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Protein

Glypican-3

Gene

GPC3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cell surface proteoglycan that bears heparan sulfate (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).By similarity4 Publications

Miscellaneous

Used as a marker for hepatocellular carcinoma (HCC) as it is expressed in HCC but is not detectable in hepatocytes from normal or benign liver diseases (PubMed:12851874). When attached to the cell surface, stimulates the growth of HCC cells by increasing canonical Wnt signaling (PubMed:16024626). Cleavage is not required for stimulation of Wnt signaling or HCC growth (PubMed:16227623).3 Publications

GO - Molecular functioni

  • peptidyl-dipeptidase inhibitor activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionProtease inhibitor

Enzyme and pathway databases

ReactomeiR-HSA-1971475 A tetrasaccharide linker sequence is required for GAG synthesis
R-HSA-2022928 HS-GAG biosynthesis
R-HSA-2024096 HS-GAG degradation
R-HSA-3560783 Defective B4GALT7 causes EDS, progeroid type
R-HSA-3560801 Defective B3GAT3 causes JDSSDHD
R-HSA-3656237 Defective EXT2 causes exostoses 2
R-HSA-3656253 Defective EXT1 causes exostoses 1, TRPS2 and CHDS
R-HSA-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-4420332 Defective B3GALT6 causes EDSP2 and SEMDJL1
R-HSA-8957275 Post-translational protein phosphorylation
R-HSA-975634 Retinoid metabolism and transport
SignaLinkiP51654
SIGNORiP51654

Names & Taxonomyi

Protein namesi
Recommended name:
Glypican-3
Alternative name(s):
GTR2-2
Intestinal protein OCI-5
MXR7
Cleaved into the following 2 chains:
Glypican-3 alpha subunit1 Publication
Glypican-3 beta subunit1 Publication
Gene namesi
Name:GPC3
Synonyms:OCI5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

EuPathDBiHostDB:ENSG00000147257.13
HGNCiHGNC:4451 GPC3
MIMi300037 gene
neXtProtiNX_P51654

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Simpson-Golabi-Behmel syndrome 1 (SGBS1)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by pre- and postnatal overgrowth (gigantism), facial dysmorphism and a variety of inconstant visceral and skeletal malformations. Characteristic dysmorphic features include macrocephaly with coarse, distinctive facies with a large protruding jaw, broad nasal bridge and cleft palate. Cardiac defects are frequent.
See also OMIM:312870
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_021385296W → R in SGBS1. 1 PublicationCorresponds to variant dbSNP:rs104894854EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi355 – 358RQYR → AQYA: Abolishes proteolytic processing. Abolishes interaction with WNT5A and ability to regulate Wnt signaling. Increases binding of hedgehog protein SHH to the PTC1 receptor and abolishes ability to inhibit hedgehog signaling. 3 Publications4
Mutagenesisi355R → A: No effect on proteolytic processing. 1 Publication1
Mutagenesisi358R → A: No effect on proteolytic processing. 1 Publication1
Mutagenesisi371 – 374KVLK → AVLA: No effect on proteolytic processing. 1 Publication4
Mutagenesisi387 – 389RRR → AAA: No effect on proteolytic processing. 1 Publication3
Mutagenesisi394 – 396KLK → ALA: No effect on proteolytic processing. 1 Publication3

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi2719
GeneReviewsiGPC3
MalaCardsiGPC3
MIMi312870 phenotype
OpenTargetsiENSG00000147257
Orphaneti654 Nephroblastoma
373 Simpson-Golabi-Behmel syndrome
PharmGKBiPA28832

Polymorphism and mutation databases

BioMutaiGPC3
DMDMi1708022

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 241 PublicationAdd BLAST24
ChainiPRO_000044541025 – 358Glypican-3 alpha subunit1 PublicationAdd BLAST334
ChainiPRO_0000445411359 – 554Glypican-3 beta subunit1 PublicationAdd BLAST196
PropeptideiPRO_0000012310555 – 580Removed in mature formSequence analysisAdd BLAST26

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei25Pyrrolidone carboxylic acid1 Publication1
Disulfide bondi35 ↔ 72By similarity
Disulfide bondi65 ↔ 262By similarity
Disulfide bondi73 ↔ 265By similarity
Glycosylationi124N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi197 ↔ 349By similarity
Glycosylationi241N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi252 ↔ 285By similarity
Disulfide bondi274 ↔ 422Interchain (between alpha and beta chains)By similarity
Disulfide bondi278 ↔ 410Interchain (between alpha and beta chains)By similarity
Modified residuei352Phosphoserine; by FAM20C1 Publication1
Glycosylationi418N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi495O-linked (Xyl...) (heparan sulfate) serineSequence analysis1
Glycosylationi509O-linked (Xyl...) (heparan sulfate) serineSequence analysis1
Lipidationi554GPI-anchor amidated asparagineSequence analysis1

Post-translational modificationi

O-glycosylated; contains heparan sulfate.1 Publication
Cleaved intracellularly by a furin-like convertase to generate 2 subunits, alpha and beta, which remain associated through disulfide bonds and are associated with the cell surface via the GPI-anchor (PubMed:14610063). This processing is essential for its role in inhibition of hedgehog signaling (PubMed:25653284). A second proteolytic event may result in cleavage of the protein on the cell surface, separating it from the GPI-anchor and leading to its shedding from the cell surface (PubMed:14610063).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei358 – 359Cleavage2 Publications2

Keywords - PTMi

Disulfide bond, Glycoprotein, GPI-anchor, Heparan sulfate, Lipoprotein, Phosphoprotein, Proteoglycan, Pyrrolidone carboxylic acid

Proteomic databases

MaxQBiP51654
PaxDbiP51654
PeptideAtlasiP51654
PRIDEiP51654
ProteomicsDBi56359
TopDownProteomicsiP51654-1 [P51654-1]

PTM databases

iPTMnetiP51654
PhosphoSitePlusiP51654

Expressioni

Tissue specificityi

Highly expressed in lung, liver and kidney.1 Publication

Gene expression databases

BgeeiENSG00000147257 Expressed in 172 organ(s), highest expression level in kidney
CleanExiHS_GPC3
ExpressionAtlasiP51654 baseline and differential
GenevisibleiP51654 HS

Organism-specific databases

HPAiHPA006316

Interactioni

Subunit structurei

Heterodimer; disulfide-linked (PubMed:14610063). Cleavage by a furin-like convertase results in production of alpha and beta chains which form a disulfide-linked heterodimer (PubMed:14610063). Interacts with DPP4 (PubMed:17549790). Interacts with FGF2 (By similarity). Interacts with WNT5A (PubMed:14610063). Also interacts with WNT3A and WNT7B (PubMed:16227623). Interacts with hedgehog protein SHH; the heparan sulfate chains are not required for the interaction (By similarity). Also interacts with hedgehog protein IHH (By similarity). Interacts with CD81 (By similarity). Interacts with Wnt receptors FZD4, FZD7 and FZD8; the heparan sulfate chains are required for the interaction (PubMed:24496449).By similarity4 Publications

Protein-protein interaction databases

BioGridi108983, 24 interactors
DIPiDIP-61509N
IntActiP51654, 5 interactors
STRINGi9606.ENSP00000377836

Structurei

3D structure databases

ProteinModelPortaliP51654
SMRiP51654
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the glypican family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3821 Eukaryota
ENOG410XST2 LUCA
GeneTreeiENSGT00550000074430
HOGENOMiHOG000049177
HOVERGENiHBG005896
InParanoidiP51654
KOiK08109
OMAiPGYVCSH
OrthoDBiEOG091G06T6
PhylomeDBiP51654
TreeFamiTF105317

Family and domain databases

InterProiView protein in InterPro
IPR001863 Glypican
IPR015501 Glypican-3
IPR019803 Glypican_CS
PANTHERiPTHR10822 PTHR10822, 1 hit
PTHR10822:SF4 PTHR10822:SF4, 1 hit
PfamiView protein in Pfam
PF01153 Glypican, 1 hit
PROSITEiView protein in PROSITE
PS01207 GLYPICAN, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: P51654-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MAGTVRTACL VVAMLLSLDF PGQAQPPPPP PDATCHQVRS FFQRLQPGLK
60 70 80 90 100
WVPETPVPGS DLQVCLPKGP TCCSRKMEEK YQLTARLNME QLLQSASMEL
110 120 130 140 150
KFLIIQNAAV FQEAFEIVVR HAKNYTNAMF KNNYPSLTPQ AFEFVGEFFT
160 170 180 190 200
DVSLYILGSD INVDDMVNEL FDSLFPVIYT QLMNPGLPDS ALDINECLRG
210 220 230 240 250
ARRDLKVFGN FPKLIMTQVS KSLQVTRIFL QALNLGIEVI NTTDHLKFSK
260 270 280 290 300
DCGRMLTRMW YCSYCQGLMM VKPCGGYCNV VMQGCMAGVV EIDKYWREYI
310 320 330 340 350
LSLEELVNGM YRIYDMENVL LGLFSTIHDS IQYVQKNAGK LTTTIGKLCA
360 370 380 390 400
HSQQRQYRSA YYPEDLFIDK KVLKVAHVEH EETLSSRRRE LIQKLKSFIS
410 420 430 440 450
FYSALPGYIC SHSPVAENDT LCWNGQELVE RYSQKAARNG MKNQFNLHEL
460 470 480 490 500
KMKGPEPVVS QIIDKLKHIN QLLRTMSMPK GRVLDKNLDE EGFESGDCGD
510 520 530 540 550
DEDECIGGSG DGMIKVKNQL RFLAELAYDL DVDDAPGNSQ QATPKDNEIS
560 570 580
TFHNLGNVHS PLKLLTSMAI SVVCFFFLVH
Length:580
Mass (Da):65,563
Last modified:October 1, 1996 - v1
Checksum:i19485B76D3CE15FC
GO
Isoform 2 (identifier: P51654-2) [UniParc]FASTAAdd to basket
Also known as: Variant B

The sequence of this isoform differs from the canonical sequence as follows:
     59-112: Missing.

Show »
Length:526
Mass (Da):59,475
Checksum:iA0858770AF739C17
GO
Isoform 3 (identifier: P51654-3) [UniParc]FASTAAdd to basket
Also known as: Variant C

The sequence of this isoform differs from the canonical sequence as follows:
     344-344: T → TETEKKIWHFKYPIFFLCIGLDLQ

Show »
Length:603
Mass (Da):68,414
Checksum:i1930C0382E91AF60
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0Y3U6H0Y3U6_HUMAN
Glypican-3
GPC3
256Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_021385296W → R in SGBS1. 1 PublicationCorresponds to variant dbSNP:rs104894854EnsemblClinVar.1
Natural variantiVAR_069139429V → M1 PublicationCorresponds to variant dbSNP:rs11539789EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04611759 – 112Missing in isoform 2. 1 PublicationAdd BLAST54
Alternative sequenceiVSP_046703344T → TETEKKIWHFKYPIFFLCIG LDLQ in isoform 3. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U50410 mRNA Translation: AAA93471.1
L47124 Genomic DNA Translation: AAA98131.1
L47125 mRNA Translation: AAA98132.1
L47176 mRNA Translation: AAB58806.1
Z37987 mRNA Translation: CAA86069.1
DQ349136 mRNA Translation: ABC72125.1
DQ349138 mRNA Translation: ABC72127.1
AL008712
, AC002420, AF003529, AL009174, Z99570 Genomic DNA Translation: CAI43110.1
AL009174
, AC002420, AF003529, AL008712, Z99570 Genomic DNA Translation: CAI42761.1
Z99570
, AC002420, AF003529, AL008712, AL009174 Genomic DNA Translation: CAI42277.1
AL034401 Genomic DNA No translation available.
AL662851 Genomic DNA No translation available.
Z97196 Genomic DNA No translation available.
CH471107 Genomic DNA Translation: EAX11771.1
AF003529 Genomic DNA Translation: AAB87062.1
CCDSiCCDS14638.1 [P51654-1]
CCDS55495.1 [P51654-2]
CCDS55496.1 [P51654-3]
RefSeqiNP_001158089.1, NM_001164617.1 [P51654-3]
NP_001158091.1, NM_001164619.1 [P51654-2]
NP_004475.1, NM_004484.3 [P51654-1]
UniGeneiHs.644108

Genome annotation databases

EnsembliENST00000370818; ENSP00000359854; ENSG00000147257 [P51654-1]
ENST00000394299; ENSP00000377836; ENSG00000147257 [P51654-3]
ENST00000631057; ENSP00000486325; ENSG00000147257 [P51654-2]
GeneIDi2719
KEGGihsa:2719
UCSCiuc004exe.4 human [P51654-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U50410 mRNA Translation: AAA93471.1
L47124 Genomic DNA Translation: AAA98131.1
L47125 mRNA Translation: AAA98132.1
L47176 mRNA Translation: AAB58806.1
Z37987 mRNA Translation: CAA86069.1
DQ349136 mRNA Translation: ABC72125.1
DQ349138 mRNA Translation: ABC72127.1
AL008712
, AC002420, AF003529, AL009174, Z99570 Genomic DNA Translation: CAI43110.1
AL009174
, AC002420, AF003529, AL008712, Z99570 Genomic DNA Translation: CAI42761.1
Z99570
, AC002420, AF003529, AL008712, AL009174 Genomic DNA Translation: CAI42277.1
AL034401 Genomic DNA No translation available.
AL662851 Genomic DNA No translation available.
Z97196 Genomic DNA No translation available.
CH471107 Genomic DNA Translation: EAX11771.1
AF003529 Genomic DNA Translation: AAB87062.1
CCDSiCCDS14638.1 [P51654-1]
CCDS55495.1 [P51654-2]
CCDS55496.1 [P51654-3]
RefSeqiNP_001158089.1, NM_001164617.1 [P51654-3]
NP_001158091.1, NM_001164619.1 [P51654-2]
NP_004475.1, NM_004484.3 [P51654-1]
UniGeneiHs.644108

3D structure databases

ProteinModelPortaliP51654
SMRiP51654
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108983, 24 interactors
DIPiDIP-61509N
IntActiP51654, 5 interactors
STRINGi9606.ENSP00000377836

PTM databases

iPTMnetiP51654
PhosphoSitePlusiP51654

Polymorphism and mutation databases

BioMutaiGPC3
DMDMi1708022

Proteomic databases

MaxQBiP51654
PaxDbiP51654
PeptideAtlasiP51654
PRIDEiP51654
ProteomicsDBi56359
TopDownProteomicsiP51654-1 [P51654-1]

Protocols and materials databases

DNASUi2719
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000370818; ENSP00000359854; ENSG00000147257 [P51654-1]
ENST00000394299; ENSP00000377836; ENSG00000147257 [P51654-3]
ENST00000631057; ENSP00000486325; ENSG00000147257 [P51654-2]
GeneIDi2719
KEGGihsa:2719
UCSCiuc004exe.4 human [P51654-1]

Organism-specific databases

CTDi2719
DisGeNETi2719
EuPathDBiHostDB:ENSG00000147257.13
GeneCardsiGPC3
GeneReviewsiGPC3
HGNCiHGNC:4451 GPC3
HPAiHPA006316
MalaCardsiGPC3
MIMi300037 gene
312870 phenotype
neXtProtiNX_P51654
OpenTargetsiENSG00000147257
Orphaneti654 Nephroblastoma
373 Simpson-Golabi-Behmel syndrome
PharmGKBiPA28832
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3821 Eukaryota
ENOG410XST2 LUCA
GeneTreeiENSGT00550000074430
HOGENOMiHOG000049177
HOVERGENiHBG005896
InParanoidiP51654
KOiK08109
OMAiPGYVCSH
OrthoDBiEOG091G06T6
PhylomeDBiP51654
TreeFamiTF105317

Enzyme and pathway databases

ReactomeiR-HSA-1971475 A tetrasaccharide linker sequence is required for GAG synthesis
R-HSA-2022928 HS-GAG biosynthesis
R-HSA-2024096 HS-GAG degradation
R-HSA-3560783 Defective B4GALT7 causes EDS, progeroid type
R-HSA-3560801 Defective B3GAT3 causes JDSSDHD
R-HSA-3656237 Defective EXT2 causes exostoses 2
R-HSA-3656253 Defective EXT1 causes exostoses 1, TRPS2 and CHDS
R-HSA-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-4420332 Defective B3GALT6 causes EDSP2 and SEMDJL1
R-HSA-8957275 Post-translational protein phosphorylation
R-HSA-975634 Retinoid metabolism and transport
SignaLinkiP51654
SIGNORiP51654

Miscellaneous databases

ChiTaRSiGPC3 human
GeneWikiiGlypican_3
GenomeRNAii2719
PROiPR:P51654
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000147257 Expressed in 172 organ(s), highest expression level in kidney
CleanExiHS_GPC3
ExpressionAtlasiP51654 baseline and differential
GenevisibleiP51654 HS

Family and domain databases

InterProiView protein in InterPro
IPR001863 Glypican
IPR015501 Glypican-3
IPR019803 Glypican_CS
PANTHERiPTHR10822 PTHR10822, 1 hit
PTHR10822:SF4 PTHR10822:SF4, 1 hit
PfamiView protein in Pfam
PF01153 Glypican, 1 hit
PROSITEiView protein in PROSITE
PS01207 GLYPICAN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiGPC3_HUMAN
AccessioniPrimary (citable) accession number: P51654
Secondary accession number(s): C9JLE3
, G3V1R0, Q2L880, Q2L882
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: November 7, 2018
This is version 173 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
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