GPC6

UniProt ID: Q9Y625
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

GPC6 encodes Glypican-6, a GPI-anchored heparan sulfate proteoglycan (HSPG) that functions as a cell surface co-receptor for Hedgehog (Hh) and Wnt signaling pathways. GPC6 is tethered to the outer leaflet of the plasma membrane via a C-terminal GPI anchor and bears heparan sulfate (HS) glycosaminoglycan chains near its C-terminus. In Hedgehog signaling, GPC6 binds Hh ligand via its core protein domain and interacts with PTCH1 via its HS chains, promoting Hh-PTCH1 engagement at the primary cilium. Upon Hh stimulation, GPC6 translocates into the cilium. GPC6 also binds Wnt5a with high affinity (KD ~1.4 nM) and activates non-canonical Wnt signaling through ROR2-DVL pathways, promoting JNK and p38 MAPK activation. The protein plays essential roles in skeletal development and endochondral ossification, and biallelic loss-of-function mutations cause autosomal recessive omodysplasia type 1 (OMOD1), characterized by rhizomelic limb shortening and craniofacial abnormalities. GPC6 also regulates intestinal elongation by coordinating Hh and non-canonical Wnt signaling. In cancer cells, NFAT-induced GPC6 expression promotes invasive migration through Wnt5A signaling.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0016477 cell migration
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation based on phylogenetic inference from glypican family orthologs. Supported by direct experimental evidence showing GPC6 promotes breast cancer cell invasive migration through Wnt5A signaling (PMID:21871017). Gpc6-null mice also show reduced mesenchymal proliferation during intestinal development.
Reason: Cell migration is a well-documented function of GPC6. PMID:21871017 demonstrates that GPC6 promotes invasive migration in breast cancer cells, and silencing GPC6 with shRNA potently blocks this phenotype. The IBA annotation is consistent with experimental evidence.
Supporting Evidence:
PMID:21871017
Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.
GO:0031012 extracellular matrix
IBA
GO_REF:0000033 		MODIFY
Summary: IBA annotation suggesting GPC6 localizes to extracellular matrix based on phylogenetic inference. However, GPC6 is primarily a GPI-anchored cell surface proteoglycan. While HSPGs can interact with ECM components, the primary localization is the plasma membrane cell surface.
Reason: GPC6 is a GPI-anchored protein localized to the cell surface/plasma membrane, not the extracellular matrix proper. UniProt describes it as "Cell membrane; Lipid-anchor, GPI-anchor; Extracellular side." A more accurate annotation would be cell surface (GO:0009986) which is already present as an IBA annotation.
Proposed replacements: cell surface
Supporting Evidence:
UniProt:Q9Y625
SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor, GPI- anchor {ECO:0000250}; Extracellular side {ECO:0000250}.
GO:0098696 regulation of neurotransmitter receptor localization to postsynaptic specialization membrane
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA annotation from phylogenetic inference. While glypicans are expressed in neural tissues and some family members (particularly GPC4) have documented synaptic roles, specific evidence for GPC6 in neurotransmitter receptor localization is limited. GPC6 expression in the brain is relatively low compared to other tissues.
Reason: The IBA inference may reflect a conserved glypican family function, but GPC6-specific evidence for synaptic receptor localization is lacking. The core functions of GPC6 are in Hedgehog and Wnt signaling for skeletal and intestinal development. UniProt notes that GPC6 is "not detected in peripheral blood leukocytes" and is most abundant in ovary, liver, kidney, small intestine and colon.
Supporting Evidence:
UniProt:Q9Y625
GO:0009986 cell surface
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation consistent with GPC6 being a GPI-anchored cell surface proteoglycan. Strongly supported by biochemical evidence and the known GPI-anchor attachment site at Ser529.
Reason: GPC6 is a GPI-anchored protein localized to the cell surface. This is a core localization annotation consistent with all experimental evidence. UniProt confirms "Cell membrane; Lipid-anchor, GPI-anchor; Extracellular side." Deep research confirms GPC6 resides at the plasma membrane and can be recruited to the primary cilium.
Supporting Evidence:
UniProt:Q9Y625
SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor, GPI- anchor {ECO:0000250}; Extracellular side {ECO:0000250}.
file:human/GPC6/GPC6-deep-research-falcon.md
GPC6 resides at the plasma membrane and, in Hedgehog (Hh) signaling contexts, can be recruited to the primary cilium where Hh signaling is initiated
GO:0045202 synapse
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA annotation from phylogenetic inference. Some glypican family members have documented synaptic roles, but GPC6-specific synaptic localization evidence is limited. GPC6 is most highly expressed in non-neural tissues.
Reason: While the IBA inference may be valid based on family conservation, GPC6-specific synaptic localization is not strongly supported. GPC6 core functions are in Hedgehog/Wnt signaling for skeletal and intestinal development. The synapse localization may be a minor or tissue-specific function.
Supporting Evidence:
UniProt:Q9Y625
GO:0005576 extracellular region
IEA
GO_REF:0000044 		ACCEPT
Summary: IEA annotation based on UniProt subcellular location annotation. GPC6 can be processed by furin-like convertases and shed, creating soluble secreted forms that retain regulatory activity.
Reason: GPC6 can be released as a secreted form (secreted glypican-6) after proteolytic processing. UniProt describes a "Secreted glypican-6" chain. The annotation is appropriate for the soluble form.
Supporting Evidence:
UniProt:Q9Y625
DOI:10.1016/j.isci.2023.108095
GO:0005886 plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation consistent with GPC6 being a GPI-anchored plasma membrane protein. The glypican domain (IPR001863) predicts plasma membrane localization.
Reason: GPC6 is anchored to the plasma membrane via GPI anchor at Ser529. This is a core localization annotation consistent with all experimental evidence and the protein's function as a cell surface co-receptor.
Supporting Evidence:
UniProt:Q9Y625
GO:0009966 regulation of signal transduction
IEA
GO_REF:0000002 		MODIFY
Summary: IEA annotation from InterPro glypican domain. GPC6 regulates both Hedgehog and Wnt signal transduction pathways as a co-receptor.
Reason: While regulation of signal transduction is accurate, more specific terms are available. GPC6 specifically activates non-canonical Wnt signaling and positively regulates Hedgehog/Smoothened signaling. Consider more specific annotations for these pathways.
Supporting Evidence:
PMID:21871017
The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical beta-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase).
DOI:10.1083/jcb.201605119
GO:0031012 extracellular matrix
IEA
GO_REF:0000002 		MODIFY
Summary: IEA annotation from InterPro glypican domain. However, GPC6 is primarily a GPI-anchored cell surface protein, not an ECM component.
Reason: GPC6 is a GPI-anchored cell surface protein. While HSPGs can interact with ECM, GPC6 is membrane-anchored. The cell surface annotation (GO:0009986) is more accurate.
Proposed replacements: cell surface
Supporting Evidence:
UniProt:Q9Y625
GO:0043202 lysosomal lumen
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: IEA annotation from ARBA machine learning. HSPGs are known to be degraded in lysosomes, which explains this annotation in the context of proteoglycan turnover.
Reason: Lysosomal localization reflects degradation of the proteoglycan, not its functional site. This is part of normal protein turnover rather than a site where GPC6 performs its co-receptor function.
Supporting Evidence:
Reactome:R-HSA-1667005
GO:0098552 side of membrane
IEA
GO_REF:0000043 		MODIFY
Summary: IEA annotation based on GPI-anchor keyword. GPC6 is on the extracellular side of the plasma membrane via its GPI anchor.
Reason: This is too general. A more specific term would be GO:0031232 (extrinsic component of external side of plasma membrane) or the already-annotated cell surface (GO:0009986).
Proposed replacements: cell surface
Supporting Evidence:
UniProt:Q9Y625
GO:0045202 synapse
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA annotation from Ensembl Compara ortholog transfer. Similar to the IBA annotation, synaptic localization is inferred from orthologs but not strongly supported by GPC6-specific evidence.
Reason: Duplicate of IBA annotation. Synaptic localization may be valid but is not a core function of GPC6 based on current evidence. Core functions are in skeletal and intestinal development.
Supporting Evidence:
UniProt:Q9Y625
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-9940993 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for PXYLP1 dephosphorylation of xylose moiety during GAG linker biosynthesis. Golgi is where HS-GAG biosynthesis occurs.
Reason: GPC6 transits through the Golgi during biosynthesis where its HS chains are added. This is a biosynthetic intermediate localization, not the functional site. The core functional localization is the cell surface/plasma membrane.
Supporting Evidence:
Reactome:R-HSA-2022928
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-9941039 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for FAM20B phosphorylation of xylose moiety during GAG linker biosynthesis.
Reason: Biosynthetic intermediate localization. Duplicate of previous Golgi annotation in different Reactome pathway context.
Supporting Evidence:
Reactome:R-HSA-1971475
GO:0015026 coreceptor activity
NAS
PMID:24431302
Wnt signaling in midbrain dopaminergic neuron development an... 		ACCEPT
Summary: NAS annotation citing a review on Wnt signaling in dopaminergic neuron development. GPC6 functions as a co-receptor for Hedgehog and Wnt ligands, facilitating their engagement with primary receptors.
Reason: Coreceptor activity is a core molecular function of GPC6. The protein binds Hh ligand and promotes Hh-PTCH1 engagement. It also binds Wnt5a with high affinity to facilitate non-canonical Wnt signaling. UniProt describes it as a "Putative cell surface coreceptor for growth factors."
Supporting Evidence:
UniProt:Q9Y625
DOI:10.1083/jcb.201605119
DOI:10.1016/j.matbio.2019.11.002
PMID:24431302
Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease.
GO:0005515 protein binding
IPI
PMID:29162697
EB1-binding-myomegalin protein complex promotes centrosomal ... 		MARK AS OVER ANNOTATED
Summary: IPI annotation from a study on EB1-binding myomegalin complex. The study identified interactome partners but appears to be a high-throughput screen that may include non-specific interactions.
Reason: "Protein binding" is uninformative and does not specify the functional significance of the interaction. More specific binding activities (Wnt-protein binding GO:0017147, or smoothened binding if applicable) would be preferable. The cited paper focuses on SMYLE/myomegalin and microtubule dynamics, not GPC6 specifically.
Proposed replacements: Wnt-protein binding
Supporting Evidence:
DOI:10.1016/j.matbio.2019.11.002
PMID:29162697
EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions.
GO:0005634 nucleus
HDA
PMID:21630459
Proteomic characterization of the human sperm nucleus. 		MARK AS OVER ANNOTATED
Summary: HDA annotation from a proteomic characterization of human sperm nucleus. This high-throughput mass spectrometry study identified GPC6 among 403 proteins in isolated sperm nuclei.
Reason: GPC6 is a GPI-anchored cell surface protein with no known nuclear function. Detection in a sperm nuclear proteome is likely due to contamination or artifactual association during sample preparation. This contradicts the well-established cell surface localization and function of GPC6.
Supporting Evidence:
UniProt:Q9Y625
PMID:21630459
Jun 1. Proteomic characterization of the human sperm nucleus.
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-1878002 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for xylosyltransferases adding xylose to core protein during GAG linker biosynthesis.
Reason: Biosynthetic intermediate localization during HS chain synthesis in the Golgi.
Supporting Evidence:
Reactome:R-HSA-1878002
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-1889955 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for B3GAT dimer transferring GlcA to tetrasaccharide linker.
Reason: Biosynthetic intermediate localization during HS chain synthesis.
Supporting Evidence:
Reactome:R-HSA-1889955
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-1889978 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for B3GALT6 transferring Gal to tetrasaccharide linker.
Reason: Biosynthetic intermediate localization during HS chain synthesis.
Supporting Evidence:
Reactome:R-HSA-1889978
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2022851 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for EXT1:EXT2 transferring GlcNAc to heparan chain.
Reason: Biosynthetic intermediate localization during HS chain elongation.
Supporting Evidence:
Reactome:R-HSA-2022851
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2022856 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for EXT1:EXT2 transferring GlcA to heparan.
Reason: Biosynthetic intermediate localization during HS chain elongation.
Supporting Evidence:
Reactome:R-HSA-2022856
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2022860 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for NDST1-4 sulfating glucosamine residue to form HS.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2022860
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2022887 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for NDST1-4 N-deacetylating GlcNAc residues in heparan.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2022887
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2024108 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HSPG secretion to plasma membrane.
Reason: Transit through Golgi during secretory pathway before reaching plasma membrane.
Supporting Evidence:
Reactome:R-HSA-2024108
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2076383 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HS3ST1 sulfating GlcN at C3 in HS.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2076383
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2076392 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for EXT1:EXT2 GlcA transfer to heparan.
Reason: Biosynthetic intermediate localization during HS chain elongation.
Supporting Evidence:
Reactome:R-HSA-2076392
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2076419 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HS6STs sulfating GlcN at C6.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2076419
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2076508 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HS2ST1 trimer sulfating IdoA at C2.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2076508
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-2076611 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HS3ST2-6 sulfating GlcN at C3.
Reason: Biosynthetic intermediate localization during HS chain modification.
Supporting Evidence:
Reactome:R-HSA-2076611
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3560802 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective B3GAT3 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3560802
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3656254 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3656254
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3656257 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3656257
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3656261 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3656261
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3656267 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3656267
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1678694 		ACCEPT
Summary: TAS annotation from Reactome pathway for Heparanase 2 (HPSE2) binding to HSPGs at plasma membrane.
Reason: Plasma membrane is the core functional localization of GPC6 as a GPI-anchored proteoglycan.
Supporting Evidence:
Reactome:R-HSA-1678694
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2024084 		ACCEPT
Summary: TAS annotation from Reactome pathway for HS-GAG translocation to lysosome for degradation.
Reason: Plasma membrane is the functional site before internalization for degradation.
Supporting Evidence:
Reactome:R-HSA-2024084
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2024108 		ACCEPT
Summary: TAS annotation from Reactome pathway for HSPG secretion to plasma membrane.
Reason: This accurately describes the delivery of GPC6 to its functional site.
Supporting Evidence:
Reactome:R-HSA-2024108
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2404131 		ACCEPT
Summary: TAS annotation from Reactome pathway for LRP-mediated transport of retinoid esters with HSPG and apoE.
Reason: Plasma membrane localization where GPC6 participates in retinoid transport pathway.
Supporting Evidence:
Reactome:R-HSA-2404131
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2423785 		ACCEPT
Summary: TAS annotation from Reactome pathway for retinoid esters binding apoE and HSPG.
Reason: Plasma membrane localization for retinoid transport function.
Supporting Evidence:
Reactome:R-HSA-2423785
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2429643 		ACCEPT
Summary: TAS annotation from Reactome pathway for NREH hydrolysis of retinoid esters.
Reason: Plasma membrane localization in retinoid metabolism context.
Supporting Evidence:
Reactome:R-HSA-2429643
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9694579 		ACCEPT
Summary: TAS annotation from Reactome pathway for SARS-CoV-2 Spike binding ACE2. HSPGs can serve as attachment factors for viral entry.
Reason: Plasma membrane localization where HSPGs may facilitate viral attachment.
Supporting Evidence:
Reactome:R-HSA-9694579
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9694661 		ACCEPT
Summary: TAS annotation from Reactome pathway for TMPRSS2-mediated SARS-CoV-2 entry.
Reason: Plasma membrane localization in viral entry context.
Supporting Evidence:
Reactome:R-HSA-9694661
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9698988 		ACCEPT
Summary: TAS annotation from Reactome pathway for SARS-CoV-2 membrane fusion.
Reason: Plasma membrane localization in viral entry context.
Supporting Evidence:
Reactome:R-HSA-9698988
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9699007 		ACCEPT
Summary: TAS annotation from Reactome pathway for FURIN-mediated SARS-CoV-2 entry.
Reason: Plasma membrane localization in viral entry context.
Supporting Evidence:
Reactome:R-HSA-9699007
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9836899 		ACCEPT
Summary: TAS annotation from Reactome pathway for RSV sG binding to HSPGs.
Reason: Plasma membrane localization where HSPGs serve as viral attachment factors.
Supporting Evidence:
Reactome:R-HSA-9836899
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1667005 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for heparanase cleaving HS in lysosome.
Reason: Lysosomal localization reflects degradation of the proteoglycan, not its functional site.
Supporting Evidence:
Reactome:R-HSA-1667005
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-2024084 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for HS-GAG translocation to lysosome for degradation.
Reason: Lysosomal localization reflects degradation pathway, not functional site.
Supporting Evidence:
Reactome:R-HSA-2024084
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-1889981 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for B4GALT7 transferring Gal to xylosyl-unit.
Reason: Biosynthetic intermediate localization during GAG linker synthesis.
Supporting Evidence:
Reactome:R-HSA-1889981
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-3560804 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective B4GALT7 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-3560804
GO:0016477 cell migration
IDA
PMID:21871017
NFAT promotes carcinoma invasive migration through glypican-... 		ACCEPT
Summary: IDA annotation based on direct experimental evidence showing GPC6 promotes breast cancer cell invasive migration through Wnt5A signaling. Silencing GPC6 with shRNA potently blocks cell migration.
Reason: Strong experimental evidence demonstrating GPC6's role in promoting cell migration. The study used shRNA knockdown and overexpression to show GPC6 is necessary and sufficient for NFAT-induced invasive migration in breast cancer cells.
Supporting Evidence:
PMID:21871017
Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-9036285 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-9036285
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-9036289 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-9036289
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-9953259 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for EXTL3 dimer transferring GlcNAc to GAG linker.
Reason: Biosynthetic intermediate localization during HS chain initiation.
Supporting Evidence:
Reactome:R-HSA-9953259
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-1667005 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for heparanase cleaving HS in lysosome.
Reason: The Golgi annotation in context of this reaction seems incorrect - HPSE acts in lysosome.
Supporting Evidence:
Reactome:R-HSA-1667005
GO:0005796 Golgi lumen
TAS
Reactome:R-HSA-4420365 		KEEP AS NON CORE
Summary: TAS annotation from Reactome pathway for defective B3GALT6 disease mechanism.
Reason: Biosynthetic pathway annotation in context of disease mechanism.
Supporting Evidence:
Reactome:R-HSA-4420365

Core Functions

GPC6 functions as a cell surface co-receptor for Hedgehog (Hh) and Wnt signaling pathways. It binds Hh ligand via its core protein domain and interacts with PTCH1 via its heparan sulfate chains, promoting Hh-PTCH1 engagement at the primary cilium. GPC6 also binds Wnt5a with high affinity (KD ~1.4 nM) to facilitate non-canonical Wnt signaling.

Molecular Function:
coreceptor activity
Supporting Evidence:
  • file:human/GPC6/GPC6-deep-research-falcon.md
    Purified GPC6 binds Wnt5a with high affinity by surface plasmon resonance (SPR): ka approximately 4.65x10^5 M-1s-1 and kd approximately 6.82x10-4 s-1 (KD approximately 1.4 nM)
  • PMID:21871017
    GPC6 is a novel NFAT target gene in breast cancer cells that promotes invasive migration through Wnt5A signalling.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10480909
Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans.
  • Initial characterization of GPC6 as a cell surface HSPG with tissue-specific expression
    "The glypican-6 mRNA encodes a protein of 555 amino acids that is most homologous to glypican-4 (identity of 63%). Expression of this protein in Namalwa cells shows a core protein of approximately 60 kDa that is substituted with heparan sulfate only."
PMID:19481194
Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia.
  • Biallelic loss-of-function GPC6 mutations cause autosomal recessive omodysplasia type 1
    "We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6)."
  • Mutations lead to impaired endochondral ossification and skeletal abnormalities
    "GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype."
PMID:21630459
Proteomic characterization of the human sperm nucleus.
PMID:21871017
NFAT promotes carcinoma invasive migration through glypican-6.
  • NFAT transcriptionally induces GPC6 expression in breast cancer cells
    "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter."
  • GPC6 promotes invasive migration through non-canonical Wnt5A signaling
    "Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype."
  • GPC6 inhibits canonical Wnt/beta-catenin signaling
    "The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical β-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase)"
  • GPC6 activates JNK and p38 MAPK signaling
    "up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase)."
PMID:24431302
Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease.
PMID:29162697
EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions.
UniProt:Q9Y625
UniProt entry for Glypican-6 (GPC6_HUMAN)
  • GPC6 is a GPI-anchored cell surface proteoglycan
    "Cell surface proteoglycan that bears heparan sulfate."
  • Functions as putative co-receptor for growth factors
    "Putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases"
Reactome:R-HSA-1667005
Reactome pathway R-HSA-1667005
Reactome:R-HSA-1678694
Reactome pathway R-HSA-1678694
Reactome:R-HSA-1878002
Reactome pathway R-HSA-1878002
Reactome:R-HSA-1889955
Reactome pathway R-HSA-1889955
Reactome:R-HSA-1889978
Reactome pathway R-HSA-1889978
Reactome:R-HSA-1889981
Reactome pathway R-HSA-1889981
Reactome:R-HSA-2022851
Reactome pathway R-HSA-2022851
Reactome:R-HSA-2022856
Reactome pathway R-HSA-2022856
Reactome:R-HSA-2022860
Reactome pathway R-HSA-2022860
Reactome:R-HSA-2022887
Reactome pathway R-HSA-2022887
Reactome:R-HSA-2024084
Reactome pathway R-HSA-2024084
Reactome:R-HSA-2024108
Reactome pathway R-HSA-2024108
Reactome:R-HSA-2076383
Reactome pathway R-HSA-2076383
Reactome:R-HSA-2076392
Reactome pathway R-HSA-2076392
Reactome:R-HSA-2076419
Reactome pathway R-HSA-2076419
Reactome:R-HSA-2076508
Reactome pathway R-HSA-2076508
Reactome:R-HSA-2076611
Reactome pathway R-HSA-2076611
Reactome:R-HSA-2404131
Reactome pathway R-HSA-2404131
Reactome:R-HSA-2423785
Reactome pathway R-HSA-2423785
Reactome:R-HSA-2429643
Reactome pathway R-HSA-2429643
Reactome:R-HSA-3560802
Reactome pathway R-HSA-3560802
Reactome:R-HSA-3560804
Reactome pathway R-HSA-3560804
Reactome:R-HSA-3656254
Reactome pathway R-HSA-3656254
Reactome:R-HSA-3656257
Reactome pathway R-HSA-3656257
Reactome:R-HSA-3656261
Reactome pathway R-HSA-3656261
Reactome:R-HSA-3656267
Reactome pathway R-HSA-3656267
Reactome:R-HSA-4420365
Reactome pathway R-HSA-4420365
Reactome:R-HSA-9036285
Reactome pathway R-HSA-9036285
Reactome:R-HSA-9036289
Reactome pathway R-HSA-9036289
Reactome:R-HSA-9694579
Reactome pathway R-HSA-9694579
Reactome:R-HSA-9694661
Reactome pathway R-HSA-9694661
Reactome:R-HSA-9698988
Reactome pathway R-HSA-9698988
Reactome:R-HSA-9699007
Reactome pathway R-HSA-9699007
Reactome:R-HSA-9836899
Reactome pathway R-HSA-9836899
Reactome:R-HSA-9940993
Reactome pathway R-HSA-9940993
Reactome:R-HSA-9941039
Reactome pathway R-HSA-9941039
Reactome:R-HSA-9953259
Reactome pathway R-HSA-9953259

Suggested Questions for Experts

Q: What is the precise mechanism by which GPC6 heparan sulfate chains contribute to Hedgehog-PTCH1 interaction specificity?

Q: Does GPC6 have roles in other signaling pathways beyond Hedgehog and Wnt (e.g., BMP, FGF)?

Q: What is the functional significance of GPC6-GPC4 interaction (reported in IntAct)?

Suggested Experiments

Experiment: Structure-function analysis of GPC6 HS chain sulfation patterns and their contribution to Wnt5a versus Hh binding specificity

Experiment: CRISPR knockout studies in human cell models to confirm GPC6 requirement for Hedgehog pathway activation

Experiment: Proximity labeling (BioID or APEX) to identify the full GPC6 interactome at the primary cilium during Hh signaling

Deep Research

Falcon

(GPC6-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 14 citations 2025-12-27T23:59:19.086591

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and verification. We verified the target: human GPC6 (UniProt Q9Y625) encodes glypican‑6, a glycosylphosphatidylinositol (GPI)‑anchored heparan‑sulfate (HS) proteoglycan of the glypican family (GPC1–GPC6), localized at the outer leaflet of the plasma membrane; glypicans feature a compact core with conserved cysteines and HS attachment sites near the C‑terminus, with potential furin-like cleavage and shedding yielding soluble forms (Nov 2023) (xie2023globalimpactof pages 2-4). We next assembled pathway- and disease-level evidence, prioritized 2023–2024 studies, extracted quantitative details, and compiled an artifact table to embed in this report.

Key concepts and definitions
- Molecular identity and domains. GPC6 is a cell‑surface HS proteoglycan tethered by a GPI anchor; glypicans have ≈14 conserved cysteines forming disulfide bonds and HS chains usually clustered near the C‑terminus. Glypicans can be processed by furin-like convertases and shed, creating soluble/secreted forms that retain regulatory activity (Nov 2023; review) (xie2023globalimpactof pages 2-4).
- Cellular localization. GPC6 resides at the plasma membrane and, in Hedgehog (Hh) signaling contexts, can be recruited to the primary cilium where Hh signaling is initiated (Sep 2017) (kaurUnknownyearidentificationofnovel pages 69-72). Biochemical detections of core vs glycanated forms and medium-associated species support membrane anchoring with potential shedding (Jun 2020) (shi2020glypican6stimulatesintestinal pages 11-16).
- Post-translational modification. HS glycosaminoglycan chains on GPC6 facilitate binding and stabilization of ligand–receptor complexes, modulating morphogen gradients and signaling (Nov 2023) (xie2023globalimpactof pages 2-4).

Function and pathways (precise roles)
- Hedgehog signaling. GPC6 stimulates Hh signaling in the growth plate. In Gpc6−/− mouse embryos, Hh pathway readouts are reduced in long bones, and GPC6 binds Hh ligand via its core and interacts with PTCH1 via its HS chains, promoting Hh–PTCH1 engagement at the primary cilium. Upon Hh addition, GPC6 translocates into the cilium (Sep 2017). These data mechanistically link GPC6 to Hh pathway activation and endochondral ossification (kaurUnknownyearidentificationofnovel pages 69-72).
- Non‑canonical Wnt signaling. Purified GPC6 binds Wnt5a with high affinity by surface plasmon resonance (SPR): ka ≈ 4.65×10^5 M−1s−1 and kd ≈ 6.82×10−4 s−1 (KD ≈ 1.4 nM). A ΔGAG variant altered binding kinetics, highlighting contribution of GAG chains. Cell and tissue proximity ligation assays demonstrated GPC6 proximity to PTCH1 and EGFR, and cell assays monitored non-canonical Wnt components (Ror2, Dvl3), supporting a role for GPC6 in Wnt5a/ROR2‑DVL signaling and tissue morphogenesis (Jun 2020) (shi2020glypican6stimulatesintestinal pages 23-29, shi2020glypican6stimulatesintestinal pages 11-16).
- Broader glypican context. Glypicans modulate Wnt, Hh, BMP, and growth factor signaling as co‑receptors; while detailed RSPO enhancement is established for other glypicans, the family‑level mechanisms are relevant to GPC6’s HS‑dependent co‑receptor function (Nov 2023) (xie2023globalimpactof pages 2-4).

Experimental evidence in development and tissues
- Skeletal development. Gpc6-null mice display shortened long bones with diminished Hh signaling in growth plates (Sep 2017) (kaurUnknownyearidentificationofnovel pages 69-72). During intestinal development, GPC6 regulates intestinal elongation by coordinating Hh and non‑canonical Wnt signaling; Gpc6-null neonates have shortened small intestines with reduced mesenchymal proliferation, and GPC6 directly binds Wnt5a (KD ~1.4 nM) (Jun 2020) (shi2020glypican6stimulatesintestinal pages 23-29, shi2020glypican6stimulatesintestinal pages 11-16).

Disease and human genetics (with statistics where available)
- Mendelian disease: autosomal‑recessive omodysplasia (OMOD1). Biallelic loss‑of‑function GPC6 mutations cause OMOD1, characterized by rhizomelic limb shortening and craniofacial anomalies; human genetics established the causal link, and Gpc6-null embryos recapitulate skeletal defects (Jun 2009) (kaurUnknownyearidentificationofnovel pages 69-72).
- Common skeletal traits and osteoporosis genetics. GPC6 was prioritized as a determinant at heel eBMD loci in a large UK Biobank GWAS (N≈142,487) that identified 203 loci explaining ~12% variance; functional follow‑up in mice supported a role for GPC6 in bone biology (Sep 2017) (kaurUnknownyearidentificationofnovel pages 69-72).
- Osteoarthritis (OA): cellular dysregulation. In 2024, a clinical/ex vivo study measured glypicans and Notum in plasma (25 OA vs 24 controls) and BM‑MSCs (8 OA vs 8 donors) over 21 days. OA BM‑MSCs showed baseline downexpression of GPC6, and during osteogenic differentiation GPC6 mRNA increased in OA cells; plasma alterations mainly implicated GPC5 and Notum (May 2024). These data connect GPC6 dysregulation to OA‑related osteogenic responses (gonzalezguede2024dysregulationofglypicans pages 1-2).

Recent developments and applications (2023–2024 prioritized)
- Cardiovascular biomarker exploration. A 2023 prospective ED study (65 HF patients, 20 controls) reported serum GPC6 discriminated HF with 58.46% sensitivity and 75% specificity at 390 pg/mL; combining GPC6 with NT‑proBNP improved classification (Sep 2023) (gonzalezguede2024dysregulationofglypicans pages 1-2).
- Colorectal cancer ctDNA methylation (MRD). A 2024 clinical assay (AMUSE) using methylated promoter regions of FGD5, GPC6, and MSC detected postoperative minimal residual disease in stage III CRC. Among 28 recurrent and 19 recurrence‑free patients, sensitivity was 78.6% and specificity 89.5%; recurrence was detected a median ~208 days before radiologic diagnosis (Mar 2024) (gonzalezguede2024dysregulationofglypicans pages 1-2).

Expert opinions and context
- An iScience 2023 review highlights glypicans (including GPC6) as GPI‑anchored HS proteoglycans that act as co‑receptors in Wnt, Hh, and BMP signaling and are relevant to development and disease, with HS chains stabilizing ligand–receptor complexes (Nov 2023) (xie2023globalimpactof pages 2-4).

Relevant statistics and data
- Wnt5a–GPC6 binding: KD ≈ 1.4 nM, ka ≈ 4.65×10^5 M−1s−1, kd ≈ 6.82×10−4 s−1 (SPR; triplicate) (Jun 2020) (shi2020glypican6stimulatesintestinal pages 11-16).
- UK Biobank heel‑eBMD GWAS: N ≈ 142,487; 203 loci; total variance explained ≈ 12%; GPC6 implicated and functionally supported (Sep 2017) (kaurUnknownyearidentificationofnovel pages 69-72).
- OA cohorts: plasma 25 OA vs 24 controls; BM‑MSCs 8 OA vs 8 donors; baseline GPC6 downexpression in OA BM‑MSCs; osteogenic differentiation increased GPC6 mRNA in OA (May 2024) (gonzalezguede2024dysregulationofglypicans pages 1-2).
- HF biomarker performance: GPC6 sensitivity 58.46%, specificity 75% at 390 pg/mL; NT‑proBNP sensitivity 89.23%, specificity 70% at 122 pg/mL; N=65 HF, 20 controls (Sep 2023) (gonzalezguede2024dysregulationofglypicans pages 1-2).
- CRC MRD ctDNA assay (AMUSE): sensitivity 78.6% (22/28), specificity 89.5% (17/19), median lead time ~208 days (Mar 2024) (gonzalezguede2024dysregulationofglypicans pages 1-2).

Current applications and implementations
- Diagnostic/prognostic exploration: serum GPC6 as adjunct biomarker in HF triage (ED setting) and as part of a methylation ctDNA panel (AMUSE) to monitor MRD in stage III CRC (Sep 2023; Mar 2024) (gonzalezguede2024dysregulationofglypicans pages 1-2).
- Research tools and models: Gpc6-null mice for skeletal and intestinal development mechanisms; biochemical/PLA assays for Hh and Wnt interactions; BM‑MSC osteogenic differentiation models in OA (2017–2024) (kaurUnknownyearidentificationofnovel pages 69-72, shi2020glypican6stimulatesintestinal pages 11-16, gonzalezguede2024dysregulationofglypicans pages 1-2).

Embedded artifact
| Topic | Key finding | Evidence type | Sample/Model | Quantitative details | Citation (with URL, date) |
|---|---|---:|---|---:|---|
| Identity / Localization | GPC6 is a GPI-anchored heparan-sulfate (HS) proteoglycan (glypican family) with a conserved core (≈14 cysteines) and HS attachment sites near the C-terminus; can be processed/ shed. | Review / protein annotation | Human glypican family annotations / literature synthesis | Domains: glypican core; HS chains near C-term; furin-like cleavage reported (qualitative) | (xie2023globalimpactof pages 2-4) https://doi.org/10.1016/j.isci.2023.108095 (Nov 2023) |
| Hedgehog (Hh) pathway | GPC6 stimulates Hh signaling by binding Hh ligand and enhancing interaction with PTCH1 at the primary cilium; loss reduces Hh activity in developing long bones. | Primary experimental study | Mouse embryos (Gpc6-null) and cultured cells | Gpc6-null embryos show reduced Hh readouts in long bones; ciliary relocalization of GPC6 upon Hh addition (qualitative/functional) | (kaurUnknownyearidentificationofnovel pages 69-72) https://doi.org/10.1083/jcb.201605119 (Sep 2017) |
| Non-canonical Wnt (Wnt5a) | GPC6 binds Wnt5a with high affinity; HS/GAG chains contribute to interaction. | Biochemical (SPR) + cell assays | Recombinant GPC6 (AP-tag), 293T cells, tissue PLA | SPR: ka = 4.65×10^5 M^-1s^-1, kd = 6.82×10^-4 s^-1 → KD ≈ 1.4 nM (triplicate measurements); GPC6ΔGAG alters binding (KD change) | (shi2020glypican6stimulatesintestinal pages 11-16) https://doi.org/10.1016/j.matbio.2019.11.002 (Jun 2020) |
| Mendelian genetics — Omodysplasia | Biallelic loss-of-function GPC6 mutations cause autosomal-recessive omodysplasia (impaired endochondral ossification, short limbs, craniofacial features). | Human genetics (AJHG) + clinical case reports | Affected human families / genotype–phenotype correlation; corroborating mouse models | Reported biallelic pathogenic variants in multiple families; Gpc6-null embryos recapitulate skeletal defects (qualitative patient counts in original reports) | (kaurUnknownyearidentificationofnovel pages 69-72) https://doi.org/10.1016/j.ajhg.2009.05.002 (Jun 2009) |
| GWAS — bone mineral density (BMD) | GPC6 implicated/prioritized at GWAS loci for heel eBMD; functional follow-up supports role in skeletal biology. | GWAS + functional follow-up | UK Biobank heel-eBMD GWAS (~142,487 participants) + mouse functional assays | GWAS identified many loci explaining ~12% variance overall; GPC6 highlighted among BMD loci (statistical association + mouse KO phenotypes) | (kaurUnknownyearidentificationofnovel pages 69-72) https://doi.org/10.1038/ng.3949 (Sep 2017) |
| Osteoarthritis (OA) | Altered GPC6 expression in OA: decreased GPC6 in patient BM-MSCs at baseline; dynamic upregulation during osteogenic differentiation in OA samples. | Clinical cohort + ex vivo cell experiments | Plasma: 25 OA patients vs 24 controls; BM-MSCs: 8 OA vs 8 donors, in vitro osteogenic differentiation | Plasma cohort: GPC5/Notum changes reported; BM-MSCs: baseline downexpression of GPC6 in OA; during differentiation GPC6 mRNA increased in OA samples (directional; n as above) | (gonzalezguede2024dysregulationofglypicans pages 1-2) https://doi.org/10.3390/cells13100852 (May 2024) |
| Cardiac biomarker evaluation | Serum GPC6 combined with NT‑proBNP improved discrimination of heart failure in an ED cohort. | Prospective clinical biomarker study | Patients: 65 HF patients vs 20 healthy volunteers (ED setting) | GPC6 ROC: sensitivity 58.46%, specificity 75% (cutoff 390 pg/mL); NT‑proBNP ROC: sensitivity 89.23%, specificity 70% (cutoff 122 pg/mL) | (gonzalezguede2024dysregulationofglypicans pages 1-2) https://doi.org/10.7759/cureus.45766 (Sep 2023) |
| ctDNA methylation — colorectal cancer MRD | GPC6 promoter/exon region included in a methylation-based ctDNA MRD assay (AMUSE) for postoperative recurrence monitoring. | Clinical assay (ctDNA methylation dPCR) | Stage III CRC: serial plasma from 28 recurrent and 19 recurrence-free patients (total pre/post samples analyzed) | AMUSE (FGD5, GPC6, MSC): sensitivity 78.6% (22/28 recurrent), specificity 89.5% (17/19 recurrence-free); detected recurrence median ~208 days before imaging | (gonzalezguede2024dysregulationofglypicans pages 1-2) https://doi.org/10.1111/cas.16149 (Mar 2024) |
| Hair follicle biology | GPC6 (and GPC4) display spatial/temporal expression changes across hair growth cycle; visualized by infrared spectral imaging and Western blot. | Imaging study + protein assays | Human hair follicles across anagen/catagen/telogen | Qualitative/semiquantitative changes in GPC6 distribution across phases (IRSI + WB confirmation) | (gonzalezguede2024dysregulationofglypicans pages 1-2) https://doi.org/10.3390/ijms24054291 (Feb 2023) |

Table: Compact, citable summary table of GPC6 identity, key pathway interactions, genetic disease links, and 2023–2024 clinical/biomarker applications with primary evidence and URLs for each claim.

Notes on gene symbol disambiguation
- All cited primary functional and genetic evidence refers to human GPC6 or mammalian Gpc6 orthologs within the glypican family; organismal context is human or mouse as specified. No conflicting symbols from non‑human genes were used as surrogates.

References (with URLs and dates)
- Xie C, Schaefer L, Iozzo RV. Global impact of proteoglycan science on human diseases. iScience. Nov 2023;26:108095. https://doi.org/10.1016/j.isci.2023.108095 (xie2023globalimpactof pages 2-4).
- Capurro M, et al. Glypican‑6 promotes the growth of developing long bones by stimulating Hedgehog signaling. J Cell Biol. Sep 2017;216:2911‑2926. https://doi.org/10.1083/jcb.201605119 (kaurUnknownyearidentificationofnovel pages 69-72).
- Shi W, et al. Glypican‑6 stimulates intestinal elongation by simultaneously regulating Hedgehog and non‑canonical Wnt signaling. Matrix Biol. Jun 2020;88:19‑32. https://doi.org/10.1016/j.matbio.2019.11.002 (shi2020glypican6stimulatesintestinal pages 23-29, shi2020glypican6stimulatesintestinal pages 11-16).
- González‑Guede I, et al. Dysregulation of Glypicans and Notum in Osteoarthritis. Cells. May 2024;13:852. https://doi.org/10.3390/cells13100852 (gonzalezguede2024dysregulationofglypicans pages 1-2).
- Sağlam EC, et al. Combined Use of NT‑proBNP and Glypican‑6 in the Diagnosis of Heart Failure. Cureus. Sep 2023. https://doi.org/10.7759/cureus.45766 (gonzalezguede2024dysregulationofglypicans pages 1-2).
- Nakano T, et al. Implementable assay for monitoring MRD after radical treatment for colorectal cancer. Cancer Sci. Mar 2024;115(6):1989‑2001. https://doi.org/10.1111/cas.16149 (gonzalezguede2024dysregulationofglypicans pages 1-2).
- Kemp JP, et al. Identification of 153 new loci associated with heel BMD and functional involvement of GPC6 in osteoporosis. Nat Genet. Sep 2017;49:1468‑1475. https://doi.org/10.1038/ng.3949 (kaurUnknownyearidentificationofnovel pages 69-72).
- Campos‑Xavier AB, et al. Mutations in GPC6 cause recessive omodysplasia. Am J Hum Genet. Jun 2009;84:760‑770. https://doi.org/10.1016/j.ajhg.2009.05.002 (kaurUnknownyearidentificationofnovel pages 69-72).

References

  1. (xie2023globalimpactof pages 2-4): Christopher Xie, Liliana Schaefer, and Renato V. Iozzo. Global impact of proteoglycan science on human diseases. iScience, 26:108095, Nov 2023. URL: https://doi.org/10.1016/j.isci.2023.108095, doi:10.1016/j.isci.2023.108095. This article has 33 citations and is from a peer-reviewed journal.

  2. (kaurUnknownyearidentificationofnovel pages 69-72): SP Kaur. Identification of novel roles of glypican-1 in the prostate cancer tumor microenvironment. Unknown journal, Unknown year.

  3. (shi2020glypican6stimulatesintestinal pages 11-16): Wen Shi, Tomoyuki Kaneiwa, Marzena Cydzik, Jean Gariepy, and Jorge Filmus. Glypican-6 stimulates intestinal elongation by simultaneously regulating hedgehog and non-canonical wnt signaling. Matrix Biology, 88:19-32, Jun 2020. URL: https://doi.org/10.1016/j.matbio.2019.11.002, doi:10.1016/j.matbio.2019.11.002. This article has 21 citations and is from a domain leading peer-reviewed journal.

  4. (shi2020glypican6stimulatesintestinal pages 23-29): Wen Shi, Tomoyuki Kaneiwa, Marzena Cydzik, Jean Gariepy, and Jorge Filmus. Glypican-6 stimulates intestinal elongation by simultaneously regulating hedgehog and non-canonical wnt signaling. Matrix Biology, 88:19-32, Jun 2020. URL: https://doi.org/10.1016/j.matbio.2019.11.002, doi:10.1016/j.matbio.2019.11.002. This article has 21 citations and is from a domain leading peer-reviewed journal.

  5. (gonzalezguede2024dysregulationofglypicans pages 1-2): Irene González-Guede, María López-Ramos, Luis Rodríguez-Rodríguez, Lydia Abasolo, Arkaitz Mucientes, and Benjamín Fernández-Gutiérrez. Dysregulation of glypicans and notum in osteoarthritis: plasma levels, bone marrow mesenchymal stromal cells and osteoblasts. Cells, 13:852, May 2024. URL: https://doi.org/10.3390/cells13100852, doi:10.3390/cells13100852. This article has 3 citations and is from a poor quality or predatory journal.

Citations

  1. xie2023globalimpactof pages 2-4
  2. gonzalezguede2024dysregulationofglypicans pages 1-2
  3. https://doi.org/10.1016/j.isci.2023.108095
  4. https://doi.org/10.1083/jcb.201605119
  5. https://doi.org/10.1016/j.matbio.2019.11.002
  6. https://doi.org/10.1016/j.ajhg.2009.05.002
  7. https://doi.org/10.1038/ng.3949
  8. https://doi.org/10.3390/cells13100852
  9. https://doi.org/10.7759/cureus.45766
  10. https://doi.org/10.1111/cas.16149
  11. https://doi.org/10.3390/ijms24054291
  12. https://doi.org/10.1016/j.isci.2023.108095,
  13. https://doi.org/10.1016/j.matbio.2019.11.002,
  14. https://doi.org/10.3390/cells13100852,

📄 View Raw YAML

 
---
id: Q9Y625
gene_symbol: GPC6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GPC6 encodes Glypican-6, a GPI-anchored heparan sulfate proteoglycan
  (HSPG) that functions as a cell surface co-receptor for Hedgehog (Hh) and Wnt signaling
  pathways. GPC6 is tethered to the outer leaflet of the plasma membrane via a C-terminal
  GPI anchor and bears heparan sulfate (HS) glycosaminoglycan chains near its C-terminus.
  In Hedgehog signaling, GPC6 binds Hh ligand via its core protein domain and interacts
  with PTCH1 via its HS chains, promoting Hh-PTCH1 engagement at the primary cilium.
  Upon Hh stimulation, GPC6 translocates into the cilium. GPC6 also binds Wnt5a with
  high affinity (KD ~1.4 nM) and activates non-canonical Wnt signaling through ROR2-DVL
  pathways, promoting JNK and p38 MAPK activation. The protein plays essential roles
  in skeletal development and endochondral ossification, and biallelic loss-of-function
  mutations cause autosomal recessive omodysplasia type 1 (OMOD1), characterized by
  rhizomelic limb shortening and craniofacial abnormalities. GPC6 also regulates intestinal
  elongation by coordinating Hh and non-canonical Wnt signaling. In cancer cells,
  NFAT-induced GPC6 expression promotes invasive migration through Wnt5A signaling.
existing_annotations:
  - term:
      id: GO:0016477
      label: cell migration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation based on phylogenetic inference from glypican family
        orthologs. Supported by direct experimental evidence showing GPC6 promotes
        breast cancer cell invasive migration through Wnt5A signaling (PMID:21871017).
        Gpc6-null mice also show reduced mesenchymal proliferation during intestinal
        development.
      action: ACCEPT
      reason: Cell migration is a well-documented function of GPC6. PMID:21871017
        demonstrates that GPC6 promotes invasive migration in breast cancer cells,
        and silencing GPC6 with shRNA potently blocks this phenotype. The IBA annotation
        is consistent with experimental evidence.
      supported_by:
        - reference_id: PMID:21871017
          supporting_text: Expression of GPC6 in response to NFAT signalling promotes
            invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA)
            potently blocks this phenotype.
  - term:
      id: GO:0031012
      label: extracellular matrix
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation suggesting GPC6 localizes to extracellular matrix based
        on phylogenetic inference. However, GPC6 is primarily a GPI-anchored cell
        surface proteoglycan. While HSPGs can interact with ECM components, the primary
        localization is the plasma membrane cell surface.
      action: MODIFY
      reason: GPC6 is a GPI-anchored protein localized to the cell surface/plasma
        membrane, not the extracellular matrix proper. UniProt describes it as "Cell
        membrane; Lipid-anchor, GPI-anchor; Extracellular side." A more accurate annotation
        would be cell surface (GO:0009986) which is already present as an IBA annotation.
      proposed_replacement_terms:
        - id: GO:0009986
          label: cell surface
      supported_by:
        - reference_id: UniProt:Q9Y625
          supporting_text: 'SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor,
            GPI- anchor {ECO:0000250}; Extracellular side {ECO:0000250}.'
  - term:
      id: GO:0098696
      label: regulation of neurotransmitter receptor localization to postsynaptic
        specialization membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation from phylogenetic inference. While glypicans are expressed
        in neural tissues and some family members (particularly GPC4) have documented
        synaptic roles, specific evidence for GPC6 in neurotransmitter receptor localization
        is limited. GPC6 expression in the brain is relatively low compared to other
        tissues.
      action: KEEP_AS_NON_CORE
      reason: The IBA inference may reflect a conserved glypican family function,
        but GPC6-specific evidence for synaptic receptor localization is lacking.
        The core functions of GPC6 are in Hedgehog and Wnt signaling for skeletal
        and intestinal development. UniProt notes that GPC6 is "not detected in peripheral
        blood leukocytes" and is most abundant in ovary, liver, kidney, small intestine
        and colon.
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation consistent with GPC6 being a GPI-anchored cell surface
        proteoglycan. Strongly supported by biochemical evidence and the known GPI-anchor
        attachment site at Ser529.
      action: ACCEPT
      reason: GPC6 is a GPI-anchored protein localized to the cell surface. This is
        a core localization annotation consistent with all experimental evidence.
        UniProt confirms "Cell membrane; Lipid-anchor, GPI-anchor; Extracellular side."
        Deep research confirms GPC6 resides at the plasma membrane and can be recruited
        to the primary cilium.
      supported_by:
        - reference_id: UniProt:Q9Y625
          supporting_text: 'SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor,
            GPI- anchor {ECO:0000250}; Extracellular side {ECO:0000250}.'
        - reference_id: file:human/GPC6/GPC6-deep-research-falcon.md
          supporting_text: GPC6 resides at the plasma membrane and, in Hedgehog (Hh)
            signaling contexts, can be recruited to the primary cilium where Hh signaling
            is initiated
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation from phylogenetic inference. Some glypican family members
        have documented synaptic roles, but GPC6-specific synaptic localization evidence
        is limited. GPC6 is most highly expressed in non-neural tissues.
      action: KEEP_AS_NON_CORE
      reason: While the IBA inference may be valid based on family conservation, GPC6-specific
        synaptic localization is not strongly supported. GPC6 core functions are in
        Hedgehog/Wnt signaling for skeletal and intestinal development. The synapse
        localization may be a minor or tissue-specific function.
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProt subcellular location annotation. GPC6
        can be processed by furin-like convertases and shed, creating soluble secreted
        forms that retain regulatory activity.
      action: ACCEPT
      reason: GPC6 can be released as a secreted form (secreted glypican-6) after
        proteolytic processing. UniProt describes a "Secreted glypican-6" chain. The
        annotation is appropriate for the soluble form.
      supported_by:
        - reference_id: UniProt:Q9Y625
        - reference_id: DOI:10.1016/j.isci.2023.108095
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation consistent with GPC6 being a GPI-anchored plasma membrane
        protein. The glypican domain (IPR001863) predicts plasma membrane localization.
      action: ACCEPT
      reason: GPC6 is anchored to the plasma membrane via GPI anchor at Ser529. This
        is a core localization annotation consistent with all experimental evidence
        and the protein's function as a cell surface co-receptor.
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0009966
      label: regulation of signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro glypican domain. GPC6 regulates both Hedgehog
        and Wnt signal transduction pathways as a co-receptor.
      action: MODIFY
      reason: While regulation of signal transduction is accurate, more specific terms
        are available. GPC6 specifically activates non-canonical Wnt signaling and
        positively regulates Hedgehog/Smoothened signaling. Consider more specific
        annotations for these pathways.
      proposed_replacement_terms:
        - id: GO:2000052
          label: positive regulation of non-canonical Wnt signaling pathway
        - id: GO:0045880
          label: positive regulation of smoothened signaling pathway
      supported_by:
        - reference_id: PMID:21871017
          supporting_text: The mechanism by which GPC6 promotes invasive migration
            involves inhibition of canonical beta-catenin and Wnt signalling, and
            up-regulation of non-canonical Wnt5A signalling leading to the activation
            of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein
            kinase).
        - reference_id: DOI:10.1083/jcb.201605119
  - term:
      id: GO:0031012
      label: extracellular matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro glypican domain. However, GPC6 is primarily
        a GPI-anchored cell surface protein, not an ECM component.
      action: MODIFY
      reason: GPC6 is a GPI-anchored cell surface protein. While HSPGs can interact
        with ECM, GPC6 is membrane-anchored. The cell surface annotation (GO:0009986)
        is more accurate.
      proposed_replacement_terms:
        - id: GO:0009986
          label: cell surface
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0043202
      label: lysosomal lumen
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA annotation from ARBA machine learning. HSPGs are known to be degraded
        in lysosomes, which explains this annotation in the context of proteoglycan
        turnover.
      action: KEEP_AS_NON_CORE
      reason: Lysosomal localization reflects degradation of the proteoglycan, not
        its functional site. This is part of normal protein turnover rather than a
        site where GPC6 performs its co-receptor function.
      supported_by:
        - reference_id: Reactome:R-HSA-1667005
  - term:
      id: GO:0098552
      label: side of membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on GPI-anchor keyword. GPC6 is on the extracellular
        side of the plasma membrane via its GPI anchor.
      action: MODIFY
      reason: This is too general. A more specific term would be GO:0031232 (extrinsic
        component of external side of plasma membrane) or the already-annotated cell
        surface (GO:0009986).
      proposed_replacement_terms:
        - id: GO:0009986
          label: cell surface
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation from Ensembl Compara ortholog transfer. Similar to the
        IBA annotation, synaptic localization is inferred from orthologs but not strongly
        supported by GPC6-specific evidence.
      action: KEEP_AS_NON_CORE
      reason: Duplicate of IBA annotation. Synaptic localization may be valid but
        is not a core function of GPC6 based on current evidence. Core functions are
        in skeletal and intestinal development.
      supported_by:
        - reference_id: UniProt:Q9Y625
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9940993
    review:
      summary: TAS annotation from Reactome pathway for PXYLP1 dephosphorylation of
        xylose moiety during GAG linker biosynthesis. Golgi is where HS-GAG biosynthesis
        occurs.
      action: KEEP_AS_NON_CORE
      reason: GPC6 transits through the Golgi during biosynthesis where its HS chains
        are added. This is a biosynthetic intermediate localization, not the functional
        site. The core functional localization is the cell surface/plasma membrane.
      supported_by:
        - reference_id: Reactome:R-HSA-2022928
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9941039
    review:
      summary: TAS annotation from Reactome pathway for FAM20B phosphorylation of
        xylose moiety during GAG linker biosynthesis.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization. Duplicate of previous Golgi
        annotation in different Reactome pathway context.
      supported_by:
        - reference_id: Reactome:R-HSA-1971475
  - term:
      id: GO:0015026
      label: coreceptor activity
    evidence_type: NAS
    original_reference_id: PMID:24431302
    review:
      summary: NAS annotation citing a review on Wnt signaling in dopaminergic neuron
        development. GPC6 functions as a co-receptor for Hedgehog and Wnt ligands,
        facilitating their engagement with primary receptors.
      action: ACCEPT
      reason: Coreceptor activity is a core molecular function of GPC6. The protein
        binds Hh ligand and promotes Hh-PTCH1 engagement. It also binds Wnt5a with
        high affinity to facilitate non-canonical Wnt signaling. UniProt describes
        it as a "Putative cell surface coreceptor for growth factors."
      supported_by:
        - reference_id: UniProt:Q9Y625
        - reference_id: DOI:10.1083/jcb.201605119
        - reference_id: DOI:10.1016/j.matbio.2019.11.002
        - reference_id: PMID:24431302
          supporting_text: Wnt signaling in midbrain dopaminergic neuron development
            and regenerative medicine for Parkinson's disease.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29162697
    review:
      summary: IPI annotation from a study on EB1-binding myomegalin complex. The
        study identified interactome partners but appears to be a high-throughput
        screen that may include non-specific interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: '"Protein binding" is uninformative and does not specify the functional
        significance of the interaction. More specific binding activities (Wnt-protein
        binding GO:0017147, or smoothened binding if applicable) would be preferable.
        The cited paper focuses on SMYLE/myomegalin and microtubule dynamics, not
        GPC6 specifically.'
      proposed_replacement_terms:
        - id: GO:0017147
          label: Wnt-protein binding
      supported_by:
        - reference_id: DOI:10.1016/j.matbio.2019.11.002
        - reference_id: PMID:29162697
          supporting_text: EB1-binding-myomegalin protein complex promotes centrosomal
            microtubules functions.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: HDA
    original_reference_id: PMID:21630459
    review:
      summary: HDA annotation from a proteomic characterization of human sperm nucleus.
        This high-throughput mass spectrometry study identified GPC6 among 403 proteins
        in isolated sperm nuclei.
      action: MARK_AS_OVER_ANNOTATED
      reason: GPC6 is a GPI-anchored cell surface protein with no known nuclear function.
        Detection in a sperm nuclear proteome is likely due to contamination or artifactual
        association during sample preparation. This contradicts the well-established
        cell surface localization and function of GPC6.
      supported_by:
        - reference_id: UniProt:Q9Y625
        - reference_id: PMID:21630459
          supporting_text: Jun 1. Proteomic characterization of the human sperm nucleus.
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1878002
    review:
      summary: TAS annotation from Reactome pathway for xylosyltransferases adding
        xylose to core protein during GAG linker biosynthesis.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain synthesis in
        the Golgi.
      supported_by:
        - reference_id: Reactome:R-HSA-1878002
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1889955
    review:
      summary: TAS annotation from Reactome pathway for B3GAT dimer transferring GlcA
        to tetrasaccharide linker.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain synthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-1889955
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1889978
    review:
      summary: TAS annotation from Reactome pathway for B3GALT6 transferring Gal to
        tetrasaccharide linker.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain synthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-1889978
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2022851
    review:
      summary: TAS annotation from Reactome pathway for EXT1:EXT2 transferring GlcNAc
        to heparan chain.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain elongation.
      supported_by:
        - reference_id: Reactome:R-HSA-2022851
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2022856
    review:
      summary: TAS annotation from Reactome pathway for EXT1:EXT2 transferring GlcA
        to heparan.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain elongation.
      supported_by:
        - reference_id: Reactome:R-HSA-2022856
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2022860
    review:
      summary: TAS annotation from Reactome pathway for NDST1-4 sulfating glucosamine
        residue to form HS.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2022860
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2022887
    review:
      summary: TAS annotation from Reactome pathway for NDST1-4 N-deacetylating GlcNAc
        residues in heparan.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2022887
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2024108
    review:
      summary: TAS annotation from Reactome pathway for HSPG secretion to plasma membrane.
      action: KEEP_AS_NON_CORE
      reason: Transit through Golgi during secretory pathway before reaching plasma
        membrane.
      supported_by:
        - reference_id: Reactome:R-HSA-2024108
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2076383
    review:
      summary: TAS annotation from Reactome pathway for HS3ST1 sulfating GlcN at C3
        in HS.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2076383
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2076392
    review:
      summary: TAS annotation from Reactome pathway for EXT1:EXT2 GlcA transfer to
        heparan.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain elongation.
      supported_by:
        - reference_id: Reactome:R-HSA-2076392
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2076419
    review:
      summary: TAS annotation from Reactome pathway for HS6STs sulfating GlcN at C6.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2076419
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2076508
    review:
      summary: TAS annotation from Reactome pathway for HS2ST1 trimer sulfating IdoA
        at C2.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2076508
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2076611
    review:
      summary: TAS annotation from Reactome pathway for HS3ST2-6 sulfating GlcN at
        C3.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain modification.
      supported_by:
        - reference_id: Reactome:R-HSA-2076611
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3560802
    review:
      summary: TAS annotation from Reactome pathway for defective B3GAT3 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3560802
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3656254
    review:
      summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3656254
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3656257
    review:
      summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3656257
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3656261
    review:
      summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3656261
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3656267
    review:
      summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3656267
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1678694
    review:
      summary: TAS annotation from Reactome pathway for Heparanase 2 (HPSE2) binding
        to HSPGs at plasma membrane.
      action: ACCEPT
      reason: Plasma membrane is the core functional localization of GPC6 as a GPI-anchored
        proteoglycan.
      supported_by:
        - reference_id: Reactome:R-HSA-1678694
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2024084
    review:
      summary: TAS annotation from Reactome pathway for HS-GAG translocation to lysosome
        for degradation.
      action: ACCEPT
      reason: Plasma membrane is the functional site before internalization for degradation.
      supported_by:
        - reference_id: Reactome:R-HSA-2024084
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2024108
    review:
      summary: TAS annotation from Reactome pathway for HSPG secretion to plasma membrane.
      action: ACCEPT
      reason: This accurately describes the delivery of GPC6 to its functional site.
      supported_by:
        - reference_id: Reactome:R-HSA-2024108
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2404131
    review:
      summary: TAS annotation from Reactome pathway for LRP-mediated transport of
        retinoid esters with HSPG and apoE.
      action: ACCEPT
      reason: Plasma membrane localization where GPC6 participates in retinoid transport
        pathway.
      supported_by:
        - reference_id: Reactome:R-HSA-2404131
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2423785
    review:
      summary: TAS annotation from Reactome pathway for retinoid esters binding apoE
        and HSPG.
      action: ACCEPT
      reason: Plasma membrane localization for retinoid transport function.
      supported_by:
        - reference_id: Reactome:R-HSA-2423785
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2429643
    review:
      summary: TAS annotation from Reactome pathway for NREH hydrolysis of retinoid
        esters.
      action: ACCEPT
      reason: Plasma membrane localization in retinoid metabolism context.
      supported_by:
        - reference_id: Reactome:R-HSA-2429643
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9694579
    review:
      summary: TAS annotation from Reactome pathway for SARS-CoV-2 Spike binding ACE2.
        HSPGs can serve as attachment factors for viral entry.
      action: ACCEPT
      reason: Plasma membrane localization where HSPGs may facilitate viral attachment.
      supported_by:
        - reference_id: Reactome:R-HSA-9694579
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9694661
    review:
      summary: TAS annotation from Reactome pathway for TMPRSS2-mediated SARS-CoV-2
        entry.
      action: ACCEPT
      reason: Plasma membrane localization in viral entry context.
      supported_by:
        - reference_id: Reactome:R-HSA-9694661
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9698988
    review:
      summary: TAS annotation from Reactome pathway for SARS-CoV-2 membrane fusion.
      action: ACCEPT
      reason: Plasma membrane localization in viral entry context.
      supported_by:
        - reference_id: Reactome:R-HSA-9698988
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9699007
    review:
      summary: TAS annotation from Reactome pathway for FURIN-mediated SARS-CoV-2
        entry.
      action: ACCEPT
      reason: Plasma membrane localization in viral entry context.
      supported_by:
        - reference_id: Reactome:R-HSA-9699007
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9836899
    review:
      summary: TAS annotation from Reactome pathway for RSV sG binding to HSPGs.
      action: ACCEPT
      reason: Plasma membrane localization where HSPGs serve as viral attachment factors.
      supported_by:
        - reference_id: Reactome:R-HSA-9836899
  - term:
      id: GO:0043202
      label: lysosomal lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1667005
    review:
      summary: TAS annotation from Reactome pathway for heparanase cleaving HS in
        lysosome.
      action: KEEP_AS_NON_CORE
      reason: Lysosomal localization reflects degradation of the proteoglycan, not
        its functional site.
      supported_by:
        - reference_id: Reactome:R-HSA-1667005
  - term:
      id: GO:0043202
      label: lysosomal lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2024084
    review:
      summary: TAS annotation from Reactome pathway for HS-GAG translocation to lysosome
        for degradation.
      action: KEEP_AS_NON_CORE
      reason: Lysosomal localization reflects degradation pathway, not functional
        site.
      supported_by:
        - reference_id: Reactome:R-HSA-2024084
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1889981
    review:
      summary: TAS annotation from Reactome pathway for B4GALT7 transferring Gal to
        xylosyl-unit.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during GAG linker synthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-1889981
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3560804
    review:
      summary: TAS annotation from Reactome pathway for defective B4GALT7 disease
        mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-3560804
  - term:
      id: GO:0016477
      label: cell migration
    evidence_type: IDA
    original_reference_id: PMID:21871017
    review:
      summary: IDA annotation based on direct experimental evidence showing GPC6 promotes
        breast cancer cell invasive migration through Wnt5A signaling. Silencing GPC6
        with shRNA potently blocks cell migration.
      action: ACCEPT
      reason: Strong experimental evidence demonstrating GPC6's role in promoting
        cell migration. The study used shRNA knockdown and overexpression to show
        GPC6 is necessary and sufficient for NFAT-induced invasive migration in breast
        cancer cells.
      supported_by:
        - reference_id: PMID:21871017
          supporting_text: Expression of GPC6 in response to NFAT signalling promotes
            invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA)
            potently blocks this phenotype.
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9036285
    review:
      summary: TAS annotation from Reactome pathway for defective EXT1 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-9036285
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9036289
    review:
      summary: TAS annotation from Reactome pathway for defective EXT2 disease mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-9036289
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9953259
    review:
      summary: TAS annotation from Reactome pathway for EXTL3 dimer transferring GlcNAc
        to GAG linker.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic intermediate localization during HS chain initiation.
      supported_by:
        - reference_id: Reactome:R-HSA-9953259
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1667005
    review:
      summary: TAS annotation from Reactome pathway for heparanase cleaving HS in
        lysosome.
      action: KEEP_AS_NON_CORE
      reason: The Golgi annotation in context of this reaction seems incorrect - HPSE
        acts in lysosome.
      supported_by:
        - reference_id: Reactome:R-HSA-1667005
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4420365
    review:
      summary: TAS annotation from Reactome pathway for defective B3GALT6 disease
        mechanism.
      action: KEEP_AS_NON_CORE
      reason: Biosynthetic pathway annotation in context of disease mechanism.
      supported_by:
        - reference_id: Reactome:R-HSA-4420365
core_functions:
  - molecular_function:
      id: GO:0015026
      label: coreceptor activity
    description: GPC6 functions as a cell surface co-receptor for Hedgehog (Hh) and
      Wnt signaling pathways. It binds Hh ligand via its core protein domain and interacts
      with PTCH1 via its heparan sulfate chains, promoting Hh-PTCH1 engagement at
      the primary cilium. GPC6 also binds Wnt5a with high affinity (KD ~1.4 nM) to
      facilitate non-canonical Wnt signaling.
    supported_by:
      - reference_id: file:human/GPC6/GPC6-deep-research-falcon.md
        supporting_text: 'Purified GPC6 binds Wnt5a with high affinity by surface
          plasmon resonance (SPR): ka approximately 4.65x10^5 M-1s-1 and kd approximately
          6.82x10-4 s-1 (KD approximately 1.4 nM)'
      - reference_id: PMID:21871017
        supporting_text: GPC6 is a novel NFAT target gene in breast cancer cells that
          promotes invasive migration through Wnt5A signalling.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO
      terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
      vocabulary mapping
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data
      to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10480909
    title: Glypican-6, a new member of the glypican family of cell surface heparan
      sulfate proteoglycans.
    findings:
      - statement: Initial characterization of GPC6 as a cell surface HSPG with tissue-specific
          expression
        supporting_text: The glypican-6 mRNA encodes a protein of 555 amino acids
          that is most homologous to glypican-4 (identity of 63%). Expression of this
          protein in Namalwa cells shows a core protein of approximately 60 kDa that
          is substituted with heparan sulfate only.
  - id: PMID:19481194
    title: Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair
      endochondral ossification and cause recessive omodysplasia.
    findings:
      - statement: Biallelic loss-of-function GPC6 mutations cause autosomal recessive
          omodysplasia type 1
        supporting_text: We now report that autosomal-recessive omodysplasia, a genetic
          condition characterized by short-limbed short stature, craniofacial dysmorphism,
          and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2)
          and is caused by point mutations or by larger genomic rearrangements in
          glypican 6 (GPC6).
      - statement: Mutations lead to impaired endochondral ossification and skeletal
          abnormalities
        supporting_text: GPC6 seems to have a previously unsuspected role in endochondral
          ossification and skeletal growth, and its functional abrogation results
          in a short-limb phenotype.
  - id: PMID:21630459
    title: Proteomic characterization of the human sperm nucleus.
    findings: []
  - id: PMID:21871017
    title: NFAT promotes carcinoma invasive migration through glypican-6.
    findings:
      - statement: NFAT transcriptionally induces GPC6 expression in breast cancer
          cells
        supporting_text: NFAT transcriptionally regulates GPC6 induction in breast
          cancer cells and binds to three regulatory elements in the GPC6 proximal
          promoter.
      - statement: GPC6 promotes invasive migration through non-canonical Wnt5A signaling
        supporting_text: Expression of GPC6 in response to NFAT signalling promotes
          invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA)
          potently blocks this phenotype.
      - statement: GPC6 inhibits canonical Wnt/beta-catenin signaling
        supporting_text: The mechanism by which GPC6 promotes invasive migration involves
          inhibition of canonical β-catenin and Wnt signalling, and up-regulation
          of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun
          N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase)
      - statement: GPC6 activates JNK and p38 MAPK signaling
        supporting_text: up-regulation of non-canonical Wnt5A signalling leading to
          the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated
          protein kinase).
  - id: PMID:24431302
    title: Wnt signaling in midbrain dopaminergic neuron development and regenerative
      medicine for Parkinson's disease.
    findings: []
  - id: PMID:29162697
    title: EB1-binding-myomegalin protein complex promotes centrosomal microtubules
      functions.
    findings: []
  - id: UniProt:Q9Y625
    title: UniProt entry for Glypican-6 (GPC6_HUMAN)
    findings:
      - statement: GPC6 is a GPI-anchored cell surface proteoglycan
        supporting_text: Cell surface proteoglycan that bears heparan sulfate.
      - statement: Functions as putative co-receptor for growth factors
        supporting_text: Putative cell surface coreceptor for growth factors, extracellular
          matrix proteins, proteases and anti-proteases
  - id: Reactome:R-HSA-1667005
    findings: []
    title: Reactome pathway R-HSA-1667005
  - id: Reactome:R-HSA-1678694
    findings: []
    title: Reactome pathway R-HSA-1678694
  - id: Reactome:R-HSA-1878002
    findings: []
    title: Reactome pathway R-HSA-1878002
  - id: Reactome:R-HSA-1889955
    findings: []
    title: Reactome pathway R-HSA-1889955
  - id: Reactome:R-HSA-1889978
    findings: []
    title: Reactome pathway R-HSA-1889978
  - id: Reactome:R-HSA-1889981
    findings: []
    title: Reactome pathway R-HSA-1889981
  - id: Reactome:R-HSA-2022851
    findings: []
    title: Reactome pathway R-HSA-2022851
  - id: Reactome:R-HSA-2022856
    findings: []
    title: Reactome pathway R-HSA-2022856
  - id: Reactome:R-HSA-2022860
    findings: []
    title: Reactome pathway R-HSA-2022860
  - id: Reactome:R-HSA-2022887
    findings: []
    title: Reactome pathway R-HSA-2022887
  - id: Reactome:R-HSA-2024084
    findings: []
    title: Reactome pathway R-HSA-2024084
  - id: Reactome:R-HSA-2024108
    findings: []
    title: Reactome pathway R-HSA-2024108
  - id: Reactome:R-HSA-2076383
    findings: []
    title: Reactome pathway R-HSA-2076383
  - id: Reactome:R-HSA-2076392
    findings: []
    title: Reactome pathway R-HSA-2076392
  - id: Reactome:R-HSA-2076419
    findings: []
    title: Reactome pathway R-HSA-2076419
  - id: Reactome:R-HSA-2076508
    findings: []
    title: Reactome pathway R-HSA-2076508
  - id: Reactome:R-HSA-2076611
    findings: []
    title: Reactome pathway R-HSA-2076611
  - id: Reactome:R-HSA-2404131
    findings: []
    title: Reactome pathway R-HSA-2404131
  - id: Reactome:R-HSA-2423785
    findings: []
    title: Reactome pathway R-HSA-2423785
  - id: Reactome:R-HSA-2429643
    findings: []
    title: Reactome pathway R-HSA-2429643
  - id: Reactome:R-HSA-3560802
    findings: []
    title: Reactome pathway R-HSA-3560802
  - id: Reactome:R-HSA-3560804
    findings: []
    title: Reactome pathway R-HSA-3560804
  - id: Reactome:R-HSA-3656254
    findings: []
    title: Reactome pathway R-HSA-3656254
  - id: Reactome:R-HSA-3656257
    findings: []
    title: Reactome pathway R-HSA-3656257
  - id: Reactome:R-HSA-3656261
    findings: []
    title: Reactome pathway R-HSA-3656261
  - id: Reactome:R-HSA-3656267
    findings: []
    title: Reactome pathway R-HSA-3656267
  - id: Reactome:R-HSA-4420365
    findings: []
    title: Reactome pathway R-HSA-4420365
  - id: Reactome:R-HSA-9036285
    findings: []
    title: Reactome pathway R-HSA-9036285
  - id: Reactome:R-HSA-9036289
    findings: []
    title: Reactome pathway R-HSA-9036289
  - id: Reactome:R-HSA-9694579
    findings: []
    title: Reactome pathway R-HSA-9694579
  - id: Reactome:R-HSA-9694661
    findings: []
    title: Reactome pathway R-HSA-9694661
  - id: Reactome:R-HSA-9698988
    findings: []
    title: Reactome pathway R-HSA-9698988
  - id: Reactome:R-HSA-9699007
    findings: []
    title: Reactome pathway R-HSA-9699007
  - id: Reactome:R-HSA-9836899
    findings: []
    title: Reactome pathway R-HSA-9836899
  - id: Reactome:R-HSA-9940993
    findings: []
    title: Reactome pathway R-HSA-9940993
  - id: Reactome:R-HSA-9941039
    findings: []
    title: Reactome pathway R-HSA-9941039
  - id: Reactome:R-HSA-9953259
    findings: []
    title: Reactome pathway R-HSA-9953259
proposed_new_terms: []
suggested_questions:
  - question: What is the precise mechanism by which GPC6 heparan sulfate chains contribute
      to Hedgehog-PTCH1 interaction specificity?
  - question: Does GPC6 have roles in other signaling pathways beyond Hedgehog and
      Wnt (e.g., BMP, FGF)?
  - question: What is the functional significance of GPC6-GPC4 interaction (reported
      in IntAct)?
suggested_experiments:
  - description: Structure-function analysis of GPC6 HS chain sulfation patterns and
      their contribution to Wnt5a versus Hh binding specificity
  - description: CRISPR knockout studies in human cell models to confirm GPC6 requirement
      for Hedgehog pathway activation
  - description: Proximity labeling (BioID or APEX) to identify the full GPC6 interactome
      at the primary cilium during Hh signaling