GPC4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016477 cell migration	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation based on phylogenetic inference from other glypican family members. Glypicans can modulate cell migration through their interactions with growth factors and morphogens that regulate cell motility. However, direct experimental evidence for GPC4-specific roles in cell migration is limited compared to its well-established roles in synaptogenesis and Wnt signaling. Reason: While glypicans broadly influence cell migration through growth factor modulation, this is not a defining core function of GPC4. The phylogenetic inference is reasonable but GPC4's primary characterized functions are in synapse formation and Wnt signaling co-receptor activity. Supporting Evidence: GO_REF:0000033
GO:0031012 extracellular matrix	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation indicating GPC4 localization to extracellular matrix. As a GPI-anchored proteoglycan bearing heparan sulfate chains, GPC4 can interact with ECM components. However, GPC4 is primarily described as a cell surface protein with a GPI anchor. Reason: Glypicans are known to interact with the extracellular matrix through their heparan sulfate chains. While GPC4 is primarily GPI-anchored at the cell surface, it can also be shed and found in extracellular spaces including the synaptic cleft. Supporting Evidence: GO_REF:0000033
GO:0098696 regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation reflecting GPC4's established role in regulating AMPA receptor localization at synapses. This is a well-characterized function of GPC4 in the CNS where astrocyte-derived GPC4 promotes GluA1/AMPA receptor clustering at postsynaptic sites. Reason: This annotation accurately captures a core function of GPC4. The deep research literature confirms that GPC4 promotes excitatory synapse maturation by increasing surface clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma pathway and by inducing neuronal pentraxin-1 (NPTX1) release. Supporting Evidence: GO_REF:0000033 file:human/GPC4/GPC4-deep-research-falcon.md It promotes excitatory synapse maturation by increasing surface clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma pathway and by inducing neuronal pentraxin-1 (NPTX1) release from axons.
GO:0009986 cell surface	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cell surface localization. GPC4 is GPI-anchored to the outer leaflet of the plasma membrane, making the cell surface its primary functional location. Reason: This is a core localization for GPC4. UniProt confirms cell membrane localization via GPI anchor at position Ser-529. The protein is tethered to the external side of the plasma membrane where it acts as a co-receptor for signaling molecules. Supporting Evidence: GO_REF:0000033 PMID:10585884 Expression of glypican-4 in haematopoietic-progenitor and bone-marrow-stromal cells.
GO:0045202 synapse	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for synapse localization. GPC4 is released by astrocytes into the synaptic cleft where it functions in synaptogenesis and AMPA receptor recruitment. Reason: This annotation accurately reflects GPC4's role as an astrocyte-derived synaptogenic factor that functions at synapses to promote excitatory synapse formation and maturation. This is a core function supported by extensive literature. Supporting Evidence: GO_REF:0000033
GO:0099560 synaptic membrane adhesion	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation reflecting GPC4's role in synaptic membrane adhesion. GPC4 interacts with LRRTMs and presynaptic PTPsigma to coordinate pre- and postsynaptic assembly, functioning as a trans-synaptic organizer. Reason: GPC4 functions as a synaptic organizer that bridges pre- and postsynaptic membranes through interactions with synaptic adhesion molecules. The LRRTM-GPC4-PTPsigma complex mediates trans-synaptic signaling that coordinates synapse development. Supporting Evidence: GO_REF:0000033
GO:1905606 regulation of presynapse assembly	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for regulation of presynapse assembly. GPC4's interactions with presynaptic PTPsigma contribute to presynaptic differentiation and organization. Reason: This annotation captures GPC4's role in coordinating presynaptic development through its trans-synaptic signaling function. The LRRTM-GPC4-PTPsigma pathway involves engagement of presynaptic receptor protein tyrosine phosphatase sigma to promote presynaptic differentiation. Supporting Evidence: GO_REF:0000033
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProtKB subcellular location mapping. GPC4 can be shed from the cell surface and secreted into extracellular spaces. Reason: UniProt confirms that secreted glypican-4 is released into the extracellular space. The protein contains a GPI-anchoring signal that can be cleaved to release soluble forms. Soluble GPC4 has been detected in serum and other biofluids. Supporting Evidence: GO_REF:0000044
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation based on InterPro glypican domain and UniProtKB subcellular location data. GPC4 is GPI-anchored to the plasma membrane. Reason: This is correct and well-supported. UniProt confirms GPC4 contains a GPI-anchor signal with the amidated serine at position 529, tethering it to the plasma membrane outer leaflet. Supporting Evidence: GO_REF:0000120
GO:0009966 regulation of signal transduction	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro glypican domain mapping. Glypicans regulate signal transduction by acting as co-receptors for morphogens and growth factors. Reason: This accurately captures a core function of GPC4. The glypican family modulates signaling by binding ligands (Wnt, FGF, Hedgehog) through heparan sulfate chains and presenting them to receptors. GPC4 has experimentally demonstrated roles in Wnt signaling. Supporting Evidence: GO_REF:0000002 PMID:29276006 2017 Dec 21. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
GO:0031012 extracellular matrix	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro glypican domain mapping. Duplicate of the IBA annotation for the same term. Reason: Consistent with the IBA annotation for the same term. Glypicans with heparan sulfate chains interact with ECM components. This IEA provides additional support. Supporting Evidence: GO_REF:0000002
GO:0043202 lysosomal lumen	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning models suggesting lysosomal lumen localization. This likely reflects GPC4's presence in the degradation pathway for heparan sulfate proteoglycans. Reason: Heparan sulfate proteoglycans are degraded in lysosomes. Reactome pathways confirm that HSPGs including GPC4 are translocated to lysosomes for degradation, and heparanase cleaves heparan sulfate in the lysosomal lumen. Supporting Evidence: GO_REF:0000117
GO:0098552 side of membrane	IEA GO_REF:0000043	MODIFY	Summary: IEA annotation based on UniProtKB GPI-anchor keyword mapping. GPC4 is on the extracellular side of the membrane. Reason: The term 'side of membrane' is too general. GPC4 is specifically located on the external side of the plasma membrane via its GPI anchor. A more specific term should be used. Proposed replacements: external side of plasma membrane Supporting Evidence: GO_REF:0000043 PMID:10585884 Expression of glypican-4 in haematopoietic-progenitor and bone-marrow-stromal cells.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: IPI annotation from IntAct based on high-throughput interactome study. Interaction with GPC6 (Q9Y625) detected. Reason: The term 'protein binding' is too general and uninformative. GPC4 interacts with GPC6, another glypican family member. More specific molecular function terms describing GPC4's co-receptor or signaling adapter activities would be more informative. Proposed replacements: coreceptor activity Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI annotation from HuRI reference interactome study. Interaction with PICK1 (Q9NRD5) detected. Reason: While the protein-protein interaction is likely valid (from the HuRI reference interactome), the term 'protein binding' does not provide functional insight. PICK1 is a PDZ domain protein involved in AMPA receptor trafficking, which could be relevant to GPC4's synaptic function, but the annotation as currently stated is uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI annotation from BioPlex 3.0 AP-MS study. Interaction with GPC6 (Q9Y625) detected. Reason: Duplicate evidence for GPC4-GPC6 interaction. Same concern as above - 'protein binding' is too general. The interaction between glypican family members may reflect their organization in membrane microdomains or functional cooperation. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI annotation from recent interactome study. Interaction with GPC6 (Q9Y625) detected. Reason: Third independent detection of GPC4-GPC6 interaction strengthens confidence in this interaction. However, 'protein binding' remains uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0045202 synapse	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse ortholog based on Ensembl Compara analysis. Consistent with IBA annotation for same term. Reason: This annotation is consistent with the well-established role of GPC4 at synapses. The transfer from mouse ortholog is appropriate as mouse GPC4 function in synaptogenesis is well characterized. Supporting Evidence: GO_REF:0000107
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse ortholog indicating localization at glutamatergic synapses. GPC4 promotes excitatory (glutamatergic) synapse formation. Reason: This annotation is consistent with GPC4's role in promoting GluA1-containing AMPA receptor clustering at excitatory synapses. GPC4 specifically promotes excitatory synapse maturation. Supporting Evidence: GO_REF:0000107
GO:0099560 synaptic membrane adhesion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation transferred from mouse ortholog. Consistent with IBA annotation for same term. Reason: Provides additional support for GPC4's role in synaptic membrane adhesion through ortholog transfer. Consistent with established LRRTM-GPC4-PTPsigma trans-synaptic complex. Supporting Evidence: GO_REF:0000107
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-9940993	ACCEPT	Summary: TAS annotation from Reactome pathway indicating GPC4 presence in Golgi lumen during glycosaminoglycan biosynthesis. PXYLP1 dephosphorylates xylose moiety. Reason: GPC4 transits through the Golgi during biosynthesis where its heparan sulfate chains are assembled. This is part of the normal processing of all HSPGs. Supporting Evidence: Reactome:R-HSA-9940993
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-9941039	ACCEPT	Summary: TAS annotation from Reactome pathway. FAM20B phosphorylates xylose moiety during GAG chain assembly. Reason: Part of the HS-GAG biosynthesis pathway in the Golgi. Multiple Reactome references support GPC4's transit through Golgi during biosynthesis. Supporting Evidence: Reactome:R-HSA-9941039
GO:0015026 coreceptor activity	NAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an...	ACCEPT	Summary: NAS annotation for coreceptor activity based on review discussing Wnt signaling in dopaminergic neuron development. Glypicans act as co-receptors for Wnt ligands. Reason: This is a core molecular function of GPC4. The glypican family functions as co-receptors for morphogens including Wnts, presenting them to Frizzled receptors through HS-dependent binding. This annotation accurately captures GPC4's primary molecular function. Supporting Evidence: PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease. PMID:29276006 2017 Dec 21. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
GO:0016055 Wnt signaling pathway	IMP PMID:29276006 WNT Signaling Perturbations Underlie the Genetic Heterogenei...	ACCEPT	Summary: IMP annotation based on finding pathogenic GPC4 variants in patients with Robinow syndrome, a disorder caused by Wnt/PCP pathway perturbation. Functional studies supported GPC4's role in Wnt signaling. Reason: This annotation is well-supported by experimental evidence. The study identified GPC4 as a candidate gene for Robinow syndrome and demonstrated its connection to the Wnt signaling pathway. GPC4's role in Wnt signaling is a core function of this co-receptor. Supporting Evidence: PMID:29276006 2017 Dec 21. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus	MARK AS OVER ANNOTATED	Summary: HDA annotation from proteomic characterization of human sperm nucleus. GPC4 was identified among proteins in isolated sperm nuclei. Reason: This is likely a false positive from the high-throughput proteomics study. GPC4 is a GPI-anchored cell surface proteoglycan with no known nuclear function. The sperm nucleus preparation may have contained contaminating membrane fragments or this represents an artifact. Nuclear localization contradicts all known biology of glypicans. Supporting Evidence: PMID:21630459 Jun 1. Proteomic characterization of the human sperm nucleus.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	ACCEPT	Summary: HDA annotation from proteomic analysis of parotid gland exosomes. GPC4 was identified among exosomal proteins by MudPIT mass spectrometry. Reason: This annotation is plausible. GPC4 can be shed from the cell surface and released in extracellular vesicles. The study identified GPC4 among 491 proteins in parotid exosomes. GPI-anchored proteins including glypicans are known to be incorporated into exosomes. Supporting Evidence: PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-1878002	ACCEPT	Summary: TAS annotation from Reactome. XYLTs transfer xylose to core protein during GAG synthesis. Reason: Part of the tetrasaccharide linker synthesis pathway required for GAG chain assembly. GPC4 transits through Golgi during biosynthesis. Supporting Evidence: Reactome:R-HSA-1878002
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-1889955	ACCEPT	Summary: TAS annotation from Reactome. B3GAT dimers transfer glucuronic acid during linker synthesis. Reason: Part of HS-GAG biosynthesis pathway. All TAS Golgi lumen annotations from Reactome reflect GPC4's transit through secretory pathway during biosynthesis and modification. Supporting Evidence: Reactome:R-HSA-1889955
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-1889978	ACCEPT	Summary: TAS annotation from Reactome. B3GALT6 transfers galactose during linker synthesis. Reason: Part of HS-GAG biosynthesis. Golgi localization during processing is expected. Supporting Evidence: Reactome:R-HSA-1889978
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2022851	ACCEPT	Summary: TAS annotation from Reactome. EXT1:EXT2 complex transfers GlcNAc to heparan chain. Reason: Part of heparan sulfate chain elongation in Golgi. Supporting Evidence: Reactome:R-HSA-2022851
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2022856	ACCEPT	Summary: TAS annotation from Reactome. EXT1:EXT2 complex transfers glucuronic acid to heparan. Reason: Part of HS chain elongation pathway. Supporting Evidence: Reactome:R-HSA-2022856
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2022860	ACCEPT	Summary: TAS annotation from Reactome. NDSTs sulfate glucosamine residues forming heparan sulfate. Reason: Part of HS chain modification in Golgi. Critical for generating sulfated heparan sulfate. Supporting Evidence: Reactome:R-HSA-2022860
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2022887	ACCEPT	Summary: TAS annotation from Reactome. NDSTs N-deacetylate GlcNAc residues. Reason: Part of HS chain modification pathway. Supporting Evidence: Reactome:R-HSA-2022887
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2024108	ACCEPT	Summary: TAS annotation from Reactome. HSPGs are secreted to plasma membrane. Reason: Represents transport of mature GPC4 from Golgi to plasma membrane. Supporting Evidence: Reactome:R-HSA-2024108
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2076383	ACCEPT	Summary: TAS annotation from Reactome. HS3ST1 sulfates glucosamine at C3. Reason: Part of HS chain modification pathway in Golgi. Supporting Evidence: Reactome:R-HSA-2076383
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2076392	ACCEPT	Summary: TAS annotation from Reactome. EXT1:EXT2 transfers glucuronic acid. Reason: Duplicate pathway reference for HS chain elongation. Supporting Evidence: Reactome:R-HSA-2076392
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2076419	ACCEPT	Summary: TAS annotation from Reactome. HS6STs sulfate glucosamine at C6. Reason: Part of HS chain modification in Golgi. Supporting Evidence: Reactome:R-HSA-2076419
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2076508	ACCEPT	Summary: TAS annotation from Reactome. HS2ST1 sulfates iduronic acid at C2. Reason: Part of HS chain modification. Supporting Evidence: Reactome:R-HSA-2076508
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-2076611	ACCEPT	Summary: TAS annotation from Reactome. HS3ST2-6 sulfate glucosamine at C3. Reason: Part of HS chain modification pathway. Supporting Evidence: Reactome:R-HSA-2076611
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3560802	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Defective B3GAT3 affecting linker synthesis. Reason: GPC4 is substrate for GAG biosynthesis machinery, including in disease contexts. Supporting Evidence: Reactome:R-HSA-3560802
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3656254	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Defective EXT2 in EXT1:EXT2 complex. Reason: GPC4 is affected in exostoses syndromes caused by EXT mutations. Supporting Evidence: Reactome:R-HSA-3656254
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3656257	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Defective EXT1. Reason: Part of disease pathway affecting HSPG biosynthesis. Supporting Evidence: Reactome:R-HSA-3656257
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3656261	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Reason: Part of disease pathway affecting HSPG biosynthesis. Supporting Evidence: Reactome:R-HSA-3656261
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3656267	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Reason: Part of disease pathway affecting HSPG biosynthesis. Supporting Evidence: Reactome:R-HSA-3656267
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1678694	ACCEPT	Summary: TAS annotation from Reactome. Heparanase 2 binds heparan sulfate proteoglycans at plasma membrane. Reason: GPC4 is targeted by heparanase 2 at the cell surface. Supporting Evidence: Reactome:R-HSA-1678694
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2024084	ACCEPT	Summary: TAS annotation from Reactome. HS-GAGs translocate to lysosome for degradation. Reason: GPC4 at plasma membrane is internalized for degradation. Supporting Evidence: Reactome:R-HSA-2024084
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2024108	ACCEPT	Summary: TAS annotation from Reactome. HSPGs secreted to plasma membrane. Reason: GPC4 is transported to and functions at the plasma membrane. Supporting Evidence: Reactome:R-HSA-2024108
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2404131	ACCEPT	Summary: TAS annotation from Reactome. LRPs transport retinol-HSPG complexes. Reason: HSPGs including GPC4 participate in retinoid metabolism at cell surface. Supporting Evidence: Reactome:R-HSA-2404131
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2423785	ACCEPT	Summary: TAS annotation from Reactome. Retinol-ester complexes bind apoE and HSPG. Reason: GPC4 as HSPG involved in retinoid transport pathway. Supporting Evidence: Reactome:R-HSA-2423785
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2429643	ACCEPT	Summary: TAS annotation from Reactome. NREH hydrolyzes retinol esters from HSPG complexes. Reason: Part of retinoid metabolism pathway involving HSPGs. Supporting Evidence: Reactome:R-HSA-2429643
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9694579	KEEP AS NON CORE	Summary: TAS annotation from Reactome. SARS-CoV-2 spike glycoprotein binds ACE2 on host cells. HSPGs can act as co-receptors for viral entry. Reason: While HSPGs including GPC4 may facilitate SARS-CoV-2 binding, this is not a core biological function but rather reflects pathogen exploitation of cell surface proteoglycans. Supporting Evidence: Reactome:R-HSA-9694579
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9694661	KEEP AS NON CORE	Summary: TAS annotation from Reactome. TMPRSS2 mediated spike protein cleavage. Reason: Part of viral entry pathway. Not a core function of GPC4. Supporting Evidence: Reactome:R-HSA-9694661
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9698988	KEEP AS NON CORE	Summary: TAS annotation from Reactome. SARS-CoV-2 membrane fusion. Reason: Viral entry pathway. Not a core GPC4 function. Supporting Evidence: Reactome:R-HSA-9698988
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9699007	KEEP AS NON CORE	Summary: TAS annotation from Reactome. FURIN mediated spike cleavage. Reason: Viral entry pathway. Not a core GPC4 function. Supporting Evidence: Reactome:R-HSA-9699007
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9836899	KEEP AS NON CORE	Summary: TAS annotation from Reactome. RSV sG binds to HSPGs. Reason: Viral attachment pathway. HSPGs serve as attachment factors for many pathogens but this is not a core biological function. Supporting Evidence: Reactome:R-HSA-9836899
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-1667005	ACCEPT	Summary: TAS annotation from Reactome. Heparanase cleaves heparan sulfate in lysosome. Reason: GPC4 is degraded in lysosomes where heparanase cleaves HS chains. Supporting Evidence: Reactome:R-HSA-1667005
GO:0043202 lysosomal lumen	TAS Reactome:R-HSA-2024084	ACCEPT	Summary: TAS annotation from Reactome. HS-GAGs translocate to lysosome. Reason: Part of HSPG degradation pathway. Supporting Evidence: Reactome:R-HSA-2024084
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-1889981	ACCEPT	Summary: TAS annotation from Reactome. B4GALT7 transfers galactose to xylosyl unit. Reason: Part of GAG linker synthesis in Golgi. Supporting Evidence: Reactome:R-HSA-1889981
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-3560804	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Defective B4GALT7. Reason: Disease pathway affecting GAG synthesis on GPC4. Supporting Evidence: Reactome:R-HSA-3560804
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-9036285	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Reason: Disease pathway affecting GPC4 biosynthesis. Supporting Evidence: Reactome:R-HSA-9036285
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-9036289	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Reason: Disease pathway affecting GPC4 biosynthesis. Supporting Evidence: Reactome:R-HSA-9036289
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-9953259	ACCEPT	Summary: TAS annotation from Reactome. EXTL3 transfers GlcNAc to GAG linker. Reason: Part of HS chain initiation in Golgi. Supporting Evidence: Reactome:R-HSA-9953259
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-1667005	ACCEPT	Summary: TAS annotation from Reactome. Note this reference is for lysosomal heparanase activity, may be a pathway data entry issue. Reason: While the reference describes lysosomal processing, GPC4 transits through Golgi. Supporting Evidence: Reactome:R-HSA-1667005
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-4420365	ACCEPT	Summary: TAS annotation from Reactome disease pathway. Defective B3GALT6. Reason: Disease pathway affecting GAG linker synthesis. Supporting Evidence: Reactome:R-HSA-4420365
GO:0009897 external side of plasma membrane	IDA PMID:10585884 Expression of glypican-4 in haematopoietic-progenitor and bo...	ACCEPT	Summary: IDA annotation based on direct experimental evidence. FACS analysis and confocal laser-scanning microscopy demonstrated GPC4 on the cell surface of haematopoietic progenitor cells and bone marrow stromal cells. Reason: Direct experimental evidence for external plasma membrane localization. The study showed GPC4 expression on the surface of TF-1 cells by FACS analysis and confirmed localization by confocal microscopy. This is consistent with GPC4's GPI-anchored structure placing it on the extracellular side of the membrane. Supporting Evidence: PMID:10585884 Expression of glypican-4 in haematopoietic-progenitor and bone-marrow-stromal cells.
GO:0030674 protein-macromolecule adaptor activity	NAS file:human/GPC4/GPC4-deep-research-falcon.md	NEW	Summary: GPC4 functions as a synaptic adaptor that bridges pre- and postsynaptic membranes through the LRRTM-GPC4-PTPsigma trans-synaptic complex. This adaptor function is critical for recruiting and clustering AMPA receptors at glutamatergic synapses. Reason: This annotation captures GPC4's well-characterized role as a trans-synaptic organizer that mediates protein complex assembly at synapses. The deep research literature confirms GPC4 bridges LRRTMs with presynaptic PTPsigma to coordinate synapse development and AMPA receptor recruitment. This molecular function term accurately describes GPC4's adaptor role in assembling synaptic protein complexes. Supporting Evidence: file:human/GPC4/GPC4-deep-research-falcon.md A defining role of GPC4 is as an astrocyte-derived synaptogenic factor. It promotes excitatory synapse maturation by increasing surface clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma pathway

Core Functions

GPC4 functions as a cell surface co-receptor for growth factors and morphogens, particularly Wnts. Through its heparan sulfate chains, GPC4 binds signaling ligands and presents them to their primary receptors, modulating signaling pathway activation. This co-receptor function is central to GPC4's role in development and is perturbed in Robinow syndrome.

Molecular Function:

coreceptor activity

Directly Involved In:

Wnt signaling pathway

Cellular Locations:

external side of plasma membrane

In the CNS, astrocyte-derived GPC4 is a critical synaptogenic factor that promotes excitatory synapse formation by regulating AMPA receptor localization. GPC4 increases surface clustering of GluA1-containing AMPA receptors through the LRRTM-GPC4-PTPsigma trans-synaptic complex and induces neuronal pentraxin-1 release.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

regulation of neurotransmitter receptor localization to postsynaptic specialization membrane synaptic membrane adhesion

Cellular Locations:

glutamatergic synapse

Supporting Evidence:

PMID:28514442

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:10585884

Expression of glypican-4 in haematopoietic-progenitor and bone-marrow-stromal cells

GPC4 expressed as heparan sulfate proteoglycan on cell surface

"Western blot analysis showed expression of GPC-4 as a heparan sulphate proteoglycan in the human haematopoietic-progenitor cell line TF-1 and normal human bone marrow."
Detected by FACS in TF-1 haematopoietic progenitor cells

"These results were confirmed by FACS analysis of TF-1 cells."
Confocal microscopy confirmed cell surface localization

"GPC-4-positive progenitor cells and stromal cells were enriched from normal human bone marrow by magnetic-cell sorting and analysed by confocal laser-scanning microscopy."

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT)

GPC4 detected in parotid gland exosome fraction

"Using MudPIT (multidimensional protein identification technology) mass spectrometry, we catalogued 491 proteins in the exosome fraction of human parotid saliva."
GPI-anchored proteins incorporated into exosomes

"interaction with tetraspanins and GPI-anchored proteins is necessary for ILV formation"

PMID:21630459

Proteomic characterization of the human sperm nucleus

GPC4 detected in sperm nuclear fraction (likely contamination)

"403 different proteins have been identified from the isolated sperm nuclei"

PMID:24431302

Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease

Glypicans function as Wnt co-receptors

"Wnts are a highly conserved family of lipid-modified glycoproteins that work as morphogens to activate several signaling pathways"

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks

GPC4 interacts with GPC6

"Architecture of the human interactome defines protein communities and disease networks"

PMID:29276006

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

GPC4 variants identified in Robinow syndrome patients

"we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway"
GPC4 linked to Wnt signaling pathway

"These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway"
Supports role of GPC4 in Wnt/PCP signaling

"Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved"

PMID:32296183

A reference map of the human binary protein interactome.

GPC4-PICK1 interaction detected by Y2H

"A reference map of the human binary protein interactome"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome

GPC4-GPC6 interaction detected by AP-MS

"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome"

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics

GPC4 interactions detected

"Multimodal cell maps as a foundation for structural and functional genomics"

file:human/GPC4/GPC4-deep-research-falcon.md

Deep research summary for GPC4

GPC4 is an astrocyte-derived synaptogenic factor

"A defining role of GPC4 is as an astrocyte-derived synaptogenic factor. It promotes excitatory synapse maturation by increasing surface clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma pathway and by inducing neuronal pentraxin-1 (NPTX1) release from axons."
GPC4 functions as a co-receptor for Wnt and other morphogens

"Like other glypicans, GPC4 modulates extracellular signaling by binding ligands through HS chains and presenting them to receptors, impacting Wnt, Hedgehog, and FGF pathways."

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

Deep Research

Falcon

(GPC4-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 13 citations 2025-12-27T23:52:04.631281

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 overview: We verified identity and nomenclature, assembled recent and foundational sources (with emphasis on 2023–2024), gathered disease/biomarker applications and statistics, synthesized expert perspectives, and compiled a summary artifact. Below is the comprehensive research report.

Comprehensive research report: Human GPC4 (UniProt O75487)

Identity, core concepts, and definitions
- Gene/protein identity and family: GPC4 encodes glypican‑4, a cell-surface heparan sulfate proteoglycan (HSPG) of the glypican family, tethered to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. Glypican‑4 can also exist in shed/secreted forms in extracellular fluids. These features align with the UniProt description for O75487 and recent glypican literature (hansson2024dichotomouseffectsof pages 15-17, piao2025unravelingglypican3from pages 1-2).
- Domain architecture and PTMs: Glypican core proteins share conserved cysteines and a C‑terminal region harboring heparan sulfate (HS) attachment sites and a GPI‑anchoring signal. Post‑translational modifications include HS chain glycosylation and GPI anchoring; extracellular enzymes (e.g., Notum and related lipases) and proteases can release glypicans from the membrane (piao2025unravelingglypican3from pages 17-18, yu2025heparansulfateproteoglycans pages 29-30).

Subcellular and extracellular localization
- GPC4 is primarily a GPI‑anchored cell-surface protein. In the nervous system, astrocytes release GPC4 into the synaptic cleft/extracellular space, where it functions in synaptogenesis; shed/soluble GPC4 can be detected in biofluids (yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17).

Molecular functions and mechanisms
- Co‑receptor/modulator roles: Like other glypicans, GPC4 modulates extracellular signaling by binding ligands through HS chains and presenting them to receptors, impacting Wnt, Hedgehog, and FGF pathways. These functions are conserved family mechanisms and apply to GPC4 (piao2025unravelingglypican3from pages 17-18, piao2025unravelingglypican3from pages 1-2).
- Synaptogenic signaling: A defining role of GPC4 is as an astrocyte‑derived synaptogenic factor. It promotes excitatory synapse maturation by increasing surface clustering of GluA1‑containing AMPA receptors via a LRRTM–GPC4–PTPσ pathway and by inducing neuronal pentraxin‑1 (NPTX1) release from axons. This synaptogenic mechanism is supported by foundational and integrative sources and remains central to current understanding (yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17).

Key interacting partners
- Extracellular ligands and receptors: Wnts, FGFs, Hedgehog family ligands (via HS‑dependent binding); synaptic organizers such as LRRTMs and presynaptic receptor protein tyrosine phosphatase sigma (PTPσ); neuronal pentraxin‑1 (functional mediator of AMPAR recruitment) (yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17).

Recent developments (2023–2024 focus)
- CNS synapse biology and methods: 2024 proximity labeling/trafficking work highlights dynamic exposure of synaptic proteins during activity and explicitly references astrocyte‑secreted GPC4 as an upstream modulator of AMPA receptor clustering and synaptic protein release, refining the temporal view of GPC4’s synaptic actions (yu2025heparansulfateproteoglycans pages 29-30).
- Cancer: A 2024 pan‑cancer analysis with functional perturbations demonstrates dichotomous, context‑dependent effects of GPC4—knockout suppressed glioblastoma proliferation but increased lung adenocarcinoma proliferation, with overexpression producing opposite effects. Transcriptomic links to mitogenic and survival pathways (e.g., FGF/TGF‑β components) were reported, underscoring tumor‑type specificity in GPC4 biology and potential prognostic utility (hansson2024dichotomouseffectsof pages 15-17, hansson2024dichotomouseffectsof pages 1-2).

Pathway context and cellular roles
- Wnt/Hedgehog/FGF: GPC4’s HS chains scaffold morphogens near cell surfaces, enhancing or modulating receptor engagement. Family‑level reviews indicate that such co‑receptor functions underlie developmental patterning and adult tissue signaling, consistent with GPC4’s roles (piao2025unravelingglypican3from pages 17-18, piao2025unravelingglypican3from pages 1-2).
- Synapse organization: At excitatory synapses, GPC4 complexes with LRRTM family members and engages presynaptic PTPσ to coordinate pre‑ and postsynaptic assembly, including AMPAR recruitment and presynaptic differentiation (yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17).

Applications and real‑world implementations
- Circulating biomarker potential: Clinical and review evidence indicates soluble GPC4 is measurable in serum and other fluids. Increased levels have been associated with metabolic phenotypes (obesity/insulin resistance states) and neurological conditions. A 2024 clinical cohort in Parkinson’s disease reported that serum GPC4 levels associated with cognitive performance (MoCA) and vascular risk factor stratification, suggesting biomarker potential for PD cognition/vascular comorbidity risk (hansson2024dichotomouseffectsof pages 15-17). A research report in 2023 found higher serum GPC4 in PCOS vs controls (mean ~1.82 vs ~1.30 ng/mL), with positive correlations to insulin resistance indices, aligning with prior reports that GPC4 tracks with insulin sensitivity (yu2025heparansulfateproteoglycans pages 29-30). Reviews of circulating HSPGs conclude that glypicans (including GPC4) are detectable and clinically informative across cardiovascular, metabolic, renal, and inflammatory settings (yu2025heparansulfateproteoglycans pages 29-30).
- Oncology: Context‑dependent expression/prognostic associations across TCGA and functional data suggest potential use of GPC4 as a prognostic marker and, in principle, a target, albeit with caution due to pleiotropy and divergent effects by tumor type (hansson2024dichotomouseffectsof pages 15-17, hansson2024dichotomouseffectsof pages 1-2).

Relevant statistics and data
- PCOS cohort (2023 preprint): Serum GPC4 significantly higher in PCOS (1.82 ± 0.49 ng/mL) vs controls (1.30 ± 0.61 ng/mL), with positive correlations to HOMA‑IR and fasting insulin, supporting association with insulin resistance (yu2025heparansulfateproteoglycans pages 29-30).
- Neurology (2024): In PD, GPC4 was quantified in serum, CSF, and tears; highest in serum, with serum levels associating with lower MoCA scores and higher vascular risk factor burden, supporting use for risk stratification in PD (hansson2024dichotomouseffectsof pages 15-17).
- Cancer functional genomics (2024): CRISPR/Cas9 perturbation of GPC4 decreased proliferation in glioblastoma but increased it in lung adenocarcinoma, with reversed effects upon overexpression and rescue, providing causal evidence for context‑specific roles (hansson2024dichotomouseffectsof pages 1-2).

Expert opinions and authoritative syntheses
- Synaptic HSPG perspective: Reviews emphasize glypicans as central organizers of synapse development, acting as HS‑dependent ligands/co‑receptors that specify connectivity and modulate receptor composition and plasticity. This framework incorporates GPC4’s astrocyte‑derived role and LRRTM/PTPσ interactions (yu2025heparansulfateproteoglycans pages 29-30).
- HSPG classification and mechanisms: Broad 2024 review of HSPGs consolidates their roles in vascular biology, development, and disease, reinforcing glypicans’ function as morphogen co‑receptors and reservoirs for bioactive factors; it also highlights clinical translation opportunities for circulating forms (hansson2024dichotomouseffectsof pages 15-17).
- Glypican family structural logic: Family‑level analyses detail conserved architecture (conserved cysteines, flexible C‑terminal linker), HS‑dependent ligand recruitment, and GPI‑anchored vs shed states, all directly relevant to GPC4 (piao2025unravelingglypican3from pages 17-18, piao2025unravelingglypican3from pages 1-2).

Limitations and considerations
- Assay variability: The literature notes potential issues in standardization of commercial ELISAs for GPC4; thus, cross‑study comparisons of absolute concentrations require caution (noted in broader discussions of circulating HSPGs) (yu2025heparansulfateproteoglycans pages 29-30).
- Context dependence: Cancer data demonstrate that GPC4’s effects vary by tissue type and molecular milieu; therapeutic targeting would require tumor‑specific validation (hansson2024dichotomouseffectsof pages 1-2).

Conclusions
Human GPC4 (O75487) is a GPI‑anchored, HS‑modified glypican that functions as an extracellular co‑receptor for morphogen signaling (e.g., Wnt/Hedgehog/FGF) and as an astrocyte‑derived synaptogenic organizer that recruits AMPA receptors via LRRTM/PTPσ and NPTX1‑dependent mechanisms. It localizes to the plasma membrane and synaptic cleft and can be shed into circulation. Recent 2023–2024 studies refine its dynamic role in synaptic protein trafficking and support biomarker applications, including PD cognitive/vascular risk and metabolic insulin resistance contexts. In oncology, GPC4 exerts dichotomous, context‑dependent effects, underscoring the need for precision approaches. Together, mechanistic and translational evidence establish GPC4 as a multifunctional extracellular organizer with emerging clinical utility.

To aid quick reference, we include a structured summary artifact below.

Aspect	Main points	Key sources (authors, year)	URL	Date
Identity / Gene ID	GPC4 encodes Glypican‑4, a cell-surface heparan sulfate proteoglycan (HSPG) with a GPI anchor and a releasable/secreted form.	(hansson2024dichotomouseffectsof pages 15-17, yu2025heparansulfateproteoglycans pages 29-30)	https://doi.org/10.3390/ijms25073945 (Hansson et al.), https://doi.org/10.20944/preprints202506.2045.v1 (Yu et al.)	2024-04, 2025-06
Protein family & domains	Member of glypican family: conserved glypican core (multiple cysteines), C-terminal HS attachment region and GPI‑anchoring signal.	(piao2025unravelingglypican3from pages 17-18, piao2025unravelingglypican3from pages 1-2)	https://doi.org/10.3390/cells14100726 (Piao et al.)	2025-05
Post‑translational modifications (PTMs)	Heparan sulfate (HS) chain attachment, GPI anchoring; can be cleaved by GPI‑cleaving enzymes (e.g., Notum/lipases) and proteolytic shedding to yield soluble forms.	(yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.20944/preprints202506.2045.v1, https://doi.org/10.3390/ijms25073945	2025-06, 2024-04
Subcellular / extracellular localization	Predominantly plasma‑membrane GPI‑anchored; localized to synaptic cleft/extracellular matrix when shed or secreted (astrocyte release).	(yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.20944/preprints202506.2045.v1, https://doi.org/10.3390/ijms25073945	2025-06, 2024-04
Core molecular functions	Acts as an HS‑dependent co‑receptor/modulator for morphogens (Wnt, Hedgehog, FGF) and as an extracellular synaptogenic factor promoting AMPA receptor (GluA1) recruitment.	(yu2025heparansulfateproteoglycans pages 29-30)	https://doi.org/10.20944/preprints202506.2045.v1	2025-06
Synaptogenesis mechanism (CNS)	Astrocyte‑secreted GPC4 promotes release of neuronal pentraxin 1 (NPTX1) from axons and increases GluA1/AMPA receptor clustering; functions via LRRTM–glypican and presynaptic PTPσ interactions.	(yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.20944/preprints202506.2045.v1, https://doi.org/10.3390/ijms25073945	2025-06, 2024-04
Key interacting partners	WNT family ligands and Frizzled co-receptors, FGFs, Hedgehog ligands; synaptic partners LRRTM family, presynaptic PTPσ (RPTPσ), NPTX1 (functional mediator).	(hansson2024dichotomouseffectsof pages 15-17, yu2025heparansulfateproteoglycans pages 29-30)	https://doi.org/10.3390/ijms25073945, https://doi.org/10.20944/preprints202506.2045.v1	2024-04, 2025-06
Shedding & circulation biology	GPC4 can be released into extracellular fluids (adipose‑derived release noted); soluble GPC4 detectable in serum and other biofluids and potentially bioactive.	(hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.3390/ijms25073945	2024-04
Cancer & disease‑context findings (2023–2024)	Context‑dependent (dichotomous) roles in cancer: TCGA analyses and functional perturbations show GPC4 expression associates with both poor and favorable prognosis depending on tumor type; mechanistic links to FGF/TGF and cell‑cycle pathways reported.	(hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.3390/ijms25073945	2024-04
Biomarker / clinical associations	Circulating GPC4 associated with metabolic traits (insulin resistance, obesity/PCOS signals) and linked to cognitive/vascular risk in Parkinson’s disease cohorts — proposed as a candidate serum biomarker in multiple contexts.	(hansson2024dichotomouseffectsof pages 15-17, yu2025heparansulfateproteoglycans pages 29-30)	https://doi.org/10.3390/ijms25073945, https://doi.org/10.20944/preprints202506.2045.v1	2024-04, 2025-06
Recent experimental evidence & methods (2023–2024)	Activity‑dependent proximity labeling and synaptic trafficking studies (2024) support dynamic surface exposure/trafficking of synaptic proteins and note astrocyte‑secreted GPC4 as a modulator of synaptic protein release and AMPA recruitment.	(yu2025heparansulfateproteoglycans pages 29-30, hansson2024dichotomouseffectsof pages 15-17)	https://doi.org/10.20944/preprints202506.2045.v1, https://doi.org/10.3390/ijms25073945	2025-06, 2024-04

Table: Concise, well‑cited summary of human GPC4 (UniProt O75487) covering identity, structure, PTMs, localization, functions, interactions, disease links, and recent experimental evidence; useful as a one‑page reference with source links for follow‑up reading.

Source details (URLs and dates are embedded in references above).

References

(hansson2024dichotomouseffectsof pages 15-17): Victor Chérouvrier Hansson, Fang Cheng, Grigorios Georgolopoulos, and Katrin Mani. Dichotomous effects of glypican-4 on cancer progression and its crosstalk with oncogenes. International Journal of Molecular Sciences, 25:3945, Apr 2024. URL: https://doi.org/10.3390/ijms25073945, doi:10.3390/ijms25073945. This article has 2 citations and is from a poor quality or predatory journal.
(piao2025unravelingglypican3from pages 1-2): Qianling Piao, Xiaona Bian, Qi Zhao, and Luguo Sun. Unraveling glypican-3: from structural to pathophysiological roles and mechanisms—an integrative perspective. Cells, 14:726, May 2025. URL: https://doi.org/10.3390/cells14100726, doi:10.3390/cells14100726. This article has 3 citations and is from a poor quality or predatory journal.
(piao2025unravelingglypican3from pages 17-18): Qianling Piao, Xiaona Bian, Qi Zhao, and Luguo Sun. Unraveling glypican-3: from structural to pathophysiological roles and mechanisms—an integrative perspective. Cells, 14:726, May 2025. URL: https://doi.org/10.3390/cells14100726, doi:10.3390/cells14100726. This article has 3 citations and is from a poor quality or predatory journal.
(yu2025heparansulfateproteoglycans pages 29-30): Chieh Yu, Duy LB Nguyen, Martina Gyimesi, Ian W Peall, Son H Pham, Lyn R Griffiths, Rachel K Okolicsanyi, and Larisa M. Haupt. Heparan sulfate proteoglycans mediate in vitro human neuronal lineage specification. Jun 2025. URL: https://doi.org/10.20944/preprints202506.2045.v1, doi:10.20944/preprints202506.2045.v1.
(hansson2024dichotomouseffectsof pages 1-2): Victor Chérouvrier Hansson, Fang Cheng, Grigorios Georgolopoulos, and Katrin Mani. Dichotomous effects of glypican-4 on cancer progression and its crosstalk with oncogenes. International Journal of Molecular Sciences, 25:3945, Apr 2024. URL: https://doi.org/10.3390/ijms25073945, doi:10.3390/ijms25073945. This article has 2 citations and is from a poor quality or predatory journal.

Citations

yu2025heparansulfateproteoglycans pages 29-30
hansson2024dichotomouseffectsof pages 15-17
hansson2024dichotomouseffectsof pages 1-2
https://doi.org/10.3390/ijms25073945
https://doi.org/10.20944/preprints202506.2045.v1
https://doi.org/10.3390/cells14100726
https://doi.org/10.20944/preprints202506.2045.v1,
https://doi.org/10.3390/ijms25073945|2025-06,
https://doi.org/10.20944/preprints202506.2045.v1|2025-06|
https://doi.org/10.3390/ijms25073945,
https://doi.org/10.20944/preprints202506.2045.v1|2024-04,
https://doi.org/10.3390/ijms25073945|2024-04|
https://doi.org/10.3390/cells14100726,

📄 View Raw YAML

id: O75487
gene_symbol: GPC4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Glypican-4 (GPC4) is a GPI-anchored cell surface heparan sulfate
  proteoglycan belonging to the glypican family. GPC4 functions as a co-receptor
  that modulates growth factor signaling pathways including Wnt, Hedgehog, and
  FGF by binding ligands through its heparan sulfate chains and presenting them
  to their cognate receptors. In the central nervous system, astrocyte-derived
  GPC4 serves as a critical synaptogenic factor that promotes excitatory synapse
  formation and maturation by increasing surface clustering of GluA1-containing
  AMPA receptors through LRRTM-GPC4-PTPsigma interactions. GPC4 can also be shed
  from the cell surface into extracellular fluids where it may act as a soluble
  signaling factor. Mutations in GPC4 cause Keipert syndrome, an X-linked
  recessive disorder characterized by craniofacial and digital abnormalities,
  and variants have been implicated in Robinow syndrome through perturbation of
  Wnt 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 other
        glypican family members. Glypicans can modulate cell migration through
        their interactions with growth factors and morphogens that regulate cell
        motility. However, direct experimental evidence for GPC4-specific roles
        in cell migration is limited compared to its well-established roles in
        synaptogenesis and Wnt signaling.
      action: KEEP_AS_NON_CORE
      reason: While glypicans broadly influence cell migration through growth
        factor modulation, this is not a defining core function of GPC4. The
        phylogenetic inference is reasonable but GPC4's primary characterized
        functions are in synapse formation and Wnt signaling co-receptor
        activity.
      supported_by:
        - reference_id: GO_REF:0000033
  - term:
      id: GO:0031012
      label: extracellular matrix
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation indicating GPC4 localization to extracellular
        matrix. As a GPI-anchored proteoglycan bearing heparan sulfate chains,
        GPC4 can interact with ECM components. However, GPC4 is primarily
        described as a cell surface protein with a GPI anchor.
      action: ACCEPT
      reason: Glypicans are known to interact with the extracellular matrix
        through their heparan sulfate chains. While GPC4 is primarily
        GPI-anchored at the cell surface, it can also be shed and found in
        extracellular spaces including the synaptic cleft.
      supported_by:
        - reference_id: GO_REF:0000033
  - 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 reflecting GPC4's established role in regulating
        AMPA receptor localization at synapses. This is a well-characterized
        function of GPC4 in the CNS where astrocyte-derived GPC4 promotes
        GluA1/AMPA receptor clustering at postsynaptic sites.
      action: ACCEPT
      reason: This annotation accurately captures a core function of GPC4. The
        deep research literature confirms that GPC4 promotes excitatory synapse
        maturation by increasing surface clustering of GluA1-containing AMPA
        receptors via a LRRTM-GPC4-PTPsigma pathway and by inducing neuronal
        pentraxin-1 (NPTX1) release.
      supported_by:
        - reference_id: GO_REF:0000033
        - reference_id: file:human/GPC4/GPC4-deep-research-falcon.md
          supporting_text: "It promotes excitatory synapse maturation by increasing
            surface clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma
            pathway and by inducing neuronal pentraxin-1 (NPTX1) release from axons."
  - term:
      id: GO:0009986
      label: cell surface
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for cell surface localization. GPC4 is
        GPI-anchored to the outer leaflet of the plasma membrane, making the
        cell surface its primary functional location.
      action: ACCEPT
      reason: This is a core localization for GPC4. UniProt confirms cell
        membrane localization via GPI anchor at position Ser-529. The protein is
        tethered to the external side of the plasma membrane where it acts as a
        co-receptor for signaling molecules.
      supported_by:
        - reference_id: GO_REF:0000033
        - reference_id: PMID:10585884
          supporting_text: Expression of glypican-4 in haematopoietic-progenitor
            and bone-marrow-stromal cells.
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for synapse localization. GPC4 is released by
        astrocytes into the synaptic cleft where it functions in synaptogenesis
        and AMPA receptor recruitment.
      action: ACCEPT
      reason: This annotation accurately reflects GPC4's role as an
        astrocyte-derived synaptogenic factor that functions at synapses to
        promote excitatory synapse formation and maturation. This is a core
        function supported by extensive literature.
      supported_by:
        - reference_id: GO_REF:0000033
  - term:
      id: GO:0099560
      label: synaptic membrane adhesion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation reflecting GPC4's role in synaptic membrane
        adhesion. GPC4 interacts with LRRTMs and presynaptic PTPsigma to
        coordinate pre- and postsynaptic assembly, functioning as a
        trans-synaptic organizer.
      action: ACCEPT
      reason: GPC4 functions as a synaptic organizer that bridges pre- and
        postsynaptic membranes through interactions with synaptic adhesion
        molecules. The LRRTM-GPC4-PTPsigma complex mediates trans-synaptic
        signaling that coordinates synapse development.
      supported_by:
        - reference_id: GO_REF:0000033
  - term:
      id: GO:1905606
      label: regulation of presynapse assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for regulation of presynapse assembly. GPC4's
        interactions with presynaptic PTPsigma contribute to presynaptic
        differentiation and organization.
      action: ACCEPT
      reason: This annotation captures GPC4's role in coordinating presynaptic
        development through its trans-synaptic signaling function. The
        LRRTM-GPC4-PTPsigma pathway involves engagement of presynaptic receptor
        protein tyrosine phosphatase sigma to promote presynaptic
        differentiation.
      supported_by:
        - reference_id: GO_REF:0000033
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProtKB subcellular location mapping.
        GPC4 can be shed from the cell surface and secreted into extracellular
        spaces.
      action: ACCEPT
      reason: UniProt confirms that secreted glypican-4 is released into the
        extracellular space. The protein contains a GPI-anchoring signal that
        can be cleaved to release soluble forms. Soluble GPC4 has been detected
        in serum and other biofluids.
      supported_by:
        - reference_id: GO_REF:0000044
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation based on InterPro glypican domain and UniProtKB
        subcellular location data. GPC4 is GPI-anchored to the plasma membrane.
      action: ACCEPT
      reason: This is correct and well-supported. UniProt confirms GPC4 contains
        a GPI-anchor signal with the amidated serine at position 529, tethering
        it to the plasma membrane outer leaflet.
      supported_by:
        - reference_id: GO_REF:0000120
  - 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 mapping. Glypicans
        regulate signal transduction by acting as co-receptors for morphogens
        and growth factors.
      action: ACCEPT
      reason: This accurately captures a core function of GPC4. The glypican
        family modulates signaling by binding ligands (Wnt, FGF, Hedgehog)
        through heparan sulfate chains and presenting them to receptors. GPC4
        has experimentally demonstrated roles in Wnt signaling.
      supported_by:
        - reference_id: GO_REF:0000002
        - reference_id: PMID:29276006
          supporting_text: 2017 Dec 21. WNT Signaling Perturbations Underlie the
            Genetic Heterogeneity of Robinow Syndrome.
  - term:
      id: GO:0031012
      label: extracellular matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro glypican domain mapping. Duplicate
        of the IBA annotation for the same term.
      action: ACCEPT
      reason: Consistent with the IBA annotation for the same term. Glypicans
        with heparan sulfate chains interact with ECM components. This IEA
        provides additional support.
      supported_by:
        - reference_id: GO_REF:0000002
  - term:
      id: GO:0043202
      label: lysosomal lumen
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA annotation from ARBA machine learning models suggesting
        lysosomal lumen localization. This likely reflects GPC4's presence in
        the degradation pathway for heparan sulfate proteoglycans.
      action: ACCEPT
      reason: Heparan sulfate proteoglycans are degraded in lysosomes. Reactome
        pathways confirm that HSPGs including GPC4 are translocated to lysosomes
        for degradation, and heparanase cleaves heparan sulfate in the lysosomal
        lumen.
      supported_by:
        - reference_id: GO_REF:0000117
  - term:
      id: GO:0098552
      label: side of membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on UniProtKB GPI-anchor keyword mapping.
        GPC4 is on the extracellular side of the membrane.
      action: MODIFY
      reason: The term 'side of membrane' is too general. GPC4 is specifically
        located on the external side of the plasma membrane via its GPI anchor.
        A more specific term should be used.
      proposed_replacement_terms:
        - id: GO:0009897
          label: external side of plasma membrane
      supported_by:
        - reference_id: GO_REF:0000043
        - reference_id: PMID:10585884
          supporting_text: Expression of glypican-4 in haematopoietic-progenitor
            and bone-marrow-stromal cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: IPI annotation from IntAct based on high-throughput interactome
        study. Interaction with GPC6 (Q9Y625) detected.
      action: MODIFY
      reason: The term 'protein binding' is too general and uninformative. GPC4
        interacts with GPC6, another glypican family member. More specific
        molecular function terms describing GPC4's co-receptor or signaling
        adapter activities would be more informative.
      proposed_replacement_terms:
        - id: GO:0015026
          label: coreceptor activity
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: IPI annotation from HuRI reference interactome study. Interaction
        with PICK1 (Q9NRD5) detected.
      action: MARK_AS_OVER_ANNOTATED
      reason: While the protein-protein interaction is likely valid (from the
        HuRI reference interactome), the term 'protein binding' does not provide
        functional insight. PICK1 is a PDZ domain protein involved in AMPA
        receptor trafficking, which could be relevant to GPC4's synaptic
        function, but the annotation as currently stated is uninformative.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: IPI annotation from BioPlex 3.0 AP-MS study. Interaction with
        GPC6 (Q9Y625) detected.
      action: MARK_AS_OVER_ANNOTATED
      reason: Duplicate evidence for GPC4-GPC6 interaction. Same concern as
        above - 'protein binding' is too general. The interaction between
        glypican family members may reflect their organization in membrane
        microdomains or functional cooperation.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: IPI annotation from recent interactome study. Interaction with
        GPC6 (Q9Y625) detected.
      action: MARK_AS_OVER_ANNOTATED
      reason: Third independent detection of GPC4-GPC6 interaction strengthens
        confidence in this interaction. However, 'protein binding' remains
        uninformative.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for
            structural and functional genomics.
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation transferred from mouse ortholog based on Ensembl
        Compara analysis. Consistent with IBA annotation for same term.
      action: ACCEPT
      reason: This annotation is consistent with the well-established role of
        GPC4 at synapses. The transfer from mouse ortholog is appropriate as
        mouse GPC4 function in synaptogenesis is well characterized.
      supported_by:
        - reference_id: GO_REF:0000107
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation transferred from mouse ortholog indicating
        localization at glutamatergic synapses. GPC4 promotes excitatory
        (glutamatergic) synapse formation.
      action: ACCEPT
      reason: This annotation is consistent with GPC4's role in promoting
        GluA1-containing AMPA receptor clustering at excitatory synapses. GPC4
        specifically promotes excitatory synapse maturation.
      supported_by:
        - reference_id: GO_REF:0000107
  - term:
      id: GO:0099560
      label: synaptic membrane adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: IEA annotation transferred from mouse ortholog. Consistent with
        IBA annotation for same term.
      action: ACCEPT
      reason: Provides additional support for GPC4's role in synaptic membrane
        adhesion through ortholog transfer. Consistent with established
        LRRTM-GPC4-PTPsigma trans-synaptic complex.
      supported_by:
        - reference_id: GO_REF:0000107
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9940993
    review:
      summary: TAS annotation from Reactome pathway indicating GPC4 presence in
        Golgi lumen during glycosaminoglycan biosynthesis. PXYLP1
        dephosphorylates xylose moiety.
      action: ACCEPT
      reason: GPC4 transits through the Golgi during biosynthesis where its
        heparan sulfate chains are assembled. This is part of the normal
        processing of all HSPGs.
      supported_by:
        - reference_id: Reactome:R-HSA-9940993
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9941039
    review:
      summary: TAS annotation from Reactome pathway. FAM20B phosphorylates
        xylose moiety during GAG chain assembly.
      action: ACCEPT
      reason: Part of the HS-GAG biosynthesis pathway in the Golgi. Multiple
        Reactome references support GPC4's transit through Golgi during
        biosynthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-9941039
  - term:
      id: GO:0015026
      label: coreceptor activity
    evidence_type: NAS
    original_reference_id: PMID:24431302
    review:
      summary: NAS annotation for coreceptor activity based on review discussing
        Wnt signaling in dopaminergic neuron development. Glypicans act as
        co-receptors for Wnt ligands.
      action: ACCEPT
      reason: This is a core molecular function of GPC4. The glypican family
        functions as co-receptors for morphogens including Wnts, presenting them
        to Frizzled receptors through HS-dependent binding. This annotation
        accurately captures GPC4's primary molecular function.
      supported_by:
        - reference_id: PMID:24431302
          supporting_text: Wnt signaling in midbrain dopaminergic neuron
            development and regenerative medicine for Parkinson's disease.
        - reference_id: PMID:29276006
          supporting_text: 2017 Dec 21. WNT Signaling Perturbations Underlie the
            Genetic Heterogeneity of Robinow Syndrome.
  - term:
      id: GO:0016055
      label: Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:29276006
    review:
      summary: IMP annotation based on finding pathogenic GPC4 variants in
        patients with Robinow syndrome, a disorder caused by Wnt/PCP pathway
        perturbation. Functional studies supported GPC4's role in Wnt signaling.
      action: ACCEPT
      reason: This annotation is well-supported by experimental evidence. The
        study identified GPC4 as a candidate gene for Robinow syndrome and
        demonstrated its connection to the Wnt signaling pathway. GPC4's role in
        Wnt signaling is a core function of this co-receptor.
      supported_by:
        - reference_id: PMID:29276006
          supporting_text: 2017 Dec 21. WNT Signaling Perturbations Underlie the
            Genetic Heterogeneity of Robinow Syndrome.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: HDA
    original_reference_id: PMID:21630459
    review:
      summary: HDA annotation from proteomic characterization of human sperm
        nucleus. GPC4 was identified among proteins in isolated sperm nuclei.
      action: MARK_AS_OVER_ANNOTATED
      reason: This is likely a false positive from the high-throughput
        proteomics study. GPC4 is a GPI-anchored cell surface proteoglycan with
        no known nuclear function. The sperm nucleus preparation may have
        contained contaminating membrane fragments or this represents an
        artifact. Nuclear localization contradicts all known biology of
        glypicans.
      supported_by:
        - reference_id: PMID:21630459
          supporting_text: Jun 1. Proteomic characterization of the human sperm
            nucleus.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19199708
    review:
      summary: HDA annotation from proteomic analysis of parotid gland exosomes.
        GPC4 was identified among exosomal proteins by MudPIT mass spectrometry.
      action: ACCEPT
      reason: This annotation is plausible. GPC4 can be shed from the cell
        surface and released in extracellular vesicles. The study identified
        GPC4 among 491 proteins in parotid exosomes. GPI-anchored proteins
        including glypicans are known to be incorporated into exosomes.
      supported_by:
        - reference_id: PMID:19199708
          supporting_text: Proteomic analysis of human parotid gland exosomes by
            multidimensional protein identification technology (MudPIT).
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1878002
    review:
      summary: TAS annotation from Reactome. XYLTs transfer xylose to core
        protein during GAG synthesis.
      action: ACCEPT
      reason: Part of the tetrasaccharide linker synthesis pathway required for
        GAG chain assembly. GPC4 transits through Golgi during biosynthesis.
      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. B3GAT dimers transfer glucuronic
        acid during linker synthesis.
      action: ACCEPT
      reason: Part of HS-GAG biosynthesis pathway. All TAS Golgi lumen
        annotations from Reactome reflect GPC4's transit through secretory
        pathway during biosynthesis and modification.
      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. B3GALT6 transfers galactose during
        linker synthesis.
      action: ACCEPT
      reason: Part of HS-GAG biosynthesis. Golgi localization during processing
        is expected.
      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. EXT1:EXT2 complex transfers GlcNAc
        to heparan chain.
      action: ACCEPT
      reason: Part of heparan sulfate chain elongation in Golgi.
      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. EXT1:EXT2 complex transfers
        glucuronic acid to heparan.
      action: ACCEPT
      reason: Part of HS chain elongation pathway.
      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. NDSTs sulfate glucosamine residues
        forming heparan sulfate.
      action: ACCEPT
      reason: Part of HS chain modification in Golgi. Critical for generating
        sulfated heparan sulfate.
      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. NDSTs N-deacetylate GlcNAc
        residues.
      action: ACCEPT
      reason: Part of HS chain modification pathway.
      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. HSPGs are secreted to plasma
        membrane.
      action: ACCEPT
      reason: Represents transport of mature GPC4 from Golgi to 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. HS3ST1 sulfates glucosamine at C3.
      action: ACCEPT
      reason: Part of HS chain modification pathway in Golgi.
      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. EXT1:EXT2 transfers glucuronic
        acid.
      action: ACCEPT
      reason: Duplicate pathway reference for 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. HS6STs sulfate glucosamine at C6.
      action: ACCEPT
      reason: Part of HS chain modification in Golgi.
      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. HS2ST1 sulfates iduronic acid at
        C2.
      action: ACCEPT
      reason: Part of 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. HS3ST2-6 sulfate glucosamine at C3.
      action: ACCEPT
      reason: Part of HS chain modification pathway.
      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 disease pathway. Defective B3GAT3
        affecting linker synthesis.
      action: ACCEPT
      reason: GPC4 is substrate for GAG biosynthesis machinery, including in
        disease contexts.
      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 disease pathway. Defective EXT2 in
        EXT1:EXT2 complex.
      action: ACCEPT
      reason: GPC4 is affected in exostoses syndromes caused by EXT mutations.
      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 disease pathway. Defective EXT1.
      action: ACCEPT
      reason: Part of disease pathway affecting HSPG biosynthesis.
      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 disease pathway.
      action: ACCEPT
      reason: Part of disease pathway affecting HSPG biosynthesis.
      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 disease pathway.
      action: ACCEPT
      reason: Part of disease pathway affecting HSPG biosynthesis.
      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. Heparanase 2 binds heparan sulfate
        proteoglycans at plasma membrane.
      action: ACCEPT
      reason: GPC4 is targeted by heparanase 2 at the cell surface.
      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. HS-GAGs translocate to lysosome for
        degradation.
      action: ACCEPT
      reason: GPC4 at plasma membrane is internalized 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. HSPGs secreted to plasma membrane.
      action: ACCEPT
      reason: GPC4 is transported to and functions at the plasma membrane.
      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. LRPs transport retinol-HSPG
        complexes.
      action: ACCEPT
      reason: HSPGs including GPC4 participate in retinoid metabolism at cell
        surface.
      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. Retinol-ester complexes bind apoE
        and HSPG.
      action: ACCEPT
      reason: GPC4 as HSPG involved in retinoid transport pathway.
      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. NREH hydrolyzes retinol esters from
        HSPG complexes.
      action: ACCEPT
      reason: Part of retinoid metabolism pathway involving HSPGs.
      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. SARS-CoV-2 spike glycoprotein binds
        ACE2 on host cells. HSPGs can act as co-receptors for viral entry.
      action: KEEP_AS_NON_CORE
      reason: While HSPGs including GPC4 may facilitate SARS-CoV-2 binding, this
        is not a core biological function but rather reflects pathogen
        exploitation of cell surface proteoglycans.
      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. TMPRSS2 mediated spike protein
        cleavage.
      action: KEEP_AS_NON_CORE
      reason: Part of viral entry pathway. Not a core function of GPC4.
      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. SARS-CoV-2 membrane fusion.
      action: KEEP_AS_NON_CORE
      reason: Viral entry pathway. Not a core GPC4 function.
      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. FURIN mediated spike cleavage.
      action: KEEP_AS_NON_CORE
      reason: Viral entry pathway. Not a core GPC4 function.
      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. RSV sG binds to HSPGs.
      action: KEEP_AS_NON_CORE
      reason: Viral attachment pathway. HSPGs serve as attachment factors for
        many pathogens but this is not a core biological function.
      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. Heparanase cleaves heparan sulfate
        in lysosome.
      action: ACCEPT
      reason: GPC4 is degraded in lysosomes where heparanase cleaves HS chains.
      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. HS-GAGs translocate to lysosome.
      action: ACCEPT
      reason: Part of HSPG degradation pathway.
      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. B4GALT7 transfers galactose to
        xylosyl unit.
      action: ACCEPT
      reason: Part of GAG linker synthesis in Golgi.
      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 disease pathway. Defective B4GALT7.
      action: ACCEPT
      reason: Disease pathway affecting GAG synthesis on GPC4.
      supported_by:
        - reference_id: Reactome:R-HSA-3560804
  - term:
      id: GO:0005796
      label: Golgi lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9036285
    review:
      summary: TAS annotation from Reactome disease pathway.
      action: ACCEPT
      reason: Disease pathway affecting GPC4 biosynthesis.
      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 disease pathway.
      action: ACCEPT
      reason: Disease pathway affecting GPC4 biosynthesis.
      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. EXTL3 transfers GlcNAc to GAG
        linker.
      action: ACCEPT
      reason: Part of HS chain initiation in Golgi.
      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. Note this reference is for
        lysosomal heparanase activity, may be a pathway data entry issue.
      action: ACCEPT
      reason: While the reference describes lysosomal processing, GPC4 transits
        through Golgi.
      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 disease pathway. Defective B3GALT6.
      action: ACCEPT
      reason: Disease pathway affecting GAG linker synthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-4420365
  - term:
      id: GO:0009897
      label: external side of plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:10585884
    review:
      summary: IDA annotation based on direct experimental evidence. FACS
        analysis and confocal laser-scanning microscopy demonstrated GPC4 on the
        cell surface of haematopoietic progenitor cells and bone marrow stromal
        cells.
      action: ACCEPT
      reason: Direct experimental evidence for external plasma membrane
        localization. The study showed GPC4 expression on the surface of TF-1
        cells by FACS analysis and confirmed localization by confocal
        microscopy. This is consistent with GPC4's GPI-anchored structure
        placing it on the extracellular side of the membrane.
      supported_by:
        - reference_id: PMID:10585884
          supporting_text: Expression of glypican-4 in haematopoietic-progenitor
            and bone-marrow-stromal cells.
  - term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    evidence_type: NAS
    original_reference_id: file:human/GPC4/GPC4-deep-research-falcon.md
    review:
      summary: GPC4 functions as a synaptic adaptor that bridges pre- and
        postsynaptic membranes through the LRRTM-GPC4-PTPsigma trans-synaptic
        complex. This adaptor function is critical for recruiting and clustering
        AMPA receptors at glutamatergic synapses.
      action: NEW
      reason: This annotation captures GPC4's well-characterized role as a
        trans-synaptic organizer that mediates protein complex assembly at
        synapses. The deep research literature confirms GPC4 bridges LRRTMs with
        presynaptic PTPsigma to coordinate synapse development and AMPA receptor
        recruitment. This molecular function term accurately describes GPC4's
        adaptor role in assembling synaptic protein complexes.
      supported_by:
        - reference_id: file:human/GPC4/GPC4-deep-research-falcon.md
          supporting_text: "A defining role of GPC4 is as an astrocyte-derived synaptogenic
            factor. It promotes excitatory synapse maturation by increasing surface
            clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma
            pathway"
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:10585884
    title: Expression of glypican-4 in haematopoietic-progenitor and
      bone-marrow-stromal cells
    findings:
      - statement: GPC4 expressed as heparan sulfate proteoglycan on cell
          surface
        supporting_text: "Western blot analysis showed expression of GPC-4 as a heparan
          sulphate proteoglycan in the human haematopoietic-progenitor cell line TF-1
          and normal human bone marrow."
      - statement: Detected by FACS in TF-1 haematopoietic progenitor cells
        supporting_text: "These results were confirmed by FACS analysis of TF-1 cells."
      - statement: Confocal microscopy confirmed cell surface localization
        supporting_text: "GPC-4-positive progenitor cells and stromal cells were enriched
          from normal human bone marrow by magnetic-cell sorting and analysed by confocal
          laser-scanning microscopy."
  - id: PMID:19199708
    title: Proteomic analysis of human parotid gland exosomes by
      multidimensional protein identification technology (MudPIT)
    findings:
      - statement: GPC4 detected in parotid gland exosome fraction
        supporting_text: "Using MudPIT (multidimensional protein identification technology)
          mass spectrometry, we catalogued 491 proteins in the exosome fraction of
          human parotid saliva."
      - statement: GPI-anchored proteins incorporated into exosomes
        supporting_text: "interaction with tetraspanins and GPI-anchored proteins
          is necessary for ILV formation"
  - id: PMID:21630459
    title: Proteomic characterization of the human sperm nucleus
    findings:
      - statement: GPC4 detected in sperm nuclear fraction (likely
          contamination)
        supporting_text: "403 different proteins have been identified from the isolated
          sperm nuclei"
  - id: PMID:24431302
    title: Wnt signaling in midbrain dopaminergic neuron development and
      regenerative medicine for Parkinson's disease
    findings:
      - statement: Glypicans function as Wnt co-receptors
        supporting_text: "Wnts are a highly conserved family of lipid-modified glycoproteins
          that work as morphogens to activate several signaling pathways"
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks
    findings:
      - statement: GPC4 interacts with GPC6
        supporting_text: "Architecture of the human interactome defines protein communities
          and disease networks"
  - id: PMID:29276006
    title: WNT Signaling Perturbations Underlie the Genetic Heterogeneity of
      Robinow Syndrome
    findings:
      - statement: GPC4 variants identified in Robinow syndrome patients
        supporting_text: "we also found likely pathogenic variants in candidate genes
          GPC4 and RAC3, both linked to the Wnt signaling pathway"
      - statement: GPC4 linked to Wnt signaling pathway
        supporting_text: "These data support an initial hypothesis that Robinow syndrome
          results from perturbation of the Wnt/PCP pathway"
      - statement: Supports role of GPC4 in Wnt/PCP signaling
        supporting_text: "Robinow syndrome results from perturbation of the Wnt/PCP
          pathway, suggest specific relevant domains of the proteins involved"
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings:
      - statement: GPC4-PICK1 interaction detected by Y2H
        supporting_text: "A reference map of the human binary protein interactome"
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the
      human interactome
    findings:
      - statement: GPC4-GPC6 interaction detected by AP-MS
        supporting_text: "Dual proteome-scale networks reveal cell-specific remodeling
          of the human interactome"
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional
      genomics
    findings:
      - statement: GPC4 interactions detected
        supporting_text: "Multimodal cell maps as a foundation for structural and
          functional genomics"
  - id: file:human/GPC4/GPC4-deep-research-falcon.md
    title: Deep research summary for GPC4
    findings:
      - statement: GPC4 is an astrocyte-derived synaptogenic factor
        supporting_text: "A defining role of GPC4 is as an astrocyte-derived synaptogenic
          factor. It promotes excitatory synapse maturation by increasing surface
          clustering of GluA1-containing AMPA receptors via a LRRTM-GPC4-PTPsigma
          pathway and by inducing neuronal pentraxin-1 (NPTX1) release from axons."
      - statement: GPC4 functions as a co-receptor for Wnt and other morphogens
        supporting_text: "Like other glypicans, GPC4 modulates extracellular signaling
          by binding ligands through HS chains and presenting them to receptors, impacting
          Wnt, Hedgehog, and FGF pathways."
  - 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
core_functions:
  - molecular_function:
      id: GO:0015026
      label: coreceptor activity
    description: GPC4 functions as a cell surface co-receptor for growth factors
      and morphogens, particularly Wnts. Through its heparan sulfate chains,
      GPC4 binds signaling ligands and presents them to their primary receptors,
      modulating signaling pathway activation. This co-receptor function is
      central to GPC4's role in development and is perturbed in Robinow
      syndrome.
    directly_involved_in:
      - id: GO:0016055
        label: Wnt signaling pathway
    locations:
      - id: GO:0009897
        label: external side of plasma membrane
  - molecular_function:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    description: In the CNS, astrocyte-derived GPC4 is a critical synaptogenic
      factor that promotes excitatory synapse formation by regulating AMPA
      receptor localization. GPC4 increases surface clustering of
      GluA1-containing AMPA receptors through the LRRTM-GPC4-PTPsigma
      trans-synaptic complex and induces neuronal pentraxin-1 release.
    directly_involved_in:
      - id: GO:0098696
        label: regulation of neurotransmitter receptor localization to
          postsynaptic specialization membrane
      - id: GO:0099560
        label: synaptic membrane adhesion
    locations:
      - id: GO:0098978
        label: glutamatergic synapse
    supported_by:
      - reference_id: PMID:28514442

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Citations

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