Glypican-3 (GPC3) is a heparan sulfate proteoglycan of the glypican family, attached by a C-terminal GPI anchor to the extracellular face of the plasma membrane. The core protein is cleaved in the secretory pathway by a furin-like proprotein convertase into alpha and beta subunits that remain disulfide-linked, and can be released from the surface by a second cleavage. GPC3 acts as a cell-surface co-receptor/modulator of morphogen signalling: it binds Wnt ligands and, through its heparan sulfate chains, Frizzled receptors, promoting Wnt-Frizzled complex formation and canonical Wnt signalling in hepatocellular carcinoma cells, while in other cell types it can dampen canonical and non-canonical Wnt responses. It binds hedgehog proteins through its core protein, competing with Patched and driving hedgehog endocytosis and lysosomal degradation, and so restrains hedgehog signalling during development. GPC3 is expressed in fetal mesodermal tissues, liver, lung, kidney and placenta, is largely absent from adult liver but re-expressed in most hepatocellular carcinomas, and its loss of function causes the X-linked Simpson-Golabi-Behmel overgrowth syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:17549790 The Simpson-Golabi-Behmel syndrome causative glypican-3, bin... | MODIFY | Summary: IPI: GPC3 binds DPP4 (CD26), isolated as a GPC3 interactor from cell lines; binding inhibits CD26 peptidase activity. Reason: Generic protein binding is uninformative. The partner, DPP4 (P27487), is a serine dipeptidyl peptidase, and the paper reports that binding inhibits its activity, so the informative MF for the interaction itself is protease binding. The inhibitory consequence is captured on the peptidase-inhibitor row. Evidence is a single abstract-only proteomics study. Proposed replacements: protease binding Supporting Evidence: PMID:17549790 The interaction occurred with both the glycosylated and unglycosylated forms of GPC3 and led to the inhibition of CD26 peptidase activity. |
| GO:0005515 protein binding | IPI PMID:29162697 EB1-binding-myomegalin protein complex promotes centrosomal ... | REMOVE | Summary: IPI with GPC2 (Q8N158), CDK5RAP2 (Q96SN8) and GPC6 (Q9Y625) from a SMYLE/EB1/myomegalin centrosomal complex proteomics study. Reason: Bare protein binding is uninformative under the protein-binding policy. The cited paper is about the centrosomal SMYLE-EB1-AKAP9 complex; the cached abstract does not mention GPC3, and a centrosomal partner set is not consistent with a luminal/extracellular GPI-anchored proteoglycan. No informative MF can be derived. Removal does not assert the co-purification did not occur. Supporting Evidence: PMID:29162697 SMYLE depletion led to defective astral microtubules and abnormal orientation of the mitotic spindle |
| GO:0005515 protein binding | IPI PMID:39822733 A proteomic atlas of glypican-3 interacting partners: Identi... | REMOVE | Summary: IPI with alpha-fetoprotein (AFP, P02771), validated with purified proteins after a GPC3 co-IP/MS screen of HepG2 xenograft tumours. Reason: Bare protein binding is uninformative and GO has no term capturing a specific functional consequence of GPC3-AFP association. The interaction itself appears genuine (cell-free IP and colocalization) and is noted in the description context, but no function is inferred from it. Supporting Evidence: PMID:39822733 We further validated the direct interaction of GPC3 and alpha-fetoprotein (AFP) in cell-free immunoprecipitation and immunofluorescence microscopy for colocalization. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN002247069, seed mouse Gpc4 MGI:1194891): extracellular region. Reason: GPC3 is primarily GPI-anchored at the cell surface, but a second proteolytic event can release it, and soluble GPC3 is measurable in serum of HCC patients. The IBA is therefore consistent with GPC3 biology, though the extracellular soluble pool is secondary to the membrane-anchored form. Supporting Evidence: PMID:14610063 This suggests a second proteolytic event, potentially related to the shedding of GPC3 from the cell surface. PMID:12851874 GPC3 is specifically overexpressed in most HCCs and is elevated in the serum of a large proportion of patients with HCC. |
| GO:0005764 lysosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl Compara from mouse Gpc3): lysosome. Reason: GPC3 bound to hedgehog is internalized and the complex is degraded in lysosomes (mouse data, PMID:18477453, recorded By similarity in UniProt), and heparan sulfate proteoglycans are generally turned over in lysosomes. Lysosomes are a degradative destination rather than a site of GPC3 function, so this is non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. file:human/GPC3/GPC3-uniprot.txt endocytosis and its subsequent lysosomal degradation (By similarity). |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: Reactome: GPC3 is one of the FAM20C substrates phosphorylated in the ER lumen (GPC3 Ser352 is a FAM20C site per UniProt). Reason: As a secreted-pathway protein with a signal peptide, GPC3 transits the ER lumen, and UniProt records Ser352 phosphorylation by FAM20C. This is a biosynthetic transit location, not a site of function. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt /note="Phosphoserine; by FAM20C" PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1667005 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1878002 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889955 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889978 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889981 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022851 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022856 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022860 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022887 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2024108 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076383 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076392 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076419 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076508 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076611 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3560802 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3560804 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656254 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656257 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656261 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656267 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-4420365 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9036285 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9036289 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9940993 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9941039 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9953259 | KEEP AS NON CORE | Summary: Reactome places the GPC3 core protein in the Golgi lumen as one of the generic HSPG acceptor proteins in reactions of heparan sulfate chain initiation, elongation and modification (xylosyl, galactosyl and glucuronosyl transfer, EXT1:EXT2 polymerisation, NDST/HS2ST/HS3ST/HS6ST sulfation, FAM20B/PXYLP1 xylose phosphate turnover), including the matching defective-enzyme disease reactions. Reason: GPC3 is a heparan sulfate proteoglycan whose core protein transits the Golgi, where it is processed and glycanated before reaching the cell surface (PMID:14610063). As a GPI-anchored protein it faces the Golgi lumen during biosynthesis, so the location is defensible, but it is a transit compartment for a substrate of the glycosylation machinery, not where GPC3 acts. Kept as non-core. Supporting Evidence: PMID:14610063 Then, it shuttles to the Golgi complex, where it is further N-glycosylated, O-glycanated, and processed into two subunits, and travels to the cell surface. file:human/GPC3/GPC3-uniprot.txt PTM: O-glycosylated; contains heparan sulfate and/or chondroitin |
| GO:0005886 plasma membrane | EXP PMID:14610063 Processing by proprotein convertases is required for glypica... | ACCEPT | Summary: EXP: human GPC3 (wild type and a convertase-resistant mutant) expressed in cultured cells accumulates at the cell surface as a GPI-anchored, processed heterodimer. Reason: Direct experimental localization of human GPC3 at the cell surface/plasma membrane. The plasma membrane (extracellular leaflet, GPI anchor) is where GPC3 binds Wnt, Frizzled and hedgehog ligands. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface PMID:14610063 It generates two core protein subunits, designated as Ξ± and Ξ², which remain in association with one another through disulfide bonding, and with the cell surface via the GPI-tail of the Ξ² subunit. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN002585559; seeds mouse Gpc3-related MGI:104903, rat RGD:2725 and human GPC3 itself): plasma membrane. Reason: Human GPC3 is among the experimental seeds of this node (its own EXP annotation), which is expected rather than circular. Plasma membrane localization is consistent with the GPI-anchored glypican architecture. This is the node from which the horse and other mammalian GPC3 IBAs descend. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P13265}; Extracellular |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: IDA (Human Protein Atlas immunofluorescence): plasma membrane. Reason: Consistent with the experimental cell-surface localization of human GPC3. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (combined automated: Ensembl ortholog, InterPro glypican, UniProt SubCell cell membrane): plasma membrane. Reason: Matches experimental localization of human GPC3. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from rat GPC1 (P13265): plasma membrane. Reason: Glypican family membership supports GPI anchoring at the cell surface, and the location is directly established for human GPC3 in any case. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P13265}; Extracellular PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SIMILARITY: Belongs to the glypican family. |
| GO:0005886 plasma membrane | TAS PMID:7657705 K-glypican: a novel GPI-anchored heparan sulfate proteoglyca... | ACCEPT | Summary: TAS from the K-glypican cloning paper, which also cloned the mouse homologue of OCI-5 (GPC3) and describes glypicans as GPI-anchored cell-surface HSPGs. Reason: The family-level statement is correct for GPC3 and agrees with direct experimental localization. Supporting Evidence: PMID:7657705 Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored cell surface heparan sulfate proteoglycans (HSPGs). PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-140791 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-140870 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-140872 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1678694 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2024084 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2024108 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2404131 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2423785 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2429643 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9694579 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9694661 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9698988 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9699007 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9823284 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9823290 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9836899 | ACCEPT | Summary: Reactome lists GPC3 among the plasma-membrane heparan sulfate proteoglycans that participate in generic HSPG reactions (antithrombin/thrombin and factor Xa complexes, retinyl ester chylomicron remnant uptake, heparanase 2 binding, SARS-CoV-2 spike attachment, viral glycoprotein binding, HSPG delivery to the cell surface). Reason: The reactions are generic HSPG roles not specifically demonstrated for GPC3, but the location they assert, plasma membrane, is experimentally established for human GPC3, a GPI-anchored proteoglycan on the extracellular face of the cell membrane (PMID:14610063). The location claim is accepted; the reaction-level roles are not carried into core functions. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14610063}; |
| GO:0009653 anatomical structure morphogenesis | TAS PMID:8589713 Mutations in GPC3, a glypican gene, cause the Simpson-Golabi... | MARK AS OVER ANNOTATED | Summary: TAS from the SGBS gene identification paper: GPC3 loss causes pre- and postnatal overgrowth with visceral and skeletal anomalies. Reason: The paper establishes that GPC3 loss causes an overgrowth malformation syndrome; it does not show GPC3 executing morphogenesis. The organismal phenotype is downstream of GPC3's signalling-modulator role (hedgehog and Wnt regulation), which is annotated directly. The very general term adds no information and rests on phenotype. Supporting Evidence: PMID:8589713 GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. |
| GO:0009966 regulation of signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: IEA (InterPro glypican IPR001863): regulation of signal transduction. Reason: Correct but general. Human GPC3 has specific, experimentally supported regulatory roles in canonical Wnt signalling, non-canonical Wnt signalling and hedgehog (smoothened) signalling, all annotated elsewhere in this review; the replacement lists those descendants. Proposed replacements: regulation of canonical Wnt signaling pathway regulation of non-canonical Wnt signaling pathway negative regulation of smoothened signaling pathway Supporting Evidence: PMID:24496449 GPC3 plays a more direct role in the stimulation of Wnt signaling PMID:18477453 GPC3 competes with Patched for Hedgehog binding |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN002247069; seeds fly dally/dlp, human GPC4, worm lon-2): cell surface. Reason: Cell-surface location is family-wide in glypicans and directly observed for human GPC3. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface |
| GO:0016477 cell migration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN002247069, deep bilaterian node; seeds fly dally/dlp, human GPC6, worm, zebrafish knypek/gpc4): cell migration. Reason: Glypicans across Bilateria modulate cell migration by shaping Wnt/PCP, FGF and other ligand gradients, and GPC3 sits inside the clade below this node with no evidence of loss. For GPC3 the relevant evidence is regulatory (zebrafish gastrulation movements depend on processed GPC3 acting through Wnt signalling), so the term is kept but as non-core relative to the signalling-modulator activity. Supporting Evidence: PMID:14610063 only a form of GPC3 that can be processed by a convertase is able to rescue epiboly and convergence/extension movements in GPC3 morphant embryos |
| GO:0031012 extracellular matrix | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: IEA (InterPro glypican IPR001863): extracellular matrix. Reason: GPC3 is a GPI-anchored cell-surface proteoglycan; a shed form is soluble in body fluids. There is no evidence that GPC3 is a structural or resident ECM component. The InterPro2GO mapping generalises from HSPGs as a class; extracellular region (accepted as non-core) and plasma membrane describe GPC3 better. Supporting Evidence: PMID:14610063 Both GPC3 and GPC3/AQYA accumulated at the cell surface file:human/GPC3/GPC3-uniprot.txt Lipid-anchor, GPI-anchor {ECO:0000250|UniProtKB:P13265}; Extracellular |
| GO:0042074 cell migration involved in gastrulation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from zebrafish gpc3 (Q6V9Y8): cell migration involved in gastrulation, based on morphant epiboly and convergent-extension defects. Reason: The underlying zebrafish evidence is a morpholino knockdown with rescue; it shows GPC3 is required for normal gastrulation movements, not that GPC3 performs cell migration. The mechanistic contribution is modulation of Wnt signalling, captured by the Wnt regulation terms. No human data address gastrulation. Supporting Evidence: PMID:14610063 This processing is essential for GPC3 modulating Wnt signaling and cell survival in vitro and for supporting embryonic cell movements in zebrafish. |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Lysosomal lumen localization (ARBA rule; Reactome HS-GAG lysosomal degradation reactions). Reason: GPC3 bound to hedgehog is internalized and the complex is degraded in lysosomes (mouse data, PMID:18477453, recorded By similarity in UniProt), and heparan sulfate proteoglycans are generally turned over in lysosomes. Lysosomes are a degradative destination rather than a site of GPC3 function, so this is non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. file:human/GPC3/GPC3-uniprot.txt endocytosis and its subsequent lysosomal degradation (By similarity). |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1667005 | KEEP AS NON CORE | Summary: Lysosomal lumen localization (ARBA rule; Reactome HS-GAG lysosomal degradation reactions). Reason: GPC3 bound to hedgehog is internalized and the complex is degraded in lysosomes (mouse data, PMID:18477453, recorded By similarity in UniProt), and heparan sulfate proteoglycans are generally turned over in lysosomes. Lysosomes are a degradative destination rather than a site of GPC3 function, so this is non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. file:human/GPC3/GPC3-uniprot.txt endocytosis and its subsequent lysosomal degradation (By similarity). |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2024084 | KEEP AS NON CORE | Summary: Lysosomal lumen localization (ARBA rule; Reactome HS-GAG lysosomal degradation reactions). Reason: GPC3 bound to hedgehog is internalized and the complex is degraded in lysosomes (mouse data, PMID:18477453, recorded By similarity in UniProt), and heparan sulfate proteoglycans are generally turned over in lysosomes. Lysosomes are a degradative destination rather than a site of GPC3 function, so this is non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. file:human/GPC3/GPC3-uniprot.txt endocytosis and its subsequent lysosomal degradation (By similarity). |
| GO:0045732 positive regulation of protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Gpc3 (Q8CFZ4): positive regulation of protein catabolic process (GPC3 promotes hedgehog degradation). Reason: In mouse cells GPC3 binds hedgehog and induces its endocytosis and lysosomal degradation, which is part of how it antagonises hedgehog signalling. Mouse and human GPC3 are orthologs in the same PANTHER subfamily (PTHR10822:SF4). The catabolic effect is a mechanism of the core hedgehog-antagonist role rather than an independent function, so non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. |
| GO:0045807 positive regulation of endocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Gpc3 (Q8CFZ4): positive regulation of endocytosis (hedgehog-GPC3 complex internalization). Reason: Supported for mouse GPC3 with hedgehog and, for human GPC3, by Wnt-triggered endocytosis of a Wnt-Frizzled-GPC3 complex. GPC3 is itself internalized with its ligands; it is a ligand-scavenging mechanism downstream of binding, kept as non-core. Supporting Evidence: PMID:18477453 Furthermore, GPC3 induces Hedgehog endocytosis and degradation. PMID:24496449 the binding of Wnt at the cell membrane triggers the endocytosis of a complex that includes Wnt, Frizzled and GPC3 |
| GO:0045879 negative regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Gpc3 (Q8CFZ4): negative regulation of smoothened (hedgehog) signalling. Reason: Gpc3-null mouse embryos show increased hedgehog signalling, and GPC3 binds hedgehog with high affinity and competes with Patched. Convertase-processed GPC3 inhibits Shh-induced reporter activity in cultured cells (PMID:25653284, attributed by UniProt to the human protein). Transfer is grounded in shared PANTHER subfamily PTHR10822:SF4. Note that PAINT has not placed a hedgehog-regulation IBD on the GPC3 lineage, so this rests on ortholog and cell-based evidence, not phylogenetic inference. A core function. Supporting Evidence: PMID:18477453 We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development PMID:25653284 In this study, we show that processing by convertases is essential for GPC3-induced inhibition of Hh signaling. |
| GO:0060422 peptidyl-dipeptidase inhibitor activity | IDA PMID:17549790 The Simpson-Golabi-Behmel syndrome causative glypican-3, bin... | MODIFY | Summary: IDA: recombinant GPC3 binds CD26/DPP4 and inhibits its peptidase activity. Reason: The term is mis-specified: GO:0060422 is defined as inhibition of peptidyl-dipeptidase activity, which releases C-terminal dipeptides (ACE-type), whereas DPP4 is a dipeptidyl-peptidase that removes N-terminal dipeptides (GO:0008239). GO has no dipeptidyl-peptidase inhibitor term, so the parent peptidase inhibitor activity is the accurate replacement. The finding comes from a single abstract-only study and has not been independently replicated; it is treated as non-core. Proposed replacements: peptidase inhibitor activity Supporting Evidence: PMID:17549790 The interaction occurred with both the glycosylated and unglycosylated forms of GPC3 and led to the inhibition of CD26 peptidase activity. file:human/GPC3/GPC3-uniprot.txt Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). |
| GO:0060828 regulation of canonical Wnt signaling pathway | IDA PMID:14610063 Processing by proprotein convertases is required for glypica... | ACCEPT | Summary: IDA: in CHO-K1 and furin-deficient cells, convertase-processed, glycanated human GPC3 dose-dependently represses Wnt1-induced TOPflash activity. Reason: Direct evidence that human GPC3 modulates canonical Wnt signalling. Its direction is cell-type dependent: repression in CHO cells here, stimulation in HCC and 293T cells (PMID:16024626, PMID:24496449). The parent regulation term correctly covers both. Supporting Evidence: PMID:14610063 Yet, at invariant levels of Wnt1 in cotransfection mixtures, increasing the amount of wild-type GPC3 repressed Wnt1-mediated pTOPFLASH activation in a dose-dependent manner. |
| GO:0060976 coronary vasculature development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Gpc3 (Q8CFZ4): coronary vasculature development (Gpc3-deficient mouse coronary defects). Reason: This rests on a knockout phenotype in mouse; the mechanism by which GPC3 acts in coronary development is not established, and GPC3 is not shown to perform a step of vascular development. It is a downstream organismal phenotype of a signalling modulator. Not transferred as process participation. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt Required for coronary vascular development |
| GO:0072111 cell proliferation involved in kidney development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Gpc3 (Q8CFZ4): cell proliferation involved in kidney development. Reason: Gpc3-deficient mice show renal dysplasia with altered proliferation, and GPC3 modulates BMP2/BMP7/FGF7 effects on renal branching (UniProt, By similarity). SGBS patients also show renal anomalies. GPC3 acts as a growth-factor modulator here rather than as a proliferation component; tissue-specific and non-core. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis |
| GO:0072138 mesenchymal cell proliferation involved in ureteric bud development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl Compara from mouse Gpc3): mesenchymal cell proliferation involved in ureteric bud development. Reason: Gpc3-deficient mice show renal dysplasia with altered proliferation, and GPC3 modulates BMP2/BMP7/FGF7 effects on renal branching (UniProt, By similarity). SGBS patients also show renal anomalies. GPC3 acts as a growth-factor modulator here rather than as a proliferation component; tissue-specific and non-core. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis |
| GO:0072138 mesenchymal cell proliferation involved in ureteric bud development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Gpc3 (Q8CFZ4): mesenchymal cell proliferation involved in ureteric bud development. Reason: Gpc3-deficient mice show renal dysplasia with altered proliferation, and GPC3 modulates BMP2/BMP7/FGF7 effects on renal branching (UniProt, By similarity). SGBS patients also show renal anomalies. GPC3 acts as a growth-factor modulator here rather than as a proliferation component; tissue-specific and non-core. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis |
| GO:0072180 mesonephric duct morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Gpc3 (Q8CFZ4): mesonephric duct morphogenesis. Reason: Same mouse renal-development evidence base as the kidney proliferation rows: GPC3 modulates growth-factor responses during renal branching morphogenesis. Tissue-specific developmental role, non-core; the human relevance is supported by renal anomalies in SGBS but not by direct human experimental data. Supporting Evidence: file:human/GPC3/GPC3-uniprot.txt growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN000850517, bilaterian node; seeds fly dally FBgn0263930 and human GPC3 itself): positive regulation of canonical Wnt signaling. Reason: Human GPC3 is a seed of this node through its own experimental annotation, which is expected, not circular. Experimental human data show GPC3 binds Wnts and Frizzled and stimulates canonical Wnt signalling in HCC cells. PAINT curators placed this term but not the cell-type-specific repression or developmental terms, consistent with stimulation being the conserved property. Core function. Supporting Evidence: PMID:24496449 GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3, indicating that this glypican stimulates the formation of signaling complexes between Wnt and Frizzled PMID:16024626 GPC3 stimulates the in vitro and in vivo growth of hepatocellular carcinoma cells by increasing autocrine/paracrine canonical Wnt signaling |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IDA PMID:24496449 Glypican-3 binds to Frizzled and plays a direct role in the ... | ACCEPT | Summary: IDA: human GPC3 binds Frizzled via its GAG chains, promotes Wnt-Frizzled complex formation and stimulates canonical Wnt signalling in HCC cells. Reason: Direct human evidence for a co-receptor mechanism: GPC3 binds both Wnt and Frizzled and stimulates their signalling complex, and the complex is co-endocytosed. GPC6, which also binds Wnt, does not stimulate, showing specificity. Core function. Supporting Evidence: PMID:24496449 GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3, indicating that this glypican stimulates the formation of signaling complexes between Wnt and Frizzled PMID:24496449 glypican-6 (GPC6) inhibits canonical Wnt signaling, despite the fact that it binds to Wnt at the cell membrane |
| GO:1905475 regulation of protein localization to membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PTN002247069; seeds rat Gpc4 and Gpc6, RGD:1359399 and RGD:1593308): regulation of protein localization to membrane. Reason: The seeds are astrocyte-derived GPC4/GPC6 roles in recruiting receptors at synaptic membranes. GPC3 descends from the same deep node with no evidence of loss, and as a membrane-anchored co-receptor it affects whether ligands (Wnt, hedgehog) are retained at or internalized from the membrane, so the broad term is plausible. There is no GPC3-specific experimental support for receptor clustering, so it is kept as non-core. Supporting Evidence: PMID:24496449 the binding of Wnt at the cell membrane triggers the endocytosis of a complex that includes Wnt, Frizzled and GPC3 |
| GO:2000050 regulation of non-canonical Wnt signaling pathway | IDA PMID:14610063 Processing by proprotein convertases is required for glypica... | ACCEPT | Summary: IDA: human GPC3 overexpression suppresses Wnt5A/noncanonical (AP-1 reporter) Wnt signalling in CHO-K1 cells, dependent on convertase processing; Wnt5A binds processed GPC3. Reason: Direct human-protein evidence for modulation of non-canonical Wnt signalling. The direction differs between systems (suppression here; positive regulation inferred from mouse in UniProt), so the parent regulation term is appropriate. Supporting Evidence: PMID:14610063 Together, these results indicate that GPC3 overexpression suppresses noncanonical Wnt signaling in CHO-K1 cells, and suggest that PC processing of the GPC core protein is required also for this effect. PMID:14610063 Wnt 5A physically associates only with processed GPC3 |
| GO:0005109 frizzled binding | IDA PMID:24496449 Glypican-3 binds to Frizzled and plays a direct role in the ... | NEW | Summary: Human GPC3 binds the Wnt receptors FZD4, FZD7 and FZD8 directly, through its heparan sulfate chains. Reason: Frizzled binding is the mechanistic basis of GPC3 stimulation of canonical Wnt signalling and is directly shown for the human protein; not represented in GOA beyond generic protein binding. Supporting Evidence: PMID:24496449 GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3 file:human/GPC3/GPC3-uniprot.txt Interacts with Wnt receptors FZD4, |
| GO:0017147 Wnt-protein binding | IDA PMID:16024626 Glypican-3 promotes the growth of hepatocellular carcinoma b... | NEW | Summary: Human GPC3 forms complexes with Wnts (Wnt3a, Wnt7b, Wnt5a); GPC3-expressing cells bind more Wnt. Reason: Wnt binding by human GPC3 is shown by co-immunoprecipitation and cell-binding assays in two independent laboratories (Filmus; David), and is core to its co-receptor role. Not represented in GOA. Supporting Evidence: PMID:16024626 Co-immunoprecipitation experiments showed that GPC3 is able to form complexes with Wnts, and cell-binding assays indicated that GPC3-expressing cells have an increased capacity to bind Wnt. PMID:14610063 Wnt 5A physically associates only with processed GPC3 |
| GO:0097108 hedgehog family protein binding | ISS PMID:18477453 Glypican-3 inhibits Hedgehog signaling during development by... | NEW | Summary: GPC3 binds hedgehog proteins with high affinity through its core protein and competes with Patched for hedgehog binding. Reason: Hedgehog binding is the mechanism of GPC3 antagonism of hedgehog signalling. The primary data are from mouse embryos/fibroblasts (ortholog in the same PANTHER subfamily PTHR10822:SF4); the follow-up processing study, which UniProt attributes to the human entry, also shows GPC3-Shh co-immunoprecipitation. Proposed as ISS for human to keep the species basis explicit. Supporting Evidence: PMID:18477453 GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding PMID:25653284 We also showed that GPC3 binds with high affinity to Hh through its core protein, but that it does not interact with Ptc. |
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Download this section (compressed HTML)Q: Which cellular contexts determine whether GPC3 stimulates (HCC, 293T) or represses (CHO) canonical Wnt signalling, and is the difference due to convertase processing, heparan sulfate sulfation pattern, or the available Frizzled repertoire?
Q: Is hedgehog binding and hedgehog antagonism by human GPC3 demonstrated with endogenous protein in human cells, given that the defining in vivo data are from mouse?
Q: Is inhibition of DPP4/CD26 peptidase activity by GPC3 reproducible and physiologically relevant, and should GO add a dipeptidyl-peptidase inhibitor activity term distinct from the C-terminal peptidyl-dipeptidase inhibitor term currently used?
Experiment: Measure Shh binding, Shh internalization and GLI reporter activity in human cells with CRISPR knockout of endogenous GPC3, rescued with wild-type or convertase-resistant (RR-AA) GPC3, to establish hedgehog antagonism for the human protein directly.
Experiment: Quantify DPP4 enzyme kinetics with purified GPC3 alpha/beta heterodimer and core protein, and test DPP4 activity in GPC3-knockout versus wild-type HCC cells.
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