{"gene":"GPC3","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1996,"finding":"GPC3 encodes a cell-surface heparan sulfate proteoglycan (glypican-3) that forms a complex with insulin-like growth factor 2 (IGF2), as shown by western- and ligand-blotting experiments, suggesting it modulates IGF2 action in growth control.","method":"Western blotting and ligand-blotting","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — initial western/ligand blot showing GPC3-IGF2 complex, single lab, later contested by Song et al. 1997","pmids":["8589713"],"is_preprint":false},{"year":1997,"finding":"Rat GPC3 ortholog OCI-5 does NOT interact with IGF-2 (negative result); instead, OCI-5 binds FGF-2 via its heparan sulfate chains, as shown by transfection into two cell lines and inhibition by heparin or heparitinase.","method":"Transfection, co-immunoprecipitation/binding assay, heparin and heparitinase competition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with two cell lines and enzymatic/competitive inhibition controls, single lab","pmids":["9065409"],"is_preprint":false},{"year":1997,"finding":"OCI-5/GPC3 mRNA expression in intestinal epithelial cells (IEC-18) is regulated by cell shape: rounded cell morphology (confluence, low calcium, spheroid culture) increases OCI-5 transcription, while cytoskeletal disruption with colchicine (causing cell flattening) abolishes induction. Nuclear run-on analysis confirmed transcriptional regulation.","method":"RNA in situ hybridization, nuclear run-on transcription assay, cytoskeletal disruption (colchicine, vanadate), low-calcium and spheroid culture conditions","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear run-on plus multiple perturbation conditions, single lab","pmids":["9281346"],"is_preprint":false},{"year":1998,"finding":"OCI-5/GPC3 induces apoptosis in mesothelioma (II14) and breast cancer (MCF-7) cell lines but not in NIH 3T3 fibroblasts or HT-29 cells (cell-line-specific effect). Membrane anchoring via GPI is required for apoptosis induction, but glycosaminoglycan chains are not. MCF-7 cells can be rescued from GPC3-induced apoptosis by IGF-2.","method":"Transfection and ectopic expression, GPI anchor mutants, glycosaminoglycan-deficient mutants, apoptosis assay, IGF-2 rescue experiment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis (GPI anchor, GAG chains) combined with functional apoptosis assays and rescue experiment, single lab with orthogonal methods","pmids":["9628896"],"is_preprint":false},{"year":1999,"finding":"GPC3 promoter hypermethylation silences GPC3 expression in ovarian cancer cell lines; treatment with 5-aza-2'-deoxycytidine (demethylating agent) restores expression, and ectopic GPC3 expression inhibits colony formation, consistent with a tumor-suppressor role.","method":"Southern blot analysis of promoter methylation, demethylating agent treatment, colony-forming assay with ectopic GPC3 expression","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation analysis plus functional colony assay, single lab","pmids":["10029067"],"is_preprint":false},{"year":1999,"finding":"GPC3 promoter methylation on the inactive X allele mediates transcriptional repression via X inactivation; in vitro methylation of the GPC3 promoter in reporter constructs directly represses transcription.","method":"In vitro methylation of reporter constructs, Southern blot analysis of allele-specific methylation, azadeoxycytidine treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reporter assay plus allele-specific methylation analysis, single lab","pmids":["9892682"],"is_preprint":false},{"year":2000,"finding":"GPC3 is silenced in malignant mesothelioma predominantly through aberrant promoter methylation (not allelic loss or mutation); demethylation with 5-aza-2'-deoxycytidine restores GPC3 expression in MM cell lines, and ectopic GPC3 expression inhibits in vitro colony formation of MM cells.","method":"Northern blot, allelic loss analysis, mutational analysis, promoter methylation analysis, demethylating agent treatment, ectopic expression + colony formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (methylation, demethylation, functional assay), single lab","pmids":["10656689"],"is_preprint":false},{"year":2000,"finding":"A GPC3 missense mutation (W296R), which changes an amino acid conserved across all glypicans, results in a poorly processed protein that fails to increase cell surface expression of heparan sulfate, establishing it as a loss-of-function mutation affecting GPC3 processing and cell-surface localization.","method":"Mutational analysis, protein processing assay, heparan sulfate cell surface expression assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional characterization of mutant protein with multiple assays, single lab","pmids":["10814714"],"is_preprint":false},{"year":2003,"finding":"GPC3 expression is epigenetically silenced by promoter hypermethylation in non-small cell lung carcinoma lines; ectopic GPC3 expression increases apoptosis response to etoposide and inhibits growth in nude mice, supporting a tumor-suppressor role.","method":"Northern blot, pharmacologic demethylation, ectopic GPC3 expression, etoposide apoptosis assay, xenograft growth assay","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism plus functional assay in vitro and in vivo, single lab","pmids":["12816733"],"is_preprint":false},{"year":2012,"finding":"LRP1 mediates Hh-induced endocytosis of the GPC3-Hh complex: GPC3 binds Hh and competes with Patched for Hh binding; Hh binding to GPC3 triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex, reducing Hh available for signaling. GPC3 binds LRP1 through its heparan sulfate chains, and this interaction displaces GPC3 from lipid rafts.","method":"Co-immunoprecipitation, endocytosis assays, lipid raft fractionation, competition binding assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, lipid raft fractionation, endocytosis functional assay, and demonstration of mechanistic requirement, single lab with multiple orthogonal methods","pmids":["22467855"],"is_preprint":false},{"year":2013,"finding":"GPC3 (and GPC1) physically interact with BMP2 and inhibit BMP2, BMP4, and BMP7 signaling in human suture mesenchymal cells. This inhibition is independent of GPC3 cell-surface attachment and glycanation (mediated by the core protein), and acts through both SMAD-dependent and SMAD-independent BMP pathways. Immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity, and overexpression inhibits BMP2-mediated osteogenesis.","method":"Co-immunoprecipitation (GPC3-BMP2 interaction), recombinant protein addition, overexpression, immunoblockade of endogenous proteins, SMAD signaling assays, osteogenesis assays, GPI-anchor and glycanation-deficient constructs","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding (Co-IP), recombinant protein experiments, mutagenesis (glycanation/GPI), functional osteogenesis assay, multiple orthogonal approaches, single lab","pmids":["23624389"],"is_preprint":false},{"year":2013,"finding":"Knockdown of GPC3 in Huh7 HCC cells induces apoptosis and inhibits proliferation, migration, and invasion; GPC3 knockdown suppresses YAP expression at mRNA and protein levels, and addition of recombinant YAP-1 rescues cells from GPC3-knockdown-induced apoptosis, placing GPC3 upstream of YAP in the Hippo pathway.","method":"siRNA knockdown, flow cytometry (apoptosis), EdU incorporation (proliferation), migration/invasion assays, qPCR, western blot, recombinant YAP-1 rescue experiment","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA + rescue experiment with recombinant protein, multiple phenotypic readouts, single lab","pmids":["23060277"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of GPC3 in complex with the guidance receptor Unc5D reveals an octameric glycoprotein complex (4 Unc5D + 4 GPC3). Central glycan-glycan interactions are formed between N-linked glycans from GPC3 (N241 in human) and C-mannosylated tryptophans of Unc5D thrombospondin-like domains. Structure-based mutants and nanobodies modulating GPC3-Unc5 binding demonstrate that this complex guides migrating pyramidal neurons in the mouse cortex and cancer cell migration.","method":"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, embryonic xenograft neuroblastoma model, mouse cortex neuron migration assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus MD simulations, MS, mutagenesis, and in vivo functional validation across two model systems in one rigorous study","pmids":["36240740"],"is_preprint":false},{"year":2014,"finding":"GPC3 overexpression in renal carcinoma cell lines (786-O and ACHN) reduces cell proliferation through G1-phase cell cycle arrest without inducing apoptosis.","method":"GPC3 expression vector transfection, MTT assay, colony formation assay, flow cytometry (cell cycle and apoptosis)","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO/OE with defined cellular phenotype (G1 arrest), single lab, single method set","pmids":["25168166"],"is_preprint":false},{"year":2018,"finding":"GPC3 promotes HCC cell proliferation through the Hedgehog (Hh) pathway in HepG2 cells (but not HLE cells), as shown by in vitro analysis of GPC3-overexpressing cell lines.","method":"Overexpression in HCC cell lines, RT-PCR, cell proliferation assay, Hedgehog pathway gene expression analysis","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, pathway inferred from expression changes without direct pathway perturbation","pmids":["29963171"],"is_preprint":false},{"year":2013,"finding":"Overexpression of GPC3 in Huh7 and SK-HEP-1 HCC cells inhibits proliferation and invasion through induction of apoptosis; co-treatment with IGF2 and FGF2 significantly inhibits GPC3-induced apoptotic cell death, indicating GPC3 acts as a negative regulator of IGF2 and FGF2 pathways.","method":"Transfection, Annexin V-PI flow cytometry, IGF2/FGF2 co-treatment rescue experiment","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ectopic expression with functional readouts and growth factor rescue experiment, single lab, two cell lines","pmids":["23338845"],"is_preprint":false},{"year":2023,"finding":"GPC3 structural analysis predicts that the Furin cleavage site of GPC3 is exposed and accessible, facilitating cleavage events. Furin-dependent GPC3 cleaved domains were detected in serum small extracellular vesicles (sEVs) isolated from HCC patients.","method":"In silico structural prediction, isolation of sEVs from patient serum and hepatocyte culture media, western blotting for GPC3 domains","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — computational prediction plus sEV detection, no direct functional validation of Furin cleavage, single lab","pmids":["37446098"],"is_preprint":false},{"year":2001,"finding":"GPC3 protein is expressed in human placenta and localizes specifically to the differentiated syncytiotrophoblast layer, as confirmed by in situ hybridization and immunohistochemistry; cytotrophoblasts increase GPC3 expression during trophoblast differentiation, while fibroblasts and choriocarcinoma lines do not express GPC3.","method":"In situ hybridization, immunohistochemistry, RT-PCR in cell lines and primary cultures","journal":"Histology and histopathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by ISH + IHC with functional differentiation context, replicated in primary and cell line models","pmids":["11193214"],"is_preprint":false}],"current_model":"GPC3 is a GPI-anchored cell-surface heparan sulfate proteoglycan that regulates growth and cell guidance through multiple mechanisms: its core protein directly binds and inhibits BMP2/4/7 and competes with Patched for Hedgehog binding, triggering LRP1-mediated endocytosis and degradation of the GPC3-Hh complex; it forms a structurally defined octameric complex with Unc5D guidance receptors via glycan-glycan interactions to regulate cell migration; it induces GPI-anchor-dependent, GAG-independent apoptosis in a cell-type-specific manner and can suppress proliferation via G1 arrest or YAP downregulation; and its promoter is subject to epigenetic silencing by CpG methylation in multiple cancer types, with loss of GPC3 associated with overgrowth (Simpson-Golabi-Behmel syndrome)."},"narrative":{"mechanistic_narrative":"GPC3 is a GPI-anchored cell-surface heparan sulfate proteoglycan that regulates cell growth, survival, and guidance by physically engaging multiple ligands and receptors at the plasma membrane [PMID:8589713, PMID:9628896, PMID:23624389]. Through its core protein it directly binds and inhibits BMP2/4/7 signaling in a manner independent of GPI anchoring and glycanation, acting through both SMAD-dependent and SMAD-independent pathways [PMID:23624389], while its heparan sulfate chains bind FGF-2 [PMID:9065409] and LRP1; binding of Hedgehog to GPC3 competes with Patched and triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex, attenuating Hedgehog signaling [PMID:22467855]. Structurally, GPC3 assembles into a defined octameric complex with the guidance receptor Unc5D via glycan-glycan contacts between its N-linked glycans and C-mannosylated tryptophans of Unc5D, and this complex directs migration of cortical pyramidal neurons and cancer cells [PMID:36240740]. GPC3 also induces GPI-anchor-dependent, glycosaminoglycan-independent apoptosis in a cell-type-specific manner, an effect reversible by IGF-2 [PMID:9628896], and it can suppress proliferation through G1 arrest [PMID:25168166] or by acting upstream of YAP in the Hippo pathway [PMID:23060277]. Its promoter is recurrently silenced by CpG methylation across ovarian cancer, mesothelioma, and lung carcinoma, where re-expression suppresses colony formation and tumor growth, consistent with a context-dependent tumor-suppressor role [PMID:10029067, PMID:10656689, PMID:12816733]. A conserved missense mutation (W296R) yields a poorly processed protein that fails to reach the cell surface, defining a loss-of-function mechanism [PMID:10814714].","teleology":[{"year":1996,"claim":"Established GPC3 as a cell-surface heparan sulfate proteoglycan and provided the first candidate ligand by detecting a complex with IGF2, framing GPC3 as a modulator of growth-factor action.","evidence":"Western and ligand-blotting of glypican-3","pmids":["8589713"],"confidence":"Medium","gaps":["IGF2 interaction was later contested by an ortholog study","no functional consequence of the complex demonstrated"]},{"year":1997,"claim":"Reassigned the ligand specificity by showing the rat ortholog does not bind IGF-2 but instead binds FGF-2 through its heparan sulfate chains, distinguishing core-protein from glycan-mediated interactions.","evidence":"Transfection, binding assay, heparin/heparitinase competition in two cell lines","pmids":["9065409"],"confidence":"Medium","gaps":["functional outcome of FGF-2 binding not established","species/ortholog difference vs human GPC3 not resolved"]},{"year":1997,"claim":"Linked GPC3 transcription to cell shape and cytoskeletal state, indicating context-dependent regulation of its expression.","evidence":"Nuclear run-on, in situ hybridization, cytoskeletal disruption and culture-geometry perturbations in IEC-18 cells","pmids":["9281346"],"confidence":"Medium","gaps":["transcription factors mediating shape-dependent induction unidentified","relevance to in vivo growth control unknown"]},{"year":1998,"claim":"Defined GPC3 as a cell-type-specific inducer of apoptosis and dissected the structural requirements, showing GPI anchoring is required while glycosaminoglycan chains are dispensable, and that IGF-2 can rescue.","evidence":"Ectopic expression with GPI-anchor and GAG-deficient mutants, apoptosis assays, IGF-2 rescue across multiple cell lines","pmids":["9628896"],"confidence":"High","gaps":["molecular death pathway downstream of GPI-anchored GPC3 not identified","basis of cell-type specificity unexplained"]},{"year":1999,"claim":"Identified promoter hypermethylation as the silencing mechanism for GPC3 in cancer and X-inactivation, and showed re-expression suppresses colony formation, establishing a tumor-suppressor candidacy.","evidence":"Southern blot methylation analysis, in vitro reporter methylation, demethylating agent treatment, colony assays in ovarian cancer","pmids":["10029067","9892682"],"confidence":"Medium","gaps":["growth-suppressive mechanism downstream of re-expression not defined","single-lab functional readout"]},{"year":2000,"claim":"Generalized epigenetic silencing to mesothelioma and characterized a loss-of-function missense mutation, connecting GPC3 inactivation to defective protein processing and surface localization.","evidence":"Methylation/demethylation and colony assays in mesothelioma; mutational and processing/heparan-sulfate surface-expression assays for W296R","pmids":["10656689","10814714"],"confidence":"Medium","gaps":["whether W296R recapitulates disease phenotype in vivo not tested","tumor-suppressor mechanism still uncharacterized"]},{"year":2001,"claim":"Localized GPC3 protein to the differentiated syncytiotrophoblast and showed its induction during trophoblast differentiation, anchoring its role in a defined developmental tissue context.","evidence":"In situ hybridization, immunohistochemistry, RT-PCR in primary and cell-line trophoblasts","pmids":["11193214"],"confidence":"Medium","gaps":["functional role in placental development not tested","signaling partners in syncytiotrophoblast unknown"]},{"year":2003,"claim":"Extended the epigenetic-silencing/tumor-suppressor model to lung carcinoma with in vivo evidence, showing re-expression sensitizes to etoposide-induced apoptosis and inhibits xenograft growth.","evidence":"Demethylation, ectopic expression, etoposide apoptosis assay, nude mouse xenograft","pmids":["12816733"],"confidence":"Medium","gaps":["molecular basis of apoptosis sensitization not defined","in vivo data from single model"]},{"year":2012,"claim":"Resolved a mechanism for GPC3 control of Hedgehog signaling, showing GPC3 competes with Patched for Hh and that Hh binding triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex via its heparan sulfate chains.","evidence":"Reciprocal co-immunoprecipitation, competition binding, lipid raft fractionation, endocytosis assays","pmids":["22467855"],"confidence":"High","gaps":["in vivo relevance to Hedgehog-driven development/disease not addressed","fate of internalized Hh signaling output not quantified"]},{"year":2013,"claim":"Demonstrated direct core-protein-mediated inhibition of BMP signaling, separating this ligand-trap function from membrane anchoring and glycanation and linking it to control of osteogenesis.","evidence":"Co-IP of GPC3-BMP2, recombinant protein, immunoblockade, GPI/glycanation-deficient constructs, SMAD and osteogenesis assays","pmids":["23624389"],"confidence":"High","gaps":["structural basis of BMP-core protein interaction not defined","in vivo skeletal phenotype not tested in this study"]},{"year":2013,"claim":"Placed GPC3 upstream of YAP in the Hippo pathway in hepatocellular carcinoma and reaffirmed growth-factor antagonism, where knockdown induces apoptosis rescued by YAP-1, and overexpression-induced apoptosis is blunted by IGF2/FGF2.","evidence":"siRNA knockdown, recombinant YAP-1 rescue, ectopic expression with IGF2/FGF2 rescue, apoptosis and proliferation/invasion assays in HCC lines","pmids":["23060277","23338845"],"confidence":"Medium","gaps":["direction of GPC3 effect in HCC (pro- vs anti-tumor) varies by context","mechanism linking GPC3 to YAP regulation unresolved"]},{"year":2014,"claim":"Showed GPC3 can restrain proliferation independently of apoptosis via G1-phase cell cycle arrest in renal carcinoma, broadening its growth-suppressive repertoire.","evidence":"Overexpression, MTT, colony formation, cell-cycle and apoptosis flow cytometry in 786-O and ACHN cells","pmids":["25168166"],"confidence":"Medium","gaps":["cell-cycle regulators mediating G1 arrest not identified","context-dependence relative to apoptotic effect unexplained"]},{"year":2022,"claim":"Provided the structural basis for GPC3 as a guidance co-receptor by solving the GPC3-Unc5D octameric complex assembled through glycan-glycan interactions, and validated its role in neuronal and cancer cell migration.","evidence":"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutants, nanobodies, mouse cortex and xenograft migration assays","pmids":["36240740"],"confidence":"High","gaps":["signaling output downstream of the GPC3-Unc5D complex not defined","how this guidance function integrates with GPC3's ligand-trap roles unknown"]},{"year":null,"claim":"How GPC3's distinct activities — apoptosis induction, BMP/FGF/Hh modulation, YAP regulation, and Unc5D-mediated guidance — are coordinated within a single cell and which dominate in specific developmental and tumor contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no unified model reconciling tumor-suppressor vs tumor-promoting roles","downstream effectors of GPI-anchor-dependent apoptosis unknown","physiological significance of Furin cleavage and sEV-associated fragments not functionally established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,8]}],"complexes":["GPC3-Unc5D octameric complex","GPC3-Hedgehog-LRP1 complex"],"partners":["BMP2","FGF2","LRP1","UNC5D","IGF2","YAP1"],"other_free_text":[]}},"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":613,"is_preprint":false},{"pmid":"20054179","id":"PMC_20054179","title":"Human SGBS cells - a unique tool for studies of human fat cell biology.","date":"2008","source":"Obesity facts","url":"https://pubmed.ncbi.nlm.nih.gov/20054179","citation_count":226,"is_preprint":false},{"pmid":"28123387","id":"PMC_28123387","title":"Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28123387","citation_count":190,"is_preprint":false},{"pmid":"39604730","id":"PMC_39604730","title":"Interleukin-15-armoured GPC3 CAR T cells for patients with solid 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A novel biomarker and molecular target.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39725192","citation_count":15,"is_preprint":false},{"pmid":"32384580","id":"PMC_32384580","title":"In Depth Quantitative Proteomic and Transcriptomic Characterization of Human Adipocyte Differentiation using the SGBS Cell Line.","date":"2020","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32384580","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51802,"output_tokens":4357,"usd":0.110381,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12292,"output_tokens":4290,"usd":0.084355,"stage2_stop_reason":"end_turn"},"total_usd":0.194736,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"GPC3 encodes a cell-surface heparan sulfate proteoglycan (glypican-3) that forms a complex with insulin-like growth factor 2 (IGF2), as shown by western- and ligand-blotting experiments, suggesting it modulates IGF2 action in growth control.\",\n      \"method\": \"Western blotting and ligand-blotting\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — initial western/ligand blot showing GPC3-IGF2 complex, single lab, later contested by Song et al. 1997\",\n      \"pmids\": [\"8589713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Rat GPC3 ortholog OCI-5 does NOT interact with IGF-2 (negative result); instead, OCI-5 binds FGF-2 via its heparan sulfate chains, as shown by transfection into two cell lines and inhibition by heparin or heparitinase.\",\n      \"method\": \"Transfection, co-immunoprecipitation/binding assay, heparin and heparitinase competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with two cell lines and enzymatic/competitive inhibition controls, single lab\",\n      \"pmids\": [\"9065409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"OCI-5/GPC3 mRNA expression in intestinal epithelial cells (IEC-18) is regulated by cell shape: rounded cell morphology (confluence, low calcium, spheroid culture) increases OCI-5 transcription, while cytoskeletal disruption with colchicine (causing cell flattening) abolishes induction. Nuclear run-on analysis confirmed transcriptional regulation.\",\n      \"method\": \"RNA in situ hybridization, nuclear run-on transcription assay, cytoskeletal disruption (colchicine, vanadate), low-calcium and spheroid culture conditions\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear run-on plus multiple perturbation conditions, single lab\",\n      \"pmids\": [\"9281346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"OCI-5/GPC3 induces apoptosis in mesothelioma (II14) and breast cancer (MCF-7) cell lines but not in NIH 3T3 fibroblasts or HT-29 cells (cell-line-specific effect). Membrane anchoring via GPI is required for apoptosis induction, but glycosaminoglycan chains are not. MCF-7 cells can be rescued from GPC3-induced apoptosis by IGF-2.\",\n      \"method\": \"Transfection and ectopic expression, GPI anchor mutants, glycosaminoglycan-deficient mutants, apoptosis assay, IGF-2 rescue experiment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis (GPI anchor, GAG chains) combined with functional apoptosis assays and rescue experiment, single lab with orthogonal methods\",\n      \"pmids\": [\"9628896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GPC3 promoter hypermethylation silences GPC3 expression in ovarian cancer cell lines; treatment with 5-aza-2'-deoxycytidine (demethylating agent) restores expression, and ectopic GPC3 expression inhibits colony formation, consistent with a tumor-suppressor role.\",\n      \"method\": \"Southern blot analysis of promoter methylation, demethylating agent treatment, colony-forming assay with ectopic GPC3 expression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation analysis plus functional colony assay, single lab\",\n      \"pmids\": [\"10029067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GPC3 promoter methylation on the inactive X allele mediates transcriptional repression via X inactivation; in vitro methylation of the GPC3 promoter in reporter constructs directly represses transcription.\",\n      \"method\": \"In vitro methylation of reporter constructs, Southern blot analysis of allele-specific methylation, azadeoxycytidine treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro 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 predominantly through aberrant promoter methylation (not allelic loss or mutation); demethylation with 5-aza-2'-deoxycytidine restores GPC3 expression in MM cell lines, and ectopic GPC3 expression inhibits in vitro colony formation of MM cells.\",\n      \"method\": \"Northern blot, allelic loss analysis, mutational analysis, promoter methylation analysis, demethylating agent treatment, ectopic expression + colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (methylation, demethylation, functional assay), single lab\",\n      \"pmids\": [\"10656689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A GPC3 missense mutation (W296R), which changes an amino acid conserved across all glypicans, results in a poorly processed protein that fails to increase cell surface expression of heparan sulfate, establishing it as a loss-of-function mutation affecting GPC3 processing and cell-surface localization.\",\n      \"method\": \"Mutational analysis, protein processing assay, heparan sulfate cell surface expression assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional characterization of mutant protein with multiple assays, single lab\",\n      \"pmids\": [\"10814714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GPC3 expression is epigenetically silenced by promoter hypermethylation in non-small cell lung carcinoma lines; ectopic GPC3 expression increases apoptosis response to etoposide and inhibits growth in nude mice, supporting a tumor-suppressor role.\",\n      \"method\": \"Northern blot, pharmacologic demethylation, ectopic GPC3 expression, etoposide apoptosis assay, xenograft growth assay\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism plus functional assay in vitro and in vivo, single lab\",\n      \"pmids\": [\"12816733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRP1 mediates Hh-induced endocytosis of the GPC3-Hh complex: GPC3 binds Hh and competes with Patched for Hh binding; Hh binding to GPC3 triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex, reducing Hh available for signaling. GPC3 binds LRP1 through its heparan sulfate chains, and this interaction displaces GPC3 from lipid rafts.\",\n      \"method\": \"Co-immunoprecipitation, endocytosis assays, lipid raft fractionation, competition binding assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, lipid raft fractionation, endocytosis functional assay, and demonstration of mechanistic requirement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22467855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPC3 (and GPC1) physically interact with BMP2 and inhibit BMP2, BMP4, and BMP7 signaling in human suture mesenchymal cells. This inhibition is independent of GPC3 cell-surface attachment and glycanation (mediated by the core protein), and acts through both SMAD-dependent and SMAD-independent BMP pathways. Immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity, and overexpression inhibits BMP2-mediated osteogenesis.\",\n      \"method\": \"Co-immunoprecipitation (GPC3-BMP2 interaction), recombinant protein addition, overexpression, immunoblockade of endogenous proteins, SMAD signaling assays, osteogenesis assays, GPI-anchor and glycanation-deficient constructs\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding (Co-IP), recombinant protein experiments, mutagenesis (glycanation/GPI), functional osteogenesis assay, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"23624389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of GPC3 in Huh7 HCC cells induces apoptosis and inhibits proliferation, migration, and invasion; GPC3 knockdown suppresses YAP expression at mRNA and protein levels, and addition of recombinant YAP-1 rescues cells from GPC3-knockdown-induced apoptosis, placing GPC3 upstream of YAP in the Hippo pathway.\",\n      \"method\": \"siRNA knockdown, flow cytometry (apoptosis), EdU incorporation (proliferation), migration/invasion assays, qPCR, western blot, recombinant YAP-1 rescue experiment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA + rescue experiment with recombinant protein, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"23060277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of GPC3 in complex with the guidance receptor Unc5D reveals an octameric glycoprotein complex (4 Unc5D + 4 GPC3). Central glycan-glycan interactions are formed between N-linked glycans from GPC3 (N241 in human) and C-mannosylated tryptophans of Unc5D thrombospondin-like domains. Structure-based mutants and nanobodies modulating GPC3-Unc5 binding demonstrate that this complex guides migrating pyramidal neurons in the mouse cortex and cancer cell migration.\",\n      \"method\": \"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutagenesis, anti-GPC3 nanobodies, embryonic xenograft neuroblastoma model, mouse cortex neuron migration assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus MD simulations, MS, mutagenesis, and in vivo functional validation across two model systems in one rigorous study\",\n      \"pmids\": [\"36240740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPC3 overexpression in renal carcinoma cell lines (786-O and ACHN) reduces cell proliferation through G1-phase cell cycle arrest without inducing apoptosis.\",\n      \"method\": \"GPC3 expression vector transfection, MTT assay, colony formation assay, flow cytometry (cell cycle and apoptosis)\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO/OE with defined cellular phenotype (G1 arrest), single lab, single method set\",\n      \"pmids\": [\"25168166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPC3 promotes HCC cell proliferation through the Hedgehog (Hh) pathway in HepG2 cells (but not HLE cells), as shown by in vitro analysis of GPC3-overexpressing cell lines.\",\n      \"method\": \"Overexpression in HCC cell lines, RT-PCR, cell proliferation assay, Hedgehog pathway gene expression analysis\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, pathway inferred from expression changes without direct pathway perturbation\",\n      \"pmids\": [\"29963171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of GPC3 in Huh7 and SK-HEP-1 HCC cells inhibits proliferation and invasion through induction of apoptosis; co-treatment with IGF2 and FGF2 significantly inhibits GPC3-induced apoptotic cell death, indicating GPC3 acts as a negative regulator of IGF2 and FGF2 pathways.\",\n      \"method\": \"Transfection, Annexin V-PI flow cytometry, IGF2/FGF2 co-treatment rescue experiment\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ectopic expression with functional readouts and growth factor rescue experiment, single lab, two cell lines\",\n      \"pmids\": [\"23338845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPC3 structural analysis predicts that the Furin cleavage site of GPC3 is exposed and accessible, facilitating cleavage events. Furin-dependent GPC3 cleaved domains were detected in serum small extracellular vesicles (sEVs) isolated from HCC patients.\",\n      \"method\": \"In silico structural prediction, isolation of sEVs from patient serum and hepatocyte culture media, western blotting for GPC3 domains\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — computational prediction plus sEV detection, no direct functional validation of Furin cleavage, single lab\",\n      \"pmids\": [\"37446098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GPC3 protein is expressed in human placenta and localizes specifically to the differentiated syncytiotrophoblast layer, as confirmed by in situ hybridization and immunohistochemistry; cytotrophoblasts increase GPC3 expression during trophoblast differentiation, while fibroblasts and choriocarcinoma lines do not express GPC3.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, RT-PCR in cell lines and primary cultures\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by ISH + IHC with functional differentiation context, replicated in primary and cell line models\",\n      \"pmids\": [\"11193214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPC3 is a GPI-anchored cell-surface heparan sulfate proteoglycan that regulates growth and cell guidance through multiple mechanisms: its core protein directly binds and inhibits BMP2/4/7 and competes with Patched for Hedgehog binding, triggering LRP1-mediated endocytosis and degradation of the GPC3-Hh complex; it forms a structurally defined octameric complex with Unc5D guidance receptors via glycan-glycan interactions to regulate cell migration; it induces GPI-anchor-dependent, GAG-independent apoptosis in a cell-type-specific manner and can suppress proliferation via G1 arrest or YAP downregulation; and its promoter is subject to epigenetic silencing by CpG methylation in multiple cancer types, with loss of GPC3 associated with overgrowth (Simpson-Golabi-Behmel syndrome).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPC3 is a GPI-anchored cell-surface heparan sulfate proteoglycan that regulates cell growth, survival, and guidance by physically engaging multiple ligands and receptors at the plasma membrane [#0, #3, #10]. Through its core protein it directly binds and inhibits BMP2/4/7 signaling in a manner independent of GPI anchoring and glycanation, acting through both SMAD-dependent and SMAD-independent pathways [#10], while its heparan sulfate chains bind FGF-2 [#1] and LRP1; binding of Hedgehog to GPC3 competes with Patched and triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex, attenuating Hedgehog signaling [#9]. Structurally, GPC3 assembles into a defined octameric complex with the guidance receptor Unc5D via glycan-glycan contacts between its N-linked glycans and C-mannosylated tryptophans of Unc5D, and this complex directs migration of cortical pyramidal neurons and cancer cells [#12]. GPC3 also induces GPI-anchor-dependent, glycosaminoglycan-independent apoptosis in a cell-type-specific manner, an effect reversible by IGF-2 [#3], and it can suppress proliferation through G1 arrest [#13] or by acting upstream of YAP in the Hippo pathway [#11]. Its promoter is recurrently silenced by CpG methylation across ovarian cancer, mesothelioma, and lung carcinoma, where re-expression suppresses colony formation and tumor growth, consistent with a context-dependent tumor-suppressor role [#4, #6, #8]. A conserved missense mutation (W296R) yields a poorly processed protein that fails to reach the cell surface, defining a loss-of-function mechanism [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established GPC3 as a cell-surface heparan sulfate proteoglycan and provided the first candidate ligand by detecting a complex with IGF2, framing GPC3 as a modulator of growth-factor action.\",\n      \"evidence\": \"Western and ligand-blotting of glypican-3\",\n      \"pmids\": [\"8589713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IGF2 interaction was later contested by an ortholog study\", \"no functional consequence of the complex demonstrated\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Reassigned the ligand specificity by showing the rat ortholog does not bind IGF-2 but instead binds FGF-2 through its heparan sulfate chains, distinguishing core-protein from glycan-mediated interactions.\",\n      \"evidence\": \"Transfection, binding assay, heparin/heparitinase competition in two cell lines\",\n      \"pmids\": [\"9065409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional outcome of FGF-2 binding not established\", \"species/ortholog difference vs human GPC3 not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked GPC3 transcription to cell shape and cytoskeletal state, indicating context-dependent regulation of its expression.\",\n      \"evidence\": \"Nuclear run-on, in situ hybridization, cytoskeletal disruption and culture-geometry perturbations in IEC-18 cells\",\n      \"pmids\": [\"9281346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"transcription factors mediating shape-dependent induction unidentified\", \"relevance to in vivo growth control unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined GPC3 as a cell-type-specific inducer of apoptosis and dissected the structural requirements, showing GPI anchoring is required while glycosaminoglycan chains are dispensable, and that IGF-2 can rescue.\",\n      \"evidence\": \"Ectopic expression with GPI-anchor and GAG-deficient mutants, apoptosis assays, IGF-2 rescue across multiple cell lines\",\n      \"pmids\": [\"9628896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular death pathway downstream of GPI-anchored GPC3 not identified\", \"basis of cell-type specificity unexplained\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified promoter hypermethylation as the silencing mechanism for GPC3 in cancer and X-inactivation, and showed re-expression suppresses colony formation, establishing a tumor-suppressor candidacy.\",\n      \"evidence\": \"Southern blot methylation analysis, in vitro reporter methylation, demethylating agent treatment, colony assays in ovarian cancer\",\n      \"pmids\": [\"10029067\", \"9892682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"growth-suppressive mechanism downstream of re-expression not defined\", \"single-lab functional readout\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Generalized epigenetic silencing to mesothelioma and characterized a loss-of-function missense mutation, connecting GPC3 inactivation to defective protein processing and surface localization.\",\n      \"evidence\": \"Methylation/demethylation and colony assays in mesothelioma; mutational and processing/heparan-sulfate surface-expression assays for W296R\",\n      \"pmids\": [\"10656689\", \"10814714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether W296R recapitulates disease phenotype in vivo not tested\", \"tumor-suppressor mechanism still uncharacterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localized GPC3 protein to the differentiated syncytiotrophoblast and showed its induction during trophoblast differentiation, anchoring its role in a defined developmental tissue context.\",\n      \"evidence\": \"In situ hybridization, immunohistochemistry, RT-PCR in primary and cell-line trophoblasts\",\n      \"pmids\": [\"11193214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional role in placental development not tested\", \"signaling partners in syncytiotrophoblast unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the epigenetic-silencing/tumor-suppressor model to lung carcinoma with in vivo evidence, showing re-expression sensitizes to etoposide-induced apoptosis and inhibits xenograft growth.\",\n      \"evidence\": \"Demethylation, ectopic expression, etoposide apoptosis assay, nude mouse xenograft\",\n      \"pmids\": [\"12816733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular basis of apoptosis sensitization not defined\", \"in vivo data from single model\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved a mechanism for GPC3 control of Hedgehog signaling, showing GPC3 competes with Patched for Hh and that Hh binding triggers LRP1-dependent endocytosis and degradation of the GPC3-Hh complex via its heparan sulfate chains.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, competition binding, lipid raft fractionation, endocytosis assays\",\n      \"pmids\": [\"22467855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"in vivo relevance to Hedgehog-driven development/disease not addressed\", \"fate of internalized Hh signaling output not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated direct core-protein-mediated inhibition of BMP signaling, separating this ligand-trap function from membrane anchoring and glycanation and linking it to control of osteogenesis.\",\n      \"evidence\": \"Co-IP of GPC3-BMP2, recombinant protein, immunoblockade, GPI/glycanation-deficient constructs, SMAD and osteogenesis assays\",\n      \"pmids\": [\"23624389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of BMP-core protein interaction not defined\", \"in vivo skeletal phenotype not tested in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed GPC3 upstream of YAP in the Hippo pathway in hepatocellular carcinoma and reaffirmed growth-factor antagonism, where knockdown induces apoptosis rescued by YAP-1, and overexpression-induced apoptosis is blunted by IGF2/FGF2.\",\n      \"evidence\": \"siRNA knockdown, recombinant YAP-1 rescue, ectopic expression with IGF2/FGF2 rescue, apoptosis and proliferation/invasion assays in HCC lines\",\n      \"pmids\": [\"23060277\", \"23338845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direction of GPC3 effect in HCC (pro- vs anti-tumor) varies by context\", \"mechanism linking GPC3 to YAP regulation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed GPC3 can restrain proliferation independently of apoptosis via G1-phase cell cycle arrest in renal carcinoma, broadening its growth-suppressive repertoire.\",\n      \"evidence\": \"Overexpression, MTT, colony formation, cell-cycle and apoptosis flow cytometry in 786-O and ACHN cells\",\n      \"pmids\": [\"25168166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cell-cycle regulators mediating G1 arrest not identified\", \"context-dependence relative to apoptotic effect unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural basis for GPC3 as a guidance co-receptor by solving the GPC3-Unc5D octameric complex assembled through glycan-glycan interactions, and validated its role in neuronal and cancer cell migration.\",\n      \"evidence\": \"X-ray crystallography, MD simulations, mass spectrometry, structure-based mutants, nanobodies, mouse cortex and xenograft migration assays\",\n      \"pmids\": [\"36240740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signaling output downstream of the GPC3-Unc5D complex not defined\", \"how this guidance function integrates with GPC3's ligand-trap roles unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GPC3's distinct activities — apoptosis induction, BMP/FGF/Hh modulation, YAP regulation, and Unc5D-mediated guidance — are coordinated within a single cell and which dominate in specific developmental and tumor contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no unified model reconciling tumor-suppressor vs tumor-promoting roles\", \"downstream effectors of GPI-anchor-dependent apoptosis unknown\", \"physiological significance of Furin cleavage and sEV-associated fragments not functionally established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 8]}\n    ],\n    \"complexes\": [\n      \"GPC3-Unc5D octameric complex\",\n      \"GPC3-Hedgehog-LRP1 complex\"\n    ],\n    \"partners\": [\n      \"BMP2\",\n      \"FGF2\",\n      \"LRP1\",\n      \"UNC5D\",\n      \"IGF2\",\n      \"YAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}