition of the glycosylphosphatidylinositol (GPI) anchor. Also, the glypican-1 core protein contains two N-glycosylation sites at Asn79 & Asn116, which are found to be invariably occupied. The N-linked glycans at these sites affect Gpc-1 protein expression and heparan sulfate substitution. Nevertheless the protein is folded correctly even in the absence of N-linked glycans (Svensson et al., 2011). Recently, the structure of C-terminally truncated human N-glycosylated Gpc-1 core protein was determined at 2.55 Å resolution (Svensson et al., 2012; Awad et al., 2013), which revealed a highly extended, cylindrical (dimensions 120 x 30 x 30 Å), stable all-α-helical fold. Its structural similarity to the Dally-like protein from Drosophila (Kim et al., 2011) confirmed a conserved overall fold for the glypican family. The Gpc-1 structure consists of 14 α-helices (α1- α14) and three major loops (L1-L3). The extended helix α2 (83Å) traverses the whole protein, carrying two N-linked glycans close to its ends. The Gpc-1 structure revealed the complete arrangement of the 14 Cys residues conserved across the glypican family, in 7 disulfide bonds, 6 of them located near the molecule N terminus at a region termed "Cys-rich lobe". This lobe is followed by a region forms the heart of the structure called the "central lobe". This lobe is stabilized by evolutionary conserved hydrophobic centers. The last region of the Gpc-1 molecule is termed the "protease site lobe" because of the presence of a protease site in this part. No additional electron density was observed in the electron density maps from crystals of non-truncated glypican-1 containing the HS attachment region near the C-terminus, which suggests that this part is highly disordered. This extended long C terminus (50 residues) might thus give the core protein a freedom in its orientation when Gpc-1 is anchored to the cell membrane (Svensson et al., 2012).


GPC1 is expressed mainly in the central nervous system (CNS) and skeletal system during development but also in many other tissues in the adult.


GPC1 is a cell surface HSPG that can be internalized via a caveolin-1 associated pathway. GPC1 undergoes a recycling from cell surface to endosomes and back to the cell surface via Golgi. During recycling, the HS chains of GPC1 are degraded by heparanase and further on by a novel copper, nitric oxide and vitamin C-dependent deaminative cleavage. New HS chains are synthesized on the stubs remaining on the core protein (Cheng et al., 2002; Fransson and Mani, 2007).


Many of the functions of GPC1 are dependent on the HS side chains, which are capable of binding and/or activating and/or transporting a variety of growth factors (FGF2), cytokines, enzymes, viral proteins, and polyamines. It is known that both the core protein and the HS chains of GPC1 are important for brain function, as knock-out of GPC1 gene expression results in reduction of brain size by 30% (Jen et al., 2009) and errors in HS metabolism result in neurodegeneration and mental retardation accompanied by accumulation of amyloid β in human brain (Ohmi et al., 2011). A role for GPC1 in axonal guidance and regeneration via Slit has been proposed (Bloechlinger et al., 2004; Lau and Margolis, 2010). Several studies indicate involvement of Gpc1 in prion conversion and scrapie infection (Löfgren et al., 2008; Taylor et al., 2009; Hooper, 2011).


GPC1 belongs to the glypican family. To date, six different glypicans have been identified in vertebrates (GPC1, GPC2, GPC3, GPC4, GPC5, and GPC6), two in Drosophila melanogaster (Dally and Dally-like protein), two in C. elegans (Gpn-1 and Lon-2) and one in zebrafish (knypek). Based on sequence comparisons, vertebrate glypicans fall into two subfamilies: glypicans 1, 2, 4, 6 and glypicans 3 and 5, with approximately 25% amino acid identity between the groups.

Implicated in

Entity name
Various cancers
Many studies have shown that GPC1 is crucial for efficient cancer cell growth, metastasis, and angiogenesis of many human and mouse cancer cell types (Ding et al., 2005; Kayed et al., 2006; Aikawa et al., 2008; Whipple et al., 2012). GPC1 is up-regulated in human cancer cells such as glioma, pancreatic and breast cancers and supports and maintains the mitogenic effect of several HS-binding growth factors (Matsuda et al., 2001; Kayed et al., 2006; Su et al., 2006). Downregulation of GPC1 results in prolonged doubling times and decreased growth of cancer cells in vitro, as well as attenuated tumor growth, angiogenesis, and metastasis in vivo.
Entity name
Neurodegenerative diseases
A number of studies indicate involvement of GPC1 in the pathogenesis of several neurodegenerative diseases including Alzheimers disease (van Horssen et al., 2001; Watanabe et al., 2004; Cappai et al., 2005; OCallaghan et al., 2008; Timmer et al., 2009; Cheng et al., 2011), prion disease (Cheng et al., 2006; Löfgren et al., 2008; Taylor et al., 2009; Hooper, 2011), and Niemann-Pick type C1 disease (Mani et al., 2006). GPC1 has been localized to the amyloid plaques of Alzheimers disease. Both nitric oxide- and heparanase-induced degraded GPC1 HS have found to be associated with amyloid deposits, including the toxic amyloid β peptide aggregates in brain of human Alzheimers patients and transgenic Alzheimers mice (Sandwall et al., 2010; Cheng et al., 2011). Further, it has been shown that the HS oligosaccharides released from GPC1 by Cu/NO-vitamin C form conjugates with amyloid β peptides, thereby modulating and suppressing oligomerization of amyloid β and dissolving toxic amyloid β oligomers in hippocampal slices from Alzheimers mice (Cheng et al., 2011). Other studies have shown that amyloid β toxicity is attenuated in cells overexpressing heparanase, suggesting that HS oligosaccharides generated by cleavage with heparanase could also have a protective effect (Sandwall et al., 2010; Zhang et al., 2012).


Pubmed IDLast YearTitleAuthors
180643042008Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells.Aikawa T et al
243115932013Improvements in the order, isotropy and electron density of glypican-1 crystals by controlled dehydration.Awad W et al
150160712004Dynamic changes in glypican-1 expression in dorsal root ganglion neurons after peripheral and central axonal injury.Bloechlinger S et al
156774592005The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo.Cappai R et al
216424352011Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation.Cheng F et al
169231582006Copper-dependent co-internalization of the prion protein and glypican-1.Cheng F et al
122260792002Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes.Cheng F et al
162865102005Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells.Ding K et al
173440972007Novel aspects of vitamin C: how important is glypican-1 recycling?Fransson LA et al
206819522011Glypican-1 facilitates prion conversion in lipid rafts.Hooper NM et al
197324112009Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis.Jen YH et al
170166452006Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma.Kayed H et al
218280062011Structure of the protein core of the glypican Dally-like and localization of a region important for hedgehog signaling.Kim MS et al
198430942010Inhibitors of slit protein interactions with the heparan sulphate proteoglycan glypican-1: potential agents for the treatment of spinal cord injury.Lau E et al
187177362008Involvement of glypican-1 autoprocessing in scrapie infection.Löfgren K et al
166450042006Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts.Mani K et al
114547082001Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells.Matsuda K et al
184227602008Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells.O'Callaghan P et al
220965772011Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.Ohmi K et al
200536272010Heparan sulfate mediates amyloid-beta internalization and cytotoxicity.Sandwall E et al
167237152006Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells.Su G et al
223517612012Crystal structure of N-glycosylated human glypican-1 core protein: structure of two loops evolutionarily conserved in vertebrate glypican-1.Svensson G et al
199360542009Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.Taylor DR et al
191668232009Amyloid beta induces cellular relocalization and production of agrin and glypican-1.Timmer NM et al
150845242004Glypican-1 as an Abeta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease.Watanabe N et al
219967482012A KrasG12D-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis.Whipple CA et al
226925722012Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain.Zhang X et al
117617212001Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains.van Horssen J et al

Other Information

Locus ID:

NCBI: 2817
MIM: 600395
HGNC: 4449
Ensembl: ENSG00000063660


dbSNP: 2817
ClinVar: 2817
TCGA: ENSG00000063660


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
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
Cell surface interactions at the vascular wallREACTOMER-HSA-202733
Signal TransductionREACTOMER-HSA-162582
Visual phototransductionREACTOMER-HSA-2187338
Retinoid metabolism and transportREACTOMER-HSA-975634
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
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Signaling by Robo receptorREACTOMER-HSA-376176
Inactivation of Cdc42 and RacREACTOMER-HSA-428543
Activation of RacREACTOMER-HSA-428540
Role of Abl in Robo-Slit signalingREACTOMER-HSA-428890
Defective B3GALT6 causes EDSP2 and SEMDJL1REACTOMER-HSA-4420332
Metabolism of fat-soluble vitaminsREACTOMER-HSA-6806667
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
261068582015Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.548
186340342009Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women.130
190231252009A genome-wide association study of schizophrenia using brain activation as a quantitative phenotype.104
180643042008Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells.61
282320492017A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer.56
167237152006Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells.48
185366572008Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum.39
129724232003Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide.38
152974222004Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.34
244638212014Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells.23


Wael Awad ; Derek T Logan ; Katrin Mani

GPC1 (glypican 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-11-01

Online version: