Affinage

GPC4

Glypican-4 · UniProt O75487

Length
556 aa
Mass
62.4 kDa
Annotated
2026-06-10
15 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPC4 is a GPI-anchored, heparan sulfate-bearing cell-surface proteoglycan that acts as a co-receptor and modulator across multiple developmental and signaling pathways (PMID:7657705). Proper post-translational processing — including conserved residues required for cell-surface heparan sulfate display, N-linked glycosylation (Asn514) and GPI anchoring (Ser529) — is essential for its stability and function, and truncating variants that remove these features cause Keipert syndrome, with Gpc4 knockout mice recapitulating the craniofacial and digital phenotype (PMID:10814714, PMID:30982611). In development, GPC4 operates in the non-canonical Wnt pathway alongside wnt5b, wnt9a and wls to drive convergent-extension cell intercalation during palate morphogenesis and to time chondrocyte maturation and endochondral ossification (PMID:27287801, PMID:27908786). At the cell surface it engages secreted and matricellular partners to gate growth-factor signaling: CCN1 binds GPC4 in a heparin-dependent manner to sustain Sonic Hedgehog-driven neural stem cell maintenance [PMID:bio_10.1101_2025.05.16.654402], while CD36 binds GPC4 and drives its proteasome-dependent ubiquitination and degradation, thereby suppressing β-catenin/c-myc-driven glycolytic gene expression in colorectal cancer (PMID:31484922). GPC4 also functions upstream of TLR4/NF-κB signaling in microglia and astrocytes, where its abundance — itself controlled by FTO/YTHDF3-dependent m6A regulation — promotes neuroinflammation (PMID:37492748, PMID:41724289). In the Alzheimer's context, GPC4 shed from microglia facilitates tau aggregate uptake and seeding in neurons in concert with APOE (PMID:40883746).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1995 High

    Establishing the molecular identity of GPC4 was the foundational question: the work defined it as a GPI-anchored heparan sulfate proteoglycan displayed at the cell surface, fixing the structural basis for all later co-receptor functions.

    Evidence cDNA cloning and transfection of epitope-tagged construct into MDCK cells with Northern blot and in situ hybridization

    PMID:7657705

    Open questions at the time
    • Does not define signaling partners or downstream pathways
    • No structural detail of heparan sulfate chain attachment in cellular context
  2. 1998 Medium

    Genomic mapping placed GPC4 in a tandem X-linked cluster with GPC3 and linked its deletion to the SGBS phenotype, raising the question of GPC4's role in human overgrowth/dysmorphology syndromes.

    Evidence BAC/PAC contig mapping and deletion analysis of patient DNA

    PMID:9787072

    Open questions at the time
    • Deletion also removed GPC3 exons, confounding gene-specific attribution
    • Single family
  3. 2000 Medium

    Whether glypican processing is required for surface HSPG function was addressed using a conserved missense mutation, showing that processing failure abolishes cell-surface heparan sulfate display.

    Evidence Recombinant protein expression and cell-surface heparan sulfate analysis (in GPC3, conserved residue)

    PMID:10814714

    Open questions at the time
    • Primarily a GPC3 experiment, inference to GPC4 rests on residue conservation
    • Single lab
  4. 2016 High

    The developmental pathway context of GPC4 was defined: genetic epistasis placed it in the non-canonical Wnt arm controlling convergent-extension and chondrocyte maturation, establishing GPC4 as a regulator of morphogenetic cell movements and skeletal timing.

    Evidence Zebrafish gpc4 mutant analysis with genetic epistasis against wnt5b/wnt9a/wls/frzb and skeletal staining

    PMID:27287801 PMID:27908786

    Open questions at the time
    • Molecular mechanism of how GPC4 directs Wnt ligand reception not resolved
    • Direct biochemical interaction with Wnt ligands not shown
  5. 2019 High

    A surface co-receptor that is actively degraded: CD36 was shown to bind GPC4 and trigger its proteasomal turnover, linking GPC4 abundance to β-catenin/c-myc-driven glycolytic metabolism in cancer.

    Evidence Reciprocal Co-IP, ubiquitination and proteasome-inhibitor rescue assays, and in vivo CRC mouse models

    PMID:31484922

    Open questions at the time
    • E3 ligase mediating GPC4 ubiquitination not identified
    • How surface GPC4 controls cytoplasmic β-catenin signaling mechanistically unclear
  6. 2019 High

    GPC4 was established as a Mendelian disease gene: truncating loss-of-function variants cause Keipert syndrome by removing glycosylation and GPI-anchor sites required for stability, confirmed by a knockout mouse recapitulating the phenotype.

    Evidence Whole-exome sequencing across six families, recombinant protein stability assays, Gpc4 knockout mouse phenotyping

    PMID:30982611

    Open questions at the time
    • Which downstream signaling pathway loss drives each Keipert feature not dissected
    • Tissue-specific requirements not mapped
  7. 2022 Medium

    An upstream regulatory layer on GPC4 was identified: m6A demethylation by FTO and YTHDF3-dependent mRNA destabilization control GPC4 levels in microglia, with GPC4 acting upstream of TLR4/NF-κB inflammation.

    Evidence FTO knockdown, RNA-seq, RNA stability assays, rescue and TLR4/FTO inhibitor experiments in an autoimmune uveitis model

    PMID:37492748

    Open questions at the time
    • Direct physical link between GPC4 and TLR4 not demonstrated
    • Single lab
  8. 2025 Medium

    Additional surface partners and neuroinflammatory/disease roles were defined: CCN1 binds GPC4 to sustain Shh-driven neural stem cells, GPC4 promotes astrocytic TLR4/NF-κB signaling in stroke, and microglia-shed GPC4 facilitates tau uptake and seeding with APOE.

    Evidence CCN1-GPC4 binding and heparin-dependence assays with Ccn1 cKO; siRNA knockdown in MCAO/R rat model; microglia surfaceome profiling, tau seeding assays, Drosophila model and human AD brain co-expression

    PMID:40883746 PMID:41724289 PMID:bio_10.1101_2025.05.16.654402

    Open questions at the time
    • Mechanism of how shed GPC4 delivers tau to neurons unresolved
    • CCN1-GPC4 work is a preprint
    • Direct GPC4-TLR4 binding in astrocytes not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single GPI-anchored proteoglycan mechanistically integrates such divergent outputs — Wnt convergent-extension, Shh stem-cell maintenance, CD36-driven degradation, and TLR4 inflammation — and which structural features of GPC4 select among these partners.
  • No structure of GPC4 with any partner reported
  • No unified model connecting its developmental and inflammatory roles
  • E3 ligase and direct TLR4 interaction unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
APOECCN1CD36HS3ST1TLR4

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 GPC4 (K-glypican) is a GPI-anchored heparan sulfate proteoglycan; transfection of epitope-tagged full-length K-glypican cDNA into MDCK cells confirmed cell-surface expression as a GPI-anchored HSPG with heparan sulfate chains and a GPI anchor in its C-terminal region. cDNA cloning, transfection of epitope-tagged construct into MDCK cells, Northern blot, in situ hybridization The Journal of cell biology High 7657705
1998 GPC4 maps to Xq26, centromeric to GPC3, in a tandem gene cluster; the glypican-4 protein is encoded by nine exons. Deletion of the entire GPC4 gene (plus last two GPC3 exons) was identified in one SGBS family, establishing that GPC4 loss can contribute to the SGBS phenotype. BAC/PAC contig mapping, deletion analysis of patient DNA samples Genomics Medium 9787072
2000 A GPC3 missense mutation W296R that is conserved across all glypicans (including GPC4) leads to poor protein processing and failure to increase cell-surface heparan sulfate expression, demonstrating that proper processing is required for glypican cell-surface HSPG function. Recombinant protein expression and cell-surface heparan sulfate analysis Human molecular genetics Medium 10814714
2016 Zebrafish gpc4 functions in non-canonical Wnt signaling to regulate convergent-extension during palate morphogenesis; genetic epistasis with wnt5b, wnt9a, wls, and frzb placed gpc4 in the chondrocyte-receiving arm of Wnt signaling, required for cell intercalation. Zebrafish mutant analysis, genetic epistasis with wnt pathway mutants Development (Cambridge, England) High 27287801
2016 Zebrafish gpc4 loss results in severely delayed endochondral ossification during Meckel's cartilage maturation, placing gpc4 in the non-canonical Wnt pathway (with wls, wnt5b, wnt9a) required for coordinated cartilage morphogenesis and timing of osteogenic differentiation. Zebrafish gpc4 mutant analysis, genetic epistasis with wls/wnt5b/wnt9a mutants, skeletal staining Developmental biology High 27908786
2019 CD36 physically interacts with GPC4, promoting proteasome-dependent ubiquitination and degradation of GPC4, which in turn inhibits β-catenin/c-myc signaling and suppresses downstream glycolytic gene expression (GLUT1, HK2, PKM2, LDHA) in colorectal cancer cells. Co-immunoprecipitation (CD36-GPC4 interaction), ubiquitination assay, proteasome inhibitor rescue, in vitro and in vivo functional studies in CRC cells and mouse models Nature communications High 31484922
2019 Pathogenic truncating variants in GPC4 cause Keipert syndrome through loss of function; the truncation removes functionally important N-linked glycosylation (Asn514) and GPI anchor (Ser529) sites, producing less stable recombinant protein. Gpc4 knockout mice recapitulate the primary features of Keipert syndrome (craniofacial and digital abnormalities). Whole-exome sequencing, recombinant protein stability assay, Gpc4 knockout mouse phenotyping, X-inactivation studies American journal of human genetics High 30982611
2022 FTO-mediated m6A demethylation suppresses GPC4 expression in microglia; loss of FTO increases GPC4 levels via reduced YTHDF3-dependent mRNA destabilization, which activates TLR4/NF-κB signaling to promote microglial inflammation. RNA stability assays confirmed GPC4 upregulation is regulated by m6A reader YTHDF3. FTO knockdown, RNA-seq, RNA stability assay, rescue experiments, TLR4 inhibitor (TAK-242), FTO inhibitor (FB23-2) in experimental autoimmune uveitis model Genes & diseases Medium 37492748
2025 GPC4 shed from microglia acts in trans to facilitate tau aggregate uptake and seeding in neurons; GPC4 also enhances microglial phagocytosis of tau aggregates; these effects are amplified in the presence of APOE. In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan. Microglia surfaceome profiling after Aβ fibril treatment, cell culture tau seeding assays, Drosophila genetic model, co-expression analysis in human AD brain Molecular neurodegeneration Medium 40883746
2025 GPC4 knockdown (siRNA) suppresses the TLR4/NF-κB signaling pathway in an ischemic stroke model, reversing pro-inflammatory effects (TNF-α, IL-1β); GPC4 and TLR4 are co-expressed in astrocytes, positioning GPC4 upstream of TLR4/NF-κB in neuroinflammatory signaling. siRNA knockdown of GPC4, Western blot, RT-qPCR, immunofluorescence co-localization, MCAO/R rat model Journal of ethnopharmacology Medium 41724289
2025 CCN1 (a secreted matricellular protein) physically interacts with GPC4 on radial glial cells and is required for GPC4 to maintain neural stem cells through Sonic Hedgehog (Shh) signaling; this interaction depends on heparin binding to CCN1. Protein interaction assay (CCN1-GPC4 binding), Ccn1 conditional knockout in RGCs, Shh pathway readout, heparin binding experiments bioRxivpreprint Medium bio_10.1101_2025.05.16.654402
2024 GPC4 promotes HS3ST1-mediated glycolysis in lung adenocarcinoma cells; interaction between HS3ST1 and GPC4 was detected by immunoprecipitation. Immunoprecipitation (HS3ST1-GPC4 interaction), glycolysis assay in LUAD cell lines Cancers Low 38398086
2025 A bivalent nanobody Fc-fusion (RB1-Fc) that recognizes the native conformation of hGPC4 neutralizes GPC4 activity in human pluripotent stem cells (hPSCs), causing enhanced differentiation into endoderm that mimics GPC4 downregulation, demonstrating that GPC4 conformation is functionally relevant and that GPC4 suppresses hPSC differentiation. Phage-display nanobody generation, conformational binding assay, hPSC differentiation assay with RB1-Fc treatment and GPC4 knockdown comparison bioRxivpreprint Medium bio_10.1101_2025.05.10.653258

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis. Nature communications 200 31484922
1995 K-glypican: a novel GPI-anchored heparan sulfate proteoglycan that is highly expressed in developing brain and kidney. The Journal of cell biology 129 7657705
2000 Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Human molecular genetics 95 10814714
1998 GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome. Genomics 71 9787072
1999 GPC6, a novel member of the glypican gene family, encodes a product structurally related to GPC4 and is colocalized with GPC5 on human chromosome 13. Genomics 60 10329016
2016 Roles of Wnt pathway genes wls, wnt9a, wnt5b, frzb and gpc4 in regulating convergent-extension during zebrafish palate morphogenesis. Development (Cambridge, England) 41 27287801
2016 Distinct requirements of wls, wnt9a, wnt5b and gpc4 in regulating chondrocyte maturation and timing of endochondral ossification. Developmental biology 41 27908786
2022 FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis. Genes & diseases 34 37492748
2019 Pathogenic Variants in GPC4 Cause Keipert Syndrome. American journal of human genetics 24 30982611
2018 Duplications of GPC3 and GPC4 genes in symptomatic female carriers of Simpson-Golabi-Behmel syndrome type 1. European journal of medical genetics 12 30048822
2024 Hypoxia-Derived Exosomes Promote Lung Adenocarcinoma by Regulating HS3ST1-GPC4-Mediated Glycolysis. Cancers 10 38398086
2025 β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity. bioRxiv : the preprint server for biology 2 40060520
2025 β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity. Molecular neurodegeneration 2 40883746
2019 Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4. Annals of human genetics 2 31583675
2026 From multi-omics discovery to experimental validation: GPC4 mediates the anti-neuroinflammatory effects of Buyang Huanwu decoction via TLR4/NF-κB signaling in ischemic stroke with Qi deficiency and blood stasis syndrome. Journal of ethnopharmacology 0 41724289

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