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.
| 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. Proposed replacements: positive regulation of non-canonical Wnt signaling pathway positive regulation of smoothened signaling pathway 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 |
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Download this section (compressed HTML)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)?
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
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