{"gene":"GPC3","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1996,"finding":"GPC3 encodes a heparan sulfate proteoglycan (glypican-3) anchored to the extracellular surface, and initial western- and ligand-blotting experiments showed it forms a complex with IGF2, suggesting it modulates IGF2 action to control embryonic mesodermal growth.","method":"Western blotting and ligand blotting","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single pulldown/blotting experiment in the original discovery paper; foundational but limited mechanistic depth","pmids":["8589713"],"is_preprint":false},{"year":1998,"finding":"GPC3 (OCI-5) induces apoptosis in a cell-type-specific manner (mesothelioma and breast cancer cells but not NIH 3T3 or HT-29 cells); this apoptotic activity requires GPI membrane anchoring but not the heparan sulfate glycosaminoglycan chains. IGF2 rescues MCF-7 cells from GPC3-induced apoptosis.","method":"Ectopic expression, apoptosis assays, GPI-anchor and glycosaminoglycan chain mutants, IGF2 rescue experiment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (expression constructs, structural mutants, rescue experiment) in a single rigorous study","pmids":["9628896"],"is_preprint":false},{"year":1997,"finding":"OCI-5/GPC3 expression in intestinal epithelial cells is regulated transcriptionally by cell shape: rounding of cells (confluence, low calcium, spheroid culture) increases OCI-5 transcription, while cell flattening (colchicine) or phosphatase inhibition (vanadate) suppresses it.","method":"RNA in situ hybridization, nuclear run-on transcription assays, pharmacological perturbations of cell shape","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — nuclear run-on plus multiple orthogonal cellular perturbations; single lab","pmids":["9281346"],"is_preprint":false},{"year":1998,"finding":"The GPC3 promoter is TATA-less and driven by multiple Sp1 binding sites; three Sp1 sites (centered at –14, –34, and –92 nt) are functional as shown by DNase I footprinting and gel-shift/supershift assays, and Sp1 transactivates GPC3 in Sp1-deficient Drosophila SL2 cells.","method":"Deletion analysis, luciferase reporter assay, DNase I footprinting, EMSA/supershift, transfection in Sp1-deficient SL2 cells","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple complementary biochemical assays (footprinting, EMSA, functional reporter) in one study","pmids":["9651473"],"is_preprint":false},{"year":1999,"finding":"GPC3 expression is silenced in ovarian cancer cell lines by promoter hypermethylation; demethylation with 5-aza-2'-deoxycytidine restores expression, and ectopic GPC3 expression inhibits colony formation, supporting a tumor suppressor function in the ovary.","method":"Southern blot methylation analysis, 5-aza-CdR demethylation, colony-forming assay with ectopic GPC3","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — methylation mechanism established plus functional rescue; single lab","pmids":["10029067"],"is_preprint":false},{"year":1999,"finding":"The GPC3 promoter CpG island is subject to X-chromosome inactivation-induced hypermethylation on the inactive X allele; in vitro methylation of the GPC3 promoter represses reporter gene transcription, while tissue-specific repression on the active X does not involve promoter methylation.","method":"Reporter assay with in vitro methylated promoter constructs, Southern blot analysis of allele-specific methylation, azadeoxycytidine demethylation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro methylation-reporter assay plus allele-specific methylation analysis; single lab","pmids":["9892682"],"is_preprint":false},{"year":2000,"finding":"GPC3 is silenced in malignant mesothelioma primarily by promoter hypermethylation (not mutation or allelic loss); ectopic GPC3 expression inhibits in vitro colony formation of human MM cells, indicating a growth-suppressive function.","method":"Northern blot, methylation analysis, 5-aza-CdR demethylation, ectopic expression colony assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — methylation mechanism plus functional loss-of-function colony assay; single lab","pmids":["10656689"],"is_preprint":false},{"year":2003,"finding":"GPC3 acts as a lung tumor suppressor; its expression is epigenetically silenced by promoter hypermethylation in non-small cell lung carcinoma lines, and ectopic GPC3 expression increases apoptosis in response to etoposide and inhibits tumor growth in nude mice.","method":"Pharmacologic demethylation, ectopic expression, xenograft assay, apoptosis assay","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays (in vitro apoptosis + in vivo xenograft) in one study; single lab","pmids":["12816733"],"is_preprint":false},{"year":2012,"finding":"LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hh complex; GPC3 binds Hh and competes with Patched (Ptc) for Hh binding. The GPC3-Hh interaction triggers LRP1-dependent internalization and degradation of the complex, reducing Hh available for Ptc binding. GPC3 binds LRP1 through its heparan sulfate chains, and this interaction displaces GPC3 from lipid raft domains.","method":"Co-immunoprecipitation, endocytosis assays, heparan sulfate chain mutants, lipid raft fractionation, siRNA knockdown of LRP1","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction assays, structural mutants, and functional readout of Hh signaling inhibition; multiple orthogonal methods in one study","pmids":["22467855"],"is_preprint":false},{"year":2013,"finding":"GPC3 knockdown in Huh7 hepatocellular carcinoma cells induces apoptosis and inhibits proliferation, migration, and invasion, accompanied by suppression of YAP mRNA and protein; addition of recombinant YAP-1 rescues cells from GPC3 knockdown-induced apoptosis, placing GPC3 upstream of Hippo pathway effector YAP.","method":"siRNA knockdown, flow cytometry apoptosis assay, EdU proliferation assay, qPCR, Western blot, recombinant YAP-1 rescue","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined pathway rescue; single lab","pmids":["23060277"],"is_preprint":false},{"year":2016,"finding":"The lncRNA GPC3-AS1 physically associates with the histone acetyltransferase P300/CBP-associated factor (PCAF) and recruits it to the GPC3 gene body, increasing euchromatic histone marks and activating GPC3 transcription; GPC3-AS1-driven HCC cell proliferation and migration are dependent on upregulation of GPC3.","method":"RNA immunoprecipitation (RIP), ChIP, gain- and loss-of-function assays, xenograft","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — RIP and ChIP establish physical recruitment; functional dependence confirmed by GPC3 rescue experiments; single lab","pmids":["27573079"],"is_preprint":false},{"year":2018,"finding":"In breast cancer cells, GPC3 inhibits the canonical Wnt/β-catenin pathway both transcriptionally and by secretion into extracellular media where it competes with or sequesters Wnt ligands from Frizzled receptors. GPC3 also activates non-canonical Wnt and p38 MAPK pathways; the p38/ERK balance is shifted toward p38, driving dormancy. Inhibition of canonical Wnt by GPC3 is required for its effects on cell migration and homotypic adhesion.","method":"Luciferase reporter assay for Wnt activity, Western blotting, qRT-PCR microarray, conditioned medium experiments, lithium (GSK3β inhibitor) rescue, wound-healing and suspension growth assays","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay plus pathway rescue plus multiple phenotypic readouts; single lab","pmids":["30267212"],"is_preprint":false},{"year":2020,"finding":"GPC3 re-expression in murine breast cancer cells reverts epithelial-to-mesenchymal transition, reduces the phospho-ERK/phospho-p38 ratio, elevates p21, p27, and SOX2 (dormancy markers), and suppresses metastasis in vivo. In vivo inhibition of p38 increases invasion and experimental metastasis of GPC3-re-expressing tumors, demonstrating that GPC3 inhibits metastasis specifically through p38 MAPK pathway activation.","method":"Genetically modified cell lines, Western blotting, in vivo metastasis assays, pharmacologic p38 inhibition","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacologic epistasis plus in vivo readout; single lab","pmids":["32800275"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of Unc5D in complex with GPC3 reveal an octameric glycoprotein complex in which four Unc5D molecules form an antiparallel bundle flanked by four GPC3 molecules; central glycan-glycan interactions are formed by N-linked glycans from GPC3 (N241) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. Structure-based mutants and anti-GPC3 nanobodies that modulate Unc5-GPC3 binding demonstrate that this complex guides migrating pyramidal neurons in the mouse cortex and directs cancer cell migration in an embryonic neuroblastoma xenograft model.","method":"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, in vivo cortical neuron migration assay, embryonic xenograft neuroblastoma model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with MD simulation, MS validation, mutagenesis, and in vivo functional validation; multiple orthogonal methods","pmids":["36240740"],"is_preprint":false},{"year":2014,"finding":"GPC3 overexpression in renal cell carcinoma cell lines (786-O and ACHN) reduces cell proliferation by inducing G1 phase cell cycle arrest without triggering apoptosis.","method":"Ectopic expression, MTT assay, colony formation, flow cytometry cell cycle analysis","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 — single lab, overexpression phenotype with no pathway placement beyond cell cycle arrest","pmids":["25168166"],"is_preprint":false},{"year":2013,"finding":"GPC3 overexpression in Huh7 and SK-HEP-1 HCC cells inhibits proliferation and invasion by inducing apoptosis; co-treatment with IGF2 or FGF2 significantly suppresses GPC3-induced apoptosis, indicating GPC3 acts as a negative regulator of IGF2 and FGF2 survival pathways.","method":"Ectopic GPC3 expression, Annexin V-PI flow cytometry, IGF2/FGF2 rescue","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiments define pathway relationship; single lab","pmids":["23338845"],"is_preprint":false},{"year":2001,"finding":"GPC3 mRNA and protein are specifically localized to the differentiated syncytiotrophoblast layer of the human placenta, as determined by in situ hybridization and immunohistochemical staining; expression increases markedly during cytotrophoblast differentiation into syncytiotrophoblast in vitro.","method":"In situ hybridization, immunohistochemistry, RT-PCR during in vitro differentiation","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 — localization established but no functional consequence directly demonstrated","pmids":["11193214"],"is_preprint":false}],"current_model":"GPC3 is a GPI-anchored heparan sulfate proteoglycan that controls cell growth and migration through multiple mechanisms: it forms a complex with IGF2 to modulate IGF2 signaling; it binds Hedgehog ligands and, via LRP1-mediated endocytosis (dependent on its HS chains), sequesters Hh away from Patched to inhibit Hh signaling; it inhibits canonical Wnt/β-catenin signaling partly through extracellular competition with Wnt ligands; it activates p38 MAPK to suppress metastasis and induce tumor dormancy; it modulates Hippo pathway output through YAP; and it forms a structurally defined octameric complex with the guidance receptor Unc5D (via glycan-glycan interactions) to regulate neuronal and cancer cell migration. Its promoter is Sp1-dependent and is silenced by CpG island hypermethylation in multiple cancer types, consistent with tumor suppressor activity in mesothelioma, ovarian, lung, breast, and renal cancers, whereas it is oncogenically overexpressed in hepatocellular carcinoma where it promotes growth via Wnt and Hedgehog pathways."},"narrative":{"teleology":[{"year":1996,"claim":"The identity of GPC3 as a GPI-anchored heparan sulfate proteoglycan that binds IGF2 provided the first molecular framework for how it might control mesodermal growth.","evidence":"Western blotting and ligand blotting in transfected cells","pmids":["8589713"],"confidence":"Medium","gaps":["IGF2 binding affinity and stoichiometry not determined","Functional consequence of GPC3–IGF2 interaction on downstream signaling not tested","Single pulldown/blotting approach without reciprocal validation"]},{"year":1997,"claim":"Demonstration that GPC3 transcription is regulated by cell shape established that its expression is dynamically controlled by the physical microenvironment of epithelial cells.","evidence":"Nuclear run-on assays and pharmacological perturbations of cell shape in intestinal epithelial cells","pmids":["9281346"],"confidence":"Medium","gaps":["Transcription factor(s) mediating shape-dependent regulation not identified","Relevance to in vivo tissue architecture unknown"]},{"year":1998,"claim":"Identification of Sp1 as the direct transcriptional driver of the TATA-less GPC3 promoter and demonstration that GPC3 induces apoptosis in a GPI-anchor-dependent manner (rescued by IGF2) established its dual identity as a transcriptionally regulated growth suppressor.","evidence":"DNase I footprinting, EMSA/supershift, Sp1-deficient SL2 cell reporter assay (promoter); ectopic expression with GPI-anchor and HS-chain mutants, apoptosis assays, IGF2 rescue (function)","pmids":["9651473","9628896"],"confidence":"High","gaps":["Downstream apoptotic pathway (caspase dependence, death receptor involvement) not delineated","Why GPI anchor is essential but HS chains dispensable for apoptosis induction not explained"]},{"year":1999,"claim":"Discovery that promoter CpG island hypermethylation silences GPC3 in ovarian cancer, with demethylation restoring expression and re-expression suppressing colony formation, established the epigenetic tumor suppressor paradigm for GPC3.","evidence":"Southern blot methylation analysis, 5-aza-CdR demethylation, colony-forming assay in ovarian cancer lines; in vitro methylation-reporter assay and allele-specific methylation analysis","pmids":["10029067","9892682"],"confidence":"Medium","gaps":["Methyltransferases responsible for silencing not identified","Whether methylation-based silencing occurs at the same frequency in primary tumors vs. cell lines not established"]},{"year":2000,"claim":"Extension of the methylation-silencing mechanism to mesothelioma, and later to lung cancer (with in vivo xenograft validation), broadened GPC3's tumor suppressor role across epithelial malignancies.","evidence":"Methylation analysis, 5-aza-CdR demethylation, colony assay (mesothelioma); pharmacologic demethylation, ectopic expression, nude mouse xenograft, etoposide sensitization (lung cancer)","pmids":["10656689","12816733"],"confidence":"Medium","gaps":["Mechanism by which GPC3 sensitizes cells to etoposide-induced apoptosis not defined","No genetic loss-of-function models in vivo"]},{"year":2012,"claim":"Elucidation of the LRP1-mediated endocytic clearance mechanism showed how GPC3 inhibits Hedgehog signaling: GPC3 binds Hh via its core protein, then its HS chains recruit LRP1, which internalizes and degrades the GPC3–Hh complex away from Patched.","evidence":"Co-immunoprecipitation, endocytosis assays, HS-chain mutants, lipid raft fractionation, siRNA knockdown of LRP1","pmids":["22467855"],"confidence":"High","gaps":["Whether all three Hedgehog ligands (Shh, Ihh, Dhh) are equally cleared is untested","In vivo validation of the LRP1-dependent clearance mechanism not provided","Structural basis of GPC3–Hh recognition not determined"]},{"year":2013,"claim":"Positioning GPC3 upstream of YAP in HCC cells and demonstrating its negative regulation of both IGF2 and FGF2 survival pathways expanded the roster of signaling axes controlled by GPC3 beyond Hedgehog.","evidence":"siRNA knockdown with YAP rescue in Huh7 cells; ectopic GPC3 expression with IGF2/FGF2 rescue in HCC cells","pmids":["23060277","23338845"],"confidence":"Medium","gaps":["Whether GPC3 acts on YAP through canonical Hippo kinase cascade or an alternative route is unknown","Direct physical interaction between GPC3 and FGF2 not demonstrated","Context-dependent pro- vs. anti-growth roles in HCC not reconciled"]},{"year":2018,"claim":"Demonstration that GPC3 inhibits canonical Wnt signaling by extracellular sequestration of Wnt ligands while simultaneously activating p38 MAPK to shift the ERK/p38 ratio toward dormancy revealed a dual-pathway mechanism for metastasis suppression.","evidence":"Wnt luciferase reporters, conditioned medium experiments, GSK3β inhibitor rescue, wound-healing assays in breast cancer cells; in vivo metastasis assay with pharmacologic p38 inhibition","pmids":["30267212","32800275"],"confidence":"Medium","gaps":["Identity of the specific Wnt ligands sequestered by GPC3 not determined","Whether p38 activation is direct or mediated through an intermediary receptor is unknown","Single-lab findings; independent replication pending"]},{"year":2022,"claim":"Crystallographic resolution of the GPC3–Unc5D octameric complex, mediated by glycan–glycan interactions, revealed a structural mechanism by which GPC3 guides cortical neuron and cancer cell migration, establishing its first atomic-resolution functional model.","evidence":"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, in vivo cortical migration and embryonic neuroblastoma xenograft assays","pmids":["36240740"],"confidence":"High","gaps":["Whether the GPC3–Unc5D complex transduces intracellular signaling through Unc5D's death domain is not addressed","Relevance of the octameric complex to GPC3's tumor suppressor function in epithelial cancers is unexplored","Contribution of heparan sulfate chains vs. N-glycans to complex stability not fully parsed"]},{"year":null,"claim":"How GPC3 integrates its multiple signaling outputs (Hh, Wnt, IGF2, FGF2, p38, YAP, Unc5D) in a context-dependent manner — acting as tumor suppressor in some tissues and oncogene in HCC — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified signaling model explaining tissue-specific tumor suppressor vs. oncogenic function","No conditional genetic knockout studies dissecting individual pathway contributions in vivo","Structural basis for GPC3–Wnt and GPC3–IGF2 interactions not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,11,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[11,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,9,11,12,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7,9,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,7]}],"complexes":["GPC3–Unc5D octameric complex","GPC3–Hedgehog–LRP1 endocytic complex"],"partners":["LRP1","UNC5D","IGF2","FGF2","YAP1","SP1"],"other_free_text":[]},"mechanistic_narrative":"GPC3 encodes glypican-3, a GPI-anchored heparan sulfate proteoglycan that functions as a multivalent signaling hub controlling cell growth, apoptosis, and migration by modulating several major pathways. GPC3 forms complexes with IGF2 and FGF2 to negatively regulate their mitogenic signaling [PMID:8589713, PMID:23338845], binds Hedgehog ligands and triggers their LRP1-dependent endocytosis and degradation through its heparan sulfate chains to inhibit Hh–Patched signaling [PMID:22467855], inhibits canonical Wnt/β-catenin signaling by extracellular sequestration of Wnt ligands while activating p38 MAPK to suppress metastasis and promote tumor dormancy [PMID:30267212, PMID:32800275], and modulates Hippo pathway output through YAP [PMID:23060277]. GPC3 also forms a structurally defined octameric complex with the guidance receptor Unc5D via glycan–glycan interactions that directs cortical neuron migration and cancer cell migration in vivo [PMID:36240740]. The GPC3 promoter is Sp1-dependent and subject to CpG island hypermethylation-mediated silencing in mesothelioma, ovarian, lung, and breast cancers, where GPC3 re-expression suppresses colony formation and tumor growth, consistent with its role as a tumor suppressor in these contexts [PMID:9651473, PMID:10029067, PMID:10656689, PMID:12816733]."},"prefetch_data":{"uniprot":{"accession":"P51654","full_name":"Glypican-3","aliases":["GTR2-2","Intestinal protein OCI-5","MXR7"],"length_aa":580,"mass_kda":65.6,"function":"Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P51654/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPC3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPC3","total_profiled":1310},"omim":[{"mim_id":"619342","title":"POST-GPI ATTACHMENT TO PROTEINS 6; PGAP6","url":"https://www.omim.org/entry/619342"},{"mim_id":"615487","title":"SMALL NUCLEOLAR RNA, H/ACA BOX, 2C; SNORA2C","url":"https://www.omim.org/entry/615487"},{"mim_id":"608811","title":"METAPHYSEAL UNDERMODELING, SPONDYLAR DYSPLASIA, AND OVERGROWTH","url":"https://www.omim.org/entry/608811"},{"mim_id":"604404","title":"GLYPICAN 6; GPC6","url":"https://www.omim.org/entry/604404"},{"mim_id":"604033","title":"ENDOPLASMIC RETICULUM-TO-NUCLEUS SIGNALING 1; ERN1","url":"https://www.omim.org/entry/604033"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":669.8}],"url":"https://www.proteinatlas.org/search/GPC3"},"hgnc":{"alias_symbol":["OCI-5","SGBS","SGBS1","SGB","DGSX"],"prev_symbol":["SDYS"]},"alphafold":{"accession":"P51654","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51654","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51654-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51654-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPC3","jax_strain_url":"https://www.jax.org/strain/search?query=GPC3"},"sequence":{"accession":"P51654","fasta_url":"https://rest.uniprot.org/uniprotkb/P51654.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51654/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51654"}},"corpus_meta":[{"pmid":"8589713","id":"PMC_8589713","title":"Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8589713","citation_count":610,"is_preprint":false},{"pmid":"20054179","id":"PMC_20054179","title":"Human SGBS cells - 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Line.","date":"2020","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32384580","citation_count":15,"is_preprint":false},{"pmid":"36879804","id":"PMC_36879804","title":"HMGB1/GPC3 dual targeting vaccine induces dendritic cells-mediated CD8+T cell immune response and elicits potential therapeutic effect in hepatocellular carcinoma.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36879804","citation_count":14,"is_preprint":false},{"pmid":"35050429","id":"PMC_35050429","title":"Identification of miR-4510 as a metastasis suppressor of gastric cancer through regulation of tumor microenvironment via targeting GPC3.","date":"2022","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/35050429","citation_count":14,"is_preprint":false},{"pmid":"34725191","id":"PMC_34725191","title":"Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.","date":"2021","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34725191","citation_count":14,"is_preprint":false},{"pmid":"21362501","id":"PMC_21362501","title":"A 1 Mb-sized microdeletion Xq26.2 encompassing the GPC3 gene in a fetus with Simpson-Golabi-Behmel syndrome Report, antenatal findings and review.","date":"2011","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21362501","citation_count":14,"is_preprint":false},{"pmid":"29535817","id":"PMC_29535817","title":"Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29535817","citation_count":13,"is_preprint":false},{"pmid":"26321508","id":"PMC_26321508","title":"Whole exome sequencing identifies a novel frameshift mutation in GPC3 gene in a patient with overgrowth syndrome.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26321508","citation_count":13,"is_preprint":false},{"pmid":"30048822","id":"PMC_30048822","title":"Duplications of GPC3 and GPC4 genes in symptomatic female carriers of Simpson-Golabi-Behmel syndrome type 1.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30048822","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50212,"output_tokens":4148,"usd":0.106428},"stage2":{"model":"claude-opus-4-6","input_tokens":7603,"output_tokens":2966,"usd":0.168247},"total_usd":0.274675,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"GPC3 encodes a heparan sulfate proteoglycan (glypican-3) anchored to the extracellular surface, and initial western- and ligand-blotting experiments showed it forms a complex with IGF2, suggesting it modulates IGF2 action to control embryonic mesodermal growth.\",\n      \"method\": \"Western blotting and ligand blotting\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/blotting experiment in the original discovery paper; foundational but limited mechanistic depth\",\n      \"pmids\": [\"8589713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GPC3 (OCI-5) induces apoptosis in a cell-type-specific manner (mesothelioma and breast cancer cells but not NIH 3T3 or HT-29 cells); this apoptotic activity requires GPI membrane anchoring but not the heparan sulfate glycosaminoglycan chains. IGF2 rescues MCF-7 cells from GPC3-induced apoptosis.\",\n      \"method\": \"Ectopic expression, apoptosis assays, GPI-anchor and glycosaminoglycan chain mutants, IGF2 rescue experiment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (expression constructs, structural mutants, rescue experiment) in a single rigorous study\",\n      \"pmids\": [\"9628896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"OCI-5/GPC3 expression in intestinal epithelial cells is regulated transcriptionally by cell shape: rounding of cells (confluence, low calcium, spheroid culture) increases OCI-5 transcription, while cell flattening (colchicine) or phosphatase inhibition (vanadate) suppresses it.\",\n      \"method\": \"RNA in situ hybridization, nuclear run-on transcription assays, pharmacological perturbations of cell shape\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — nuclear run-on plus multiple orthogonal cellular perturbations; single lab\",\n      \"pmids\": [\"9281346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The GPC3 promoter is TATA-less and driven by multiple Sp1 binding sites; three Sp1 sites (centered at –14, –34, and –92 nt) are functional as shown by DNase I footprinting and gel-shift/supershift assays, and Sp1 transactivates GPC3 in Sp1-deficient Drosophila SL2 cells.\",\n      \"method\": \"Deletion analysis, luciferase reporter assay, DNase I footprinting, EMSA/supershift, transfection in Sp1-deficient SL2 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple complementary biochemical assays (footprinting, EMSA, functional reporter) in one study\",\n      \"pmids\": [\"9651473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GPC3 expression is silenced in ovarian cancer cell lines by promoter hypermethylation; demethylation with 5-aza-2'-deoxycytidine restores expression, and ectopic GPC3 expression inhibits colony formation, supporting a tumor suppressor function in the ovary.\",\n      \"method\": \"Southern blot methylation analysis, 5-aza-CdR demethylation, colony-forming assay with ectopic GPC3\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — methylation mechanism established plus functional rescue; single lab\",\n      \"pmids\": [\"10029067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The GPC3 promoter CpG island is subject to X-chromosome inactivation-induced hypermethylation on the inactive X allele; in vitro methylation of the GPC3 promoter represses reporter gene transcription, while tissue-specific repression on the active X does not involve promoter methylation.\",\n      \"method\": \"Reporter assay with in vitro methylated promoter constructs, Southern blot analysis of allele-specific methylation, azadeoxycytidine demethylation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro methylation-reporter assay plus allele-specific methylation analysis; single lab\",\n      \"pmids\": [\"9892682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GPC3 is silenced in malignant mesothelioma primarily by promoter hypermethylation (not mutation or allelic loss); ectopic GPC3 expression inhibits in vitro colony formation of human MM cells, indicating a growth-suppressive function.\",\n      \"method\": \"Northern blot, methylation analysis, 5-aza-CdR demethylation, ectopic expression colony assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — methylation mechanism plus functional loss-of-function colony assay; single lab\",\n      \"pmids\": [\"10656689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GPC3 acts as a lung tumor suppressor; its expression is epigenetically silenced by promoter hypermethylation in non-small cell lung carcinoma lines, and ectopic GPC3 expression increases apoptosis in response to etoposide and inhibits tumor growth in nude mice.\",\n      \"method\": \"Pharmacologic demethylation, ectopic expression, xenograft assay, apoptosis assay\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays (in vitro apoptosis + in vivo xenograft) in one study; single lab\",\n      \"pmids\": [\"12816733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hh complex; GPC3 binds Hh and competes with Patched (Ptc) for Hh binding. The GPC3-Hh interaction triggers LRP1-dependent internalization and degradation of the complex, reducing Hh available for Ptc binding. GPC3 binds LRP1 through its heparan sulfate chains, and this interaction displaces GPC3 from lipid raft domains.\",\n      \"method\": \"Co-immunoprecipitation, endocytosis assays, heparan sulfate chain mutants, lipid raft fractionation, siRNA knockdown of LRP1\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays, structural mutants, and functional readout of Hh signaling inhibition; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22467855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPC3 knockdown in Huh7 hepatocellular carcinoma cells induces apoptosis and inhibits proliferation, migration, and invasion, accompanied by suppression of YAP mRNA and protein; addition of recombinant YAP-1 rescues cells from GPC3 knockdown-induced apoptosis, placing GPC3 upstream of Hippo pathway effector YAP.\",\n      \"method\": \"siRNA knockdown, flow cytometry apoptosis assay, EdU proliferation assay, qPCR, Western blot, recombinant YAP-1 rescue\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined pathway rescue; single lab\",\n      \"pmids\": [\"23060277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The lncRNA GPC3-AS1 physically associates with the histone acetyltransferase P300/CBP-associated factor (PCAF) and recruits it to the GPC3 gene body, increasing euchromatic histone marks and activating GPC3 transcription; GPC3-AS1-driven HCC cell proliferation and migration are dependent on upregulation of GPC3.\",\n      \"method\": \"RNA immunoprecipitation (RIP), ChIP, gain- and loss-of-function assays, xenograft\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and ChIP establish physical recruitment; functional dependence confirmed by GPC3 rescue experiments; single lab\",\n      \"pmids\": [\"27573079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In breast cancer cells, GPC3 inhibits the canonical Wnt/β-catenin pathway both transcriptionally and by secretion into extracellular media where it competes with or sequesters Wnt ligands from Frizzled receptors. GPC3 also activates non-canonical Wnt and p38 MAPK pathways; the p38/ERK balance is shifted toward p38, driving dormancy. Inhibition of canonical Wnt by GPC3 is required for its effects on cell migration and homotypic adhesion.\",\n      \"method\": \"Luciferase reporter assay for Wnt activity, Western blotting, qRT-PCR microarray, conditioned medium experiments, lithium (GSK3β inhibitor) rescue, wound-healing and suspension growth assays\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus pathway rescue plus multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"30267212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPC3 re-expression in murine breast cancer cells reverts epithelial-to-mesenchymal transition, reduces the phospho-ERK/phospho-p38 ratio, elevates p21, p27, and SOX2 (dormancy markers), and suppresses metastasis in vivo. In vivo inhibition of p38 increases invasion and experimental metastasis of GPC3-re-expressing tumors, demonstrating that GPC3 inhibits metastasis specifically through p38 MAPK pathway activation.\",\n      \"method\": \"Genetically modified cell lines, Western blotting, in vivo metastasis assays, pharmacologic p38 inhibition\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacologic epistasis plus in vivo readout; single lab\",\n      \"pmids\": [\"32800275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of Unc5D in complex with GPC3 reveal an octameric glycoprotein complex in which four Unc5D molecules form an antiparallel bundle flanked by four GPC3 molecules; central glycan-glycan interactions are formed by N-linked glycans from GPC3 (N241) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. Structure-based mutants and anti-GPC3 nanobodies that modulate Unc5-GPC3 binding demonstrate that this complex guides migrating pyramidal neurons in the mouse cortex and directs cancer cell migration in an embryonic neuroblastoma xenograft model.\",\n      \"method\": \"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, in vivo cortical neuron migration assay, embryonic xenograft neuroblastoma model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with MD simulation, MS validation, mutagenesis, and in vivo functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"36240740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPC3 overexpression in renal cell carcinoma cell lines (786-O and ACHN) reduces cell proliferation by inducing G1 phase cell cycle arrest without triggering apoptosis.\",\n      \"method\": \"Ectopic expression, MTT assay, colony formation, flow cytometry cell cycle analysis\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression phenotype with no pathway placement beyond cell cycle arrest\",\n      \"pmids\": [\"25168166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPC3 overexpression in Huh7 and SK-HEP-1 HCC cells inhibits proliferation and invasion by inducing apoptosis; co-treatment with IGF2 or FGF2 significantly suppresses GPC3-induced apoptosis, indicating GPC3 acts as a negative regulator of IGF2 and FGF2 survival pathways.\",\n      \"method\": \"Ectopic GPC3 expression, Annexin V-PI flow cytometry, IGF2/FGF2 rescue\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiments define pathway relationship; single lab\",\n      \"pmids\": [\"23338845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GPC3 mRNA and protein are specifically localized to the differentiated syncytiotrophoblast layer of the human placenta, as determined by in situ hybridization and immunohistochemical staining; expression increases markedly during cytotrophoblast differentiation into syncytiotrophoblast in vitro.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, RT-PCR during in vitro differentiation\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization established but no functional consequence directly demonstrated\",\n      \"pmids\": [\"11193214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPC3 is a GPI-anchored heparan sulfate proteoglycan that controls cell growth and migration through multiple mechanisms: it forms a complex with IGF2 to modulate IGF2 signaling; it binds Hedgehog ligands and, via LRP1-mediated endocytosis (dependent on its HS chains), sequesters Hh away from Patched to inhibit Hh signaling; it inhibits canonical Wnt/β-catenin signaling partly through extracellular competition with Wnt ligands; it activates p38 MAPK to suppress metastasis and induce tumor dormancy; it modulates Hippo pathway output through YAP; and it forms a structurally defined octameric complex with the guidance receptor Unc5D (via glycan-glycan interactions) to regulate neuronal and cancer cell migration. Its promoter is Sp1-dependent and is silenced by CpG island hypermethylation in multiple cancer types, consistent with tumor suppressor activity in mesothelioma, ovarian, lung, breast, and renal cancers, whereas it is oncogenically overexpressed in hepatocellular carcinoma where it promotes growth via Wnt and Hedgehog pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GPC3 encodes glypican-3, a GPI-anchored heparan sulfate proteoglycan that functions as a multivalent signaling hub controlling cell growth, apoptosis, and migration by modulating several major pathways. GPC3 forms complexes with IGF2 and FGF2 to negatively regulate their mitogenic signaling [PMID:8589713, PMID:23338845], binds Hedgehog ligands and triggers their LRP1-dependent endocytosis and degradation through its heparan sulfate chains to inhibit Hh–Patched signaling [PMID:22467855], inhibits canonical Wnt/β-catenin signaling by extracellular sequestration of Wnt ligands while activating p38 MAPK to suppress metastasis and promote tumor dormancy [PMID:30267212, PMID:32800275], and modulates Hippo pathway output through YAP [PMID:23060277]. GPC3 also forms a structurally defined octameric complex with the guidance receptor Unc5D via glycan–glycan interactions that directs cortical neuron migration and cancer cell migration in vivo [PMID:36240740]. The GPC3 promoter is Sp1-dependent and subject to CpG island hypermethylation-mediated silencing in mesothelioma, ovarian, lung, and breast cancers, where GPC3 re-expression suppresses colony formation and tumor growth, consistent with its role as a tumor suppressor in these contexts [PMID:9651473, PMID:10029067, PMID:10656689, PMID:12816733].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The identity of GPC3 as a GPI-anchored heparan sulfate proteoglycan that binds IGF2 provided the first molecular framework for how it might control mesodermal growth.\",\n      \"evidence\": \"Western blotting and ligand blotting in transfected cells\",\n      \"pmids\": [\"8589713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"IGF2 binding affinity and stoichiometry not determined\",\n        \"Functional consequence of GPC3–IGF2 interaction on downstream signaling not tested\",\n        \"Single pulldown/blotting approach without reciprocal validation\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that GPC3 transcription is regulated by cell shape established that its expression is dynamically controlled by the physical microenvironment of epithelial cells.\",\n      \"evidence\": \"Nuclear run-on assays and pharmacological perturbations of cell shape in intestinal epithelial cells\",\n      \"pmids\": [\"9281346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcription factor(s) mediating shape-dependent regulation not identified\",\n        \"Relevance to in vivo tissue architecture unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of Sp1 as the direct transcriptional driver of the TATA-less GPC3 promoter and demonstration that GPC3 induces apoptosis in a GPI-anchor-dependent manner (rescued by IGF2) established its dual identity as a transcriptionally regulated growth suppressor.\",\n      \"evidence\": \"DNase I footprinting, EMSA/supershift, Sp1-deficient SL2 cell reporter assay (promoter); ectopic expression with GPI-anchor and HS-chain mutants, apoptosis assays, IGF2 rescue (function)\",\n      \"pmids\": [\"9651473\", \"9628896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream apoptotic pathway (caspase dependence, death receptor involvement) not delineated\",\n        \"Why GPI anchor is essential but HS chains dispensable for apoptosis induction not explained\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery that promoter CpG island hypermethylation silences GPC3 in ovarian cancer, with demethylation restoring expression and re-expression suppressing colony formation, established the epigenetic tumor suppressor paradigm for GPC3.\",\n      \"evidence\": \"Southern blot methylation analysis, 5-aza-CdR demethylation, colony-forming assay in ovarian cancer lines; in vitro methylation-reporter assay and allele-specific methylation analysis\",\n      \"pmids\": [\"10029067\", \"9892682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Methyltransferases responsible for silencing not identified\",\n        \"Whether methylation-based silencing occurs at the same frequency in primary tumors vs. cell lines not established\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extension of the methylation-silencing mechanism to mesothelioma, and later to lung cancer (with in vivo xenograft validation), broadened GPC3's tumor suppressor role across epithelial malignancies.\",\n      \"evidence\": \"Methylation analysis, 5-aza-CdR demethylation, colony assay (mesothelioma); pharmacologic demethylation, ectopic expression, nude mouse xenograft, etoposide sensitization (lung cancer)\",\n      \"pmids\": [\"10656689\", \"12816733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which GPC3 sensitizes cells to etoposide-induced apoptosis not defined\",\n        \"No genetic loss-of-function models in vivo\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Elucidation of the LRP1-mediated endocytic clearance mechanism showed how GPC3 inhibits Hedgehog signaling: GPC3 binds Hh via its core protein, then its HS chains recruit LRP1, which internalizes and degrades the GPC3–Hh complex away from Patched.\",\n      \"evidence\": \"Co-immunoprecipitation, endocytosis assays, HS-chain mutants, lipid raft fractionation, siRNA knockdown of LRP1\",\n      \"pmids\": [\"22467855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether all three Hedgehog ligands (Shh, Ihh, Dhh) are equally cleared is untested\",\n        \"In vivo validation of the LRP1-dependent clearance mechanism not provided\",\n        \"Structural basis of GPC3–Hh recognition not determined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Positioning GPC3 upstream of YAP in HCC cells and demonstrating its negative regulation of both IGF2 and FGF2 survival pathways expanded the roster of signaling axes controlled by GPC3 beyond Hedgehog.\",\n      \"evidence\": \"siRNA knockdown with YAP rescue in Huh7 cells; ectopic GPC3 expression with IGF2/FGF2 rescue in HCC cells\",\n      \"pmids\": [\"23060277\", \"23338845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GPC3 acts on YAP through canonical Hippo kinase cascade or an alternative route is unknown\",\n        \"Direct physical interaction between GPC3 and FGF2 not demonstrated\",\n        \"Context-dependent pro- vs. anti-growth roles in HCC not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that GPC3 inhibits canonical Wnt signaling by extracellular sequestration of Wnt ligands while simultaneously activating p38 MAPK to shift the ERK/p38 ratio toward dormancy revealed a dual-pathway mechanism for metastasis suppression.\",\n      \"evidence\": \"Wnt luciferase reporters, conditioned medium experiments, GSK3β inhibitor rescue, wound-healing assays in breast cancer cells; in vivo metastasis assay with pharmacologic p38 inhibition\",\n      \"pmids\": [\"30267212\", \"32800275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the specific Wnt ligands sequestered by GPC3 not determined\",\n        \"Whether p38 activation is direct or mediated through an intermediary receptor is unknown\",\n        \"Single-lab findings; independent replication pending\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Crystallographic resolution of the GPC3–Unc5D octameric complex, mediated by glycan–glycan interactions, revealed a structural mechanism by which GPC3 guides cortical neuron and cancer cell migration, establishing its first atomic-resolution functional model.\",\n      \"evidence\": \"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, in vivo cortical migration and embryonic neuroblastoma xenograft assays\",\n      \"pmids\": [\"36240740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the GPC3–Unc5D complex transduces intracellular signaling through Unc5D's death domain is not addressed\",\n        \"Relevance of the octameric complex to GPC3's tumor suppressor function in epithelial cancers is unexplored\",\n        \"Contribution of heparan sulfate chains vs. N-glycans to complex stability not fully parsed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GPC3 integrates its multiple signaling outputs (Hh, Wnt, IGF2, FGF2, p38, YAP, Unc5D) in a context-dependent manner — acting as tumor suppressor in some tissues and oncogene in HCC — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unified signaling model explaining tissue-specific tumor suppressor vs. oncogenic function\",\n        \"No conditional genetic knockout studies dissecting individual pathway contributions in vivo\",\n        \"Structural basis for GPC3–Wnt and GPC3–IGF2 interactions not determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 11, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 9, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7, 9, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 7]}\n    ],\n    \"complexes\": [\n      \"GPC3–Unc5D octameric complex\",\n      \"GPC3–Hedgehog–LRP1 endocytic complex\"\n    ],\n    \"partners\": [\n      \"LRP1\",\n      \"UNC5D\",\n      \"IGF2\",\n      \"FGF2\",\n      \"YAP1\",\n      \"SP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}