GPC3_MOUSE
ID GPC3_MOUSE Reviewed; 579 AA.
AC Q8CFZ4;
DT 01-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Glypican-3;
DE Contains:
DE RecName: Full=Glypican-3 alpha subunit {ECO:0000250|UniProtKB:P51654};
DE Contains:
DE RecName: Full=Glypican-3 beta subunit {ECO:0000250|UniProtKB:P51654};
DE Flags: Precursor;
GN Name=Gpc3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP DISRUPTION PHENOTYPE.
RX PubMed=10402475; DOI=10.1083/jcb.146.1.255;
RA Cano-Gauci D.F., Song H.H., Yang H., McKerlie C., Choo B., Shi W.,
RA Pullano R., Piscione T.D., Grisaru S., Soon S., Sedlackova L.,
RA Tanswell A.K., Mak T.W., Yeger H., Lockwood G.A., Rosenblum N.D.,
RA Filmus J.;
RT "Glypican-3-deficient mice exhibit developmental overgrowth and some of the
RT abnormalities typical of Simpson-Golabi-Behmel syndrome.";
RL J. Cell Biol. 146:255-264(1999).
RN [3]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=10964473; DOI=10.1006/dbio.2000.9831;
RA Paine-Saunders S., Viviano B.L., Zupicich J., Skarnes W.C., Saunders S.;
RT "glypican-3 controls cellular responses to Bmp4 in limb patterning and
RT skeletal development.";
RL Dev. Biol. 225:179-187(2000).
RN [4]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=11180950; DOI=10.1006/dbio.2000.0127;
RA Grisaru S., Cano-Gauci D., Tee J., Filmus J., Rosenblum N.D.;
RT "Glypican-3 modulates BMP- and FGF-mediated effects during renal branching
RT morphogenesis.";
RL Dev. Biol. 231:31-46(2001).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15537637; DOI=10.1074/jbc.m410090200;
RA Song H.H., Shi W., Xiang Y.Y., Filmus J.;
RT "The loss of glypican-3 induces alterations in Wnt signaling.";
RL J. Biol. Chem. 280:2116-2125(2005).
RN [6]
RP FUNCTION, INTERACTION WITH SHH, AND DISRUPTION PHENOTYPE.
RX PubMed=18477453; DOI=10.1016/j.devcel.2008.03.006;
RA Capurro M.I., Xu P., Shi W., Li F., Jia A., Filmus J.;
RT "Glypican-3 inhibits Hedgehog signaling during development by competing
RT with patched for Hedgehog binding.";
RL Dev. Cell 14:700-711(2008).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19733558; DOI=10.1016/j.ydbio.2009.08.029;
RA Ng A., Wong M., Viviano B., Erlich J.M., Alba G., Pflederer C., Jay P.Y.,
RA Saunders S.;
RT "Loss of glypican-3 function causes growth factor-dependent defects in
RT cardiac and coronary vascular development.";
RL Dev. Biol. 335:208-215(2009).
RN [8]
RP FUNCTION, AND INTERACTION WITH CD81 AND IHH.
RX PubMed=23665349; DOI=10.1016/j.ajpath.2013.03.013;
RA Bhave V.S., Mars W., Donthamsetty S., Zhang X., Tan L., Luo J., Bowen W.C.,
RA Michalopoulos G.K.;
RT "Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex.";
RL Am. J. Pathol. 183:153-159(2013).
CC -!- FUNCTION: Cell surface proteoglycan that bears heparan sulfate (By
CC similarity). Negatively regulates the hedgehog signaling pathway when
CC attached via the GPI-anchor to the cell surface by competing with the
CC hedgehog receptor PTC1 for binding to hedgehog proteins
CC (PubMed:18477453, PubMed:23665349). Binding to the hedgehog protein SHH
CC triggers internalization of the complex by endocytosis and its
CC subsequent lysosomal degradation (PubMed:18477453). Positively
CC regulates the canonical Wnt signaling pathway by binding to the Wnt
CC receptor Frizzled and stimulating the binding of the Frizzled receptor
CC to Wnt ligands (By similarity). Positively regulates the non-canonical
CC Wnt signaling pathway (PubMed:15537637). Binds to CD81 which decreases
CC the availability of free CD81 for binding to the transcriptional
CC repressor HHEX, resulting in nuclear translocation of HHEX and
CC transcriptional repression (PubMed:23665349). Inhibits the dipeptidyl
CC peptidase activity of DPP4 (By similarity). Plays a role in limb
CC patterning and skeletal development by controlling the cellular
CC response to BMP4 (PubMed:10964473). Modulates the effects of growth
CC factors BMP2, BMP7 and FGF7 on renal branching morphogenesis
CC (PubMed:11180950). Required for coronary vascular development
CC (PubMed:19733558). Plays a role in regulating cell movements during
CC gastrulation (By similarity). {ECO:0000250|UniProtKB:P51654,
CC ECO:0000250|UniProtKB:Q6V9Y8, ECO:0000269|PubMed:10964473,
CC ECO:0000269|PubMed:11180950, ECO:0000269|PubMed:15537637,
CC ECO:0000269|PubMed:18477453, ECO:0000269|PubMed:19733558,
CC ECO:0000269|PubMed:23665349}.
CC -!- SUBUNIT: Heterodimer; disulfide-linked (By similarity). Cleavage by a
CC furin-like convertase results in production of alpha and beta chains
CC which form a disulfide-linked heterodimer (By similarity). Interacts
CC with DPP4 (By similarity). Interacts with FGF2 (By similarity).
CC Interacts with WNT5A (By similarity). Also interacts with WNT3A and
CC WNT7B (By similarity). Interacts with hedgehog protein SHH; the heparan
CC sulfate chains are not required for the interaction (PubMed:18477453).
CC Also interacts with hedgehog protein IHH (PubMed:23665349). Interacts
CC with CD81 (PubMed:23665349). Interacts with Wnt receptors FZD4, FZD7
CC and FZD8; the heparan sulfate chains are required for the interaction
CC (By similarity). {ECO:0000250|UniProtKB:P13265,
CC ECO:0000250|UniProtKB:P51654, ECO:0000269|PubMed:18477453,
CC ECO:0000269|PubMed:23665349}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13265};
CC Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P13265}; Extracellular
CC side {ECO:0000250|UniProtKB:P13265}.
CC -!- TISSUE SPECIFICITY: In the developing limb, absent from the apical
CC epidermal ridge at 11 dpc but highly expressed in the underlying
CC mesenchyme (PubMed:10964473). Expression in the mesenchyme at this
CC stage is asymmetric with highest levels in the regions of the distal
CC mesenchyme within the progress zone and within the proximal anterior
CC and posterior limb bud (PubMed:10964473). At later developmental stages
CC including 12.5 and 13.5 dpc, expression is restricted to the
CC interdigital webs and the regions of chondrocytic differentiation of
CC the developing bones (PubMed:10964473). In the embryonic kidney,
CC expressed in both the ureteric bud and mesenchymal cells as early as
CC 13.5 dpc (PubMed:11180950). Expression at 16.5 dpc is similar to that
CC at 13.5 dpc but decreases by 18.5 dpc (PubMed:11180950).
CC {ECO:0000269|PubMed:10964473, ECO:0000269|PubMed:11180950}.
CC -!- PTM: O-glycosylated; contains heparan sulfate.
CC {ECO:0000250|UniProtKB:P51654}.
CC -!- PTM: Cleaved intracellularly by a furin-like convertase to generate 2
CC subunits, alpha and beta, which remain associated through disulfide
CC bonds and are associated with the cell surface via the GPI-anchor. This
CC processing is essential for its role in inhibition of hedgehog
CC signaling. A second proteolytic event may result in cleavage of the
CC protein on the cell surface, separating it from the GPI-anchor and
CC leading to its shedding from the cell surface.
CC {ECO:0000250|UniProtKB:P51654}.
CC -!- DISRUPTION PHENOTYPE: Perinatal death, developmental overgrowth, cystic
CC and dyplastic kidneys, abnormal lung development and ventral wall
CC closure defects (PubMed:10402475, PubMed:10964473). A proportion of
CC mutants also display mandibular hypoplasia and an imperforate vagina
CC (PubMed:10402475). There is an early and persistent abnormality in
CC ureteric bud development in the kidney due to increased cell
CC proliferation (PubMed:10402475). In the developing kidney, cell
CC proliferation is increased threefold in cortical collecting duct cells
CC and apoptosis is increased 16-fold in medullary collecting duct cells
CC (PubMed:11180950). High incidence of congenital cardiac malformations
CC including ventricular septal defects, common atrioventricular canal,
CC double outlet right ventricle and presence of coronary artery fistulas
CC (PubMed:19733558). Elevated levels of hedgehog pathway proteins Gli1
CC and Ptc1, indicative of activation of the hedgehog pathway and
CC increased levels of Shh (PubMed:18477453). Reduced non-canonical Wnt
CC signaling (PubMed:15537637). Similar levels of tissue and serum Igf2 to
CC wild-type mice (PubMed:10402475). {ECO:0000269|PubMed:10402475,
CC ECO:0000269|PubMed:10964473, ECO:0000269|PubMed:11180950,
CC ECO:0000269|PubMed:15537637, ECO:0000269|PubMed:18477453,
CC ECO:0000269|PubMed:19733558}.
CC -!- SIMILARITY: Belongs to the glypican family. {ECO:0000305}.
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DR EMBL; BC036126; AAH36126.1; -; mRNA.
DR CCDS; CCDS30125.1; -.
DR RefSeq; NP_057906.2; NM_016697.3.
DR AlphaFoldDB; Q8CFZ4; -.
DR SMR; Q8CFZ4; -.
DR BioGRID; 200013; 1.
DR IntAct; Q8CFZ4; 3.
DR STRING; 10090.ENSMUSP00000064131; -.
DR GlyGen; Q8CFZ4; 5 sites.
DR PhosphoSitePlus; Q8CFZ4; -.
DR MaxQB; Q8CFZ4; -.
DR PaxDb; Q8CFZ4; -.
DR PRIDE; Q8CFZ4; -.
DR ProteomicsDB; 271429; -.
DR Antibodypedia; 424; 1355 antibodies from 41 providers.
DR DNASU; 14734; -.
DR Ensembl; ENSMUST00000069360; ENSMUSP00000064131; ENSMUSG00000055653.
DR GeneID; 14734; -.
DR KEGG; mmu:14734; -.
DR UCSC; uc009teg.2; mouse.
DR CTD; 2719; -.
DR MGI; MGI:104903; Gpc3.
DR VEuPathDB; HostDB:ENSMUSG00000055653; -.
DR eggNOG; KOG3821; Eukaryota.
DR GeneTree; ENSGT01050000244955; -.
DR HOGENOM; CLU_024658_4_2_1; -.
DR InParanoid; Q8CFZ4; -.
DR OMA; EYICSHS; -.
DR OrthoDB; 1097767at2759; -.
DR PhylomeDB; Q8CFZ4; -.
DR TreeFam; TF105317; -.
DR Reactome; R-MMU-1971475; A tetrasaccharide linker sequence is required for GAG synthesis.
DR Reactome; R-MMU-2022928; HS-GAG biosynthesis.
DR Reactome; R-MMU-2024096; HS-GAG degradation.
DR Reactome; R-MMU-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-MMU-8957275; Post-translational protein phosphorylation.
DR Reactome; R-MMU-975634; Retinoid metabolism and transport.
DR BioGRID-ORCS; 14734; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Gpc3; mouse.
DR PRO; PR:Q8CFZ4; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q8CFZ4; protein.
DR Bgee; ENSMUSG00000055653; Expressed in umbilical cord and 216 other tissues.
DR ExpressionAtlas; Q8CFZ4; baseline and differential.
DR Genevisible; Q8CFZ4; MM.
DR GO; GO:0046658; C:anchored component of plasma membrane; IMP:MGI.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; IEA:InterPro.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:MGI.
DR GO; GO:0005764; C:lysosome; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0060422; F:peptidyl-dipeptidase inhibitor activity; ISS:UniProtKB.
DR GO; GO:0009887; P:animal organ morphogenesis; IMP:MGI.
DR GO; GO:0009948; P:anterior/posterior axis specification; IGI:MGI.
DR GO; GO:0010171; P:body morphogenesis; IMP:MGI.
DR GO; GO:0030282; P:bone mineralization; IMP:MGI.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IGI:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0016477; P:cell migration; IBA:GO_Central.
DR GO; GO:0042074; P:cell migration involved in gastrulation; ISS:UniProtKB.
DR GO; GO:0072111; P:cell proliferation involved in kidney development; IMP:MGI.
DR GO; GO:0072203; P:cell proliferation involved in metanephros development; IMP:MGI.
DR GO; GO:0060976; P:coronary vasculature development; IMP:MGI.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IGI:MGI.
DR GO; GO:0050673; P:epithelial cell proliferation; IMP:MGI.
DR GO; GO:0001822; P:kidney development; IMP:MGI.
DR GO; GO:0030324; P:lung development; IMP:MGI.
DR GO; GO:0072138; P:mesenchymal cell proliferation involved in ureteric bud development; IMP:UniProtKB.
DR GO; GO:0072180; P:mesonephric duct morphogenesis; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IGI:MGI.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IMP:MGI.
DR GO; GO:0045926; P:negative regulation of growth; IMP:MGI.
DR GO; GO:0010466; P:negative regulation of peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0045879; P:negative regulation of smoothened signaling pathway; IMP:MGI.
DR GO; GO:0030316; P:osteoclast differentiation; IMP:MGI.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IMP:MGI.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:MGI.
DR GO; GO:0046326; P:positive regulation of glucose import; IDA:MGI.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IMP:MGI.
DR GO; GO:2000096; P:positive regulation of Wnt signaling pathway, planar cell polarity pathway; IMP:MGI.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0040008; P:regulation of growth; IMP:MGI.
DR GO; GO:2000050; P:regulation of non-canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:1905475; P:regulation of protein localization to membrane; IBA:GO_Central.
DR GO; GO:0009617; P:response to bacterium; IEP:MGI.
DR GO; GO:0007224; P:smoothened signaling pathway; IMP:MGI.
DR GO; GO:0060071; P:Wnt signaling pathway, planar cell polarity pathway; IMP:MGI.
DR InterPro; IPR001863; Glypican.
DR InterPro; IPR015501; Glypican-3.
DR InterPro; IPR019803; Glypican_CS.
DR PANTHER; PTHR10822; PTHR10822; 1.
DR PANTHER; PTHR10822:SF4; PTHR10822:SF4; 1.
DR Pfam; PF01153; Glypican; 1.
DR PROSITE; PS01207; GLYPICAN; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; Glycoprotein; GPI-anchor; Heparan sulfate;
KW Lipoprotein; Membrane; Phosphoprotein; Protease inhibitor; Proteoglycan;
KW Pyrrolidone carboxylic acid; Reference proteome; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..357
FT /note="Glypican-3 alpha subunit"
FT /evidence="ECO:0000250|UniProtKB:P51654"
FT /id="PRO_0000445412"
FT CHAIN 358..553
FT /note="Glypican-3 beta subunit"
FT /evidence="ECO:0000250|UniProtKB:P51654"
FT /id="PRO_0000445413"
FT PROPEP 554..579
FT /note="Removed in mature form"
FT /evidence="ECO:0000255"
FT /id="PRO_0000012312"
FT REGION 533..552
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 25
FT /note="Pyrrolidone carboxylic acid"
FT /evidence="ECO:0000250|UniProtKB:P51654"
FT MOD_RES 351
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P51654"
FT LIPID 553
FT /note="GPI-anchor amidated serine"
FT /evidence="ECO:0000255"
FT CARBOHYD 123
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 240
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 417
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 494
FT /note="O-linked (Xyl...) (heparan sulfate) serine"
FT /evidence="ECO:0000255"
FT CARBOHYD 508
FT /note="O-linked (Xyl...) (heparan sulfate) serine"
FT /evidence="ECO:0000255"
FT DISULFID 34..71
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 64..261
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 72..264
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 196..348
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 251..284
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 273..421
FT /note="Interchain (between alpha and beta chains)"
FT /evidence="ECO:0000250|UniProtKB:P35052"
FT DISULFID 277..409
FT /note="Interchain (between alpha and beta chains)"
FT /evidence="ECO:0000250|UniProtKB:P35052"
SQ SEQUENCE 579 AA; 65332 MW; 066C23B3493A9346 CRC64;
MAGTVRTACL LVAMLLGLGC LGQAQPPPPP DATCHQVRSF FQRLQPGLKW VPETPVPGSD
LQVCLPKGPT CCSRKMEEKY QLTARLNMEQ LLQSASMELK FLIIQNAAVF QEAFEIVVRH
AKNYTNAMFK NNYPSLTPQA FEFVGEFFTD VSLYILGSDI NVDDMVNELF DSLFPVIYTQ
MMNPGLPESV LDINECLRGA RRDLKVFGSF PKLIMTQVSK SLQVTRIFLQ ALNLGIEVIN
TTDHLKFSKD CGRMLTRMWY CSYCQGLMMV KPCGGYCNVV MQGCMAGVVE IDKYWREYIL
SLEELVNGMY RIYDMENVLL GLFSTIHDSI QYVQKNGGKL TTTIGKLCAH SQQRQYRSAY
YPEDLFIDKK ILKVAHVEHE ETLSSRRREL IQKLKSFINF YSALPGYICS HSPVAENDTL
CWNGQELVER YSQKAARNGM KNQFNLHELK MKGPEPVVSQ IIDKLKHINQ LLRTMSVPKG
KVLDKSLDEE GLESGDCGDD EDECIGSSGD GMVKVKNQLR FLAELAYDLD VDDAPGNKQH
GNQKDNEITT SHSVGNMPSP LKILISVAIY VACFFFLVH
