{"gene":"FUT3","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1994,"finding":"The L1 mutation (Leu-20→Arg) in FUT3's transmembrane domain reduces enzyme levels in transfected COS-7 cells without altering substrate affinity, suggesting it disrupts Golgi membrane anchoring rather than catalytic activity. The L2 mutation (Ile-356→Lys) in the catalytic domain completely inactivates the enzyme.","method":"Site-directed mutagenesis, COS-7 cell transfection, enzyme activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzyme activity assays combined with mutagenesis and transfection, two distinct mutations characterized with orthogonal readouts (activity + protein levels)","pmids":["8063716"],"is_preprint":false},{"year":1997,"finding":"The T202C mutation (Trp68→Arg) in FUT3 is the principal inactivating change responsible for the Le(a-b-) phenotype, reducing enzyme activity to <1% of wild type. The C314T mutation (Thr105→Met) alone does not reduce enzyme activity; only in combination with T202C is enzyme activity abolished.","method":"Chimeric FUT3 constructs, COS-7 cell transfection, enzyme activity assay, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with chimeric constructs, enzyme activity quantification, and immunofluorescence, with clear separation of individual mutation contributions","pmids":["9268337"],"is_preprint":false},{"year":1998,"finding":"The G667A (Gly223→Arg) and G808A (Val270→Met) missense mutations each independently abolish FUT3 α(1,3/1,4)fucosyltransferase activity, while G484A (Asp162→Asn) alone retains ~20% of wild-type activity.","method":"Chimeric FUT3 constructs, COS-7 cell transfection, enzyme activity assay, Lewis antigen expression","journal":"Glycoconjugate journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — individual mutations tested in reconstitution assay with enzymatic readout and antigen expression, single lab but multiple orthogonal methods","pmids":["10211701"],"is_preprint":false},{"year":2000,"finding":"Antisense suppression of FUT3 in BxPC-3 pancreatic cancer cells reduces cell-surface sialyl-Lewis a and sialyl-Lewis x antigen expression, inhibits adhesion to E-selectin, and decreases metastatic capacity in nude mice, establishing FUT3 as a rate-limiting enzyme for sialyl-Lewis antigen synthesis and E-selectin–mediated adhesion.","method":"Antisense cDNA transfection, flow cytometry, E-selectin adhesion assay, nude mouse metastasis model","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotype, multiple orthogonal readouts (antigen expression, adhesion, metastasis)","pmids":["11058871"],"is_preprint":false},{"year":2006,"finding":"FUT3 promoter hypomethylation is required for FUT3 expression in gastric cancer cells; treatment with 5-aza-2'-deoxycytidine increases FUT3 mRNA, α-1,4 fucosyltransferase activity, and Le(a) antigen expression. Luciferase reporter assays with methylated vs. unmethylated FUT3 promoter deletion constructs confirmed that methylation directly suppresses FUT3 transcription.","method":"5-aza-2'-deoxycytidine treatment, RT-PCR, enzyme activity assay, immunohistochemistry, luciferase reporter assay","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — luciferase reporter with methylated constructs plus functional enzymatic and antigen expression readouts, single lab, multiple orthogonal methods","pmids":["16427187"],"is_preprint":false},{"year":2009,"finding":"HSV-1 activates transcription of the FUT3/FUT5/FUT6 gene cluster via Protein Kinase R (PKR) as the primary viral RNA target; PKR inhibitors (2-AP, C16) suppress FUT3, FUT5, FUT6 expression and HSV-1-induced sLe(x) surface expression. The downstream pathway involves an IKK-2-independent but IMD-0354-sensitive mechanism distinct from classical NF-κB activation.","method":"PKR inhibitor treatment, siRNA knockdown, flow cytometry for sLe(x), RT-PCR","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition and partial siRNA validation, single lab, mechanistic pathway defined for FUT3 transcriptional regulation","pmids":["19349624"],"is_preprint":false},{"year":2011,"finding":"shRNA-mediated knockdown of FUT3 (alone or with FUT5) in gastric cancer cell lines reduces sialyl-Lewis antigen surface expression, decreases adhesion to endothelial cells via E-selectin binding, and reduces binding to hyaluronic acid, without changing CD44 protein levels.","method":"Lentiviral shRNA knockdown, qRT-PCR, flow cytometry, E-selectin adhesion assay, hyaluronic acid binding assay, western blot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with multiple orthogonal functional readouts, single lab","pmids":["21978830"],"is_preprint":false},{"year":2017,"finding":"HSV-1 activates transcription of the FUT3/FUT5/FUT6 cluster on chromosome 19 specifically via NF-κB/p65 signaling; panepoxydone treatment and p65 siRNA knockdown significantly reduce viral induction of FUT3, FUT5, and FUT6, while direct interferon-mediated NF-κB stimulation alone is insufficient to activate the cluster in uninfected cells.","method":"NF-κB inhibitor (panepoxydone), siRNA targeting p65, RT-PCR for FUT3/5/6 transcription","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and siRNA epistasis, single lab, two orthogonal methods","pmids":["28973293"],"is_preprint":false},{"year":2018,"finding":"FUT3 knockdown in pancreatic cancer cells (Capan-1) inhibits cell proliferation, reduces migration and invasion, impairs adhesion to E-selectin, and suppresses TGF-β-induced epithelial-mesenchymal transition (EMT); overexpression has the opposite effects.","method":"shRNA knockdown, overexpression, wound healing assay, transwell invasion assay, E-selectin adhesion assay, in vivo xenograft","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts, single lab","pmids":["29963165"],"is_preprint":false},{"year":2021,"finding":"DDX39B RNA helicase binds directly to FUT3 pre-mRNA, promotes its splicing and mRNA nuclear export, thereby upregulating FUT3 expression; elevated FUT3 increases fucosylation of TGFβR-I, activating the TGF-β signaling pathway to drive EMT and colorectal cancer metastasis.","method":"RIP-seq, RNA-seq, Minigene splicing assay, nuclear/cytoplasmic RNA fractionation, gain/loss-of-function, in vivo metastasis model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RIP-seq, Minigene assay, fractionation) establishing the DDX39B→FUT3→TGFβR-I fucosylation→EMT axis","pmids":["33436563"],"is_preprint":false},{"year":2023,"finding":"FUT3 knockdown in lung adenocarcinoma cells suppresses tumor proliferation, migration, and glucose metabolism; GSEA and western blot indicate FUT3 positively regulates NF-κB signaling, and FUT3 downregulation inactivates NF-κB pathway markers in vitro and suppresses tumorigenesis in vivo.","method":"siRNA knockdown, immunofluorescence, metabolite activity assay, western blot (NF-κB markers), subcutaneous tumor model, GSEA","journal":"BMC pulmonary medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with in vitro and in vivo readouts and NF-κB pathway markers, single lab","pmids":["37946130"],"is_preprint":false},{"year":2024,"finding":"FUT3 directly synthesizes Lea glycans on ITGA6 (integrin α6) and GLG1; mass spectrometry identified Lea structures at specific N-glycosylation sites on both proteins. FUT3 silencing causes integrin α6β4 aggregation at the plasma membrane (associated with focal adhesion/hemidesmosome formation) and reduces GLG1 distribution in intracellular vesicles, thereby promoting gastric cancer cell migration.","method":"Lea-antibody capture coupled with mass spectrometry (glycosite identification), immunofluorescence, siRNA silencing, cell migration/invasion assays","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct substrate identification by mass spectrometry with glycosite mapping, combined with functional loss-of-function experiments, single lab but multiple orthogonal methods","pmids":["39477144"],"is_preprint":false},{"year":2025,"finding":"FUT3 directly binds GRP78 and fucosylates it; this fucosylation activates the PERK/ATF4/STC2 ER stress signaling pathway, enhancing survival and proliferation of colorectal cancer cells under glucose-deficient conditions.","method":"Co-immunoprecipitation, western blot, glycosylation assay, pathway inhibition, cell proliferation assay","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP establishing FUT3–GRP78 interaction with downstream pathway readout, single lab, single paper","pmids":["41392296"],"is_preprint":false},{"year":2025,"finding":"FUT3 physically interacts with B3GNT3 (β-1,3-N-acetylglucosaminyltransferase 3) via co-immunoprecipitation; this interaction activates NF-κB signaling to drive autophagy, pancreatic cancer progression, and gemcitabine chemoresistance. FUT3 knockdown suppresses these effects in cells and mouse xenografts.","method":"Co-immunoprecipitation, western blot, RT-qPCR, electron microscopy (autophagy), xenograft model, CCK-8/MTT/wound healing/transwell assays","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP for interaction, multiple functional readouts, single lab, single paper","pmids":["41366466"],"is_preprint":false}],"current_model":"FUT3 encodes an α(1,3/1,4)-fucosyltransferase that localizes to the Golgi and catalyzes the addition of fucose to type 1 and type 2 chain precursors to synthesize Lewis a, Lewis b, sialyl-Lewis a, and sialyl-Lewis x antigens; specific missense mutations in its transmembrane (e.g., Leu-20→Arg, reducing Golgi anchoring) or catalytic domain (e.g., Ile-356→Lys, Gly223→Arg) abolish activity; its expression is regulated by promoter methylation and, during HSV-1 infection, by PKR- and NF-κB/p65-dependent transcriptional activation; in cancer contexts, FUT3 fucosylates substrates including TGFβR-I (activating TGF-β/EMT signaling), GRP78 (activating PERK/ATF4/STC2 ER stress survival), ITGA6, and GLG1, and physically interacts with B3GNT3 to activate NF-κB, collectively driving E-selectin–mediated adhesion, metastasis, chemoresistance, and glucose metabolism reprogramming."},"narrative":{"mechanistic_narrative":"FUT3 encodes an α(1,3/1,4)-fucosyltransferase that synthesizes Lewis-type glycan antigens, and it serves as a rate-limiting enzyme for sialyl-Lewis antigen production that drives E-selectin–mediated adhesion and metastasis in epithelial cancers [PMID:11058871]. Structure–function studies define discrete determinants of activity: a transmembrane mutation (Leu-20→Arg) lowers enzyme levels by disrupting Golgi anchoring without affecting substrate affinity, whereas catalytic-domain substitutions (Ile-356→Lys, Gly223→Arg, Val270→Met, and Trp68→Arg) abolish activity, the last accounting for the Lewis-negative phenotype [PMID:8063716, PMID:9268337, PMID:10211701]. FUT3 expression is controlled at multiple levels — promoter hypomethylation is required for transcription [PMID:16427187], and viral infection by HSV-1 induces the FUT3/FUT5/FUT6 cluster through a PKR- and NF-κB/p65-dependent transcriptional mechanism [PMID:19349624, PMID:28973293], while DDX39B binds FUT3 pre-mRNA to promote its splicing and nuclear export [PMID:33436563]. In cancer, FUT3 fucosylates specific protein substrates to rewire signaling: it modifies TGFβR-I to activate TGF-β/EMT signaling [PMID:33436563], binds and fucosylates GRP78 to activate PERK/ATF4/STC2 ER-stress survival signaling under glucose deprivation [PMID:41392296], and synthesizes Lewis-a glycans on ITGA6 (integrin α6) and GLG1, controlling integrin α6β4 surface distribution and cell migration [PMID:39477144]. FUT3 additionally promotes proliferation, invasion, glucose metabolism, and chemoresistance, acting in part through NF-κB activation and a physical interaction with B3GNT3 [PMID:29963165, PMID:37946130, PMID:41366466].","teleology":[{"year":1994,"claim":"Separated which structural regions of FUT3 govern protein stability versus catalysis, establishing that distinct mutations impair Golgi anchoring or enzymatic function.","evidence":"Site-directed mutagenesis with COS-7 transfection and enzyme activity assays","pmids":["8063716"],"confidence":"High","gaps":["No crystal structure or atomic model of the catalytic domain","Mechanism by which Leu-20→Arg destabilizes Golgi anchoring inferred, not directly imaged"]},{"year":1997,"claim":"Identified the principal inactivating mutation underlying the Lewis-negative phenotype and showed mutation combinations determine activity loss.","evidence":"Chimeric FUT3 constructs, COS-7 transfection, enzyme activity assay, immunofluorescence","pmids":["9268337"],"confidence":"High","gaps":["Population frequency and physiological consequences of Le(a-b-) not addressed in this corpus"]},{"year":1998,"claim":"Extended the mutational map of FUT3 catalytic residues by quantifying the activity impact of individual missense changes.","evidence":"Chimeric constructs, COS-7 transfection, enzyme activity and Lewis antigen expression","pmids":["10211701"],"confidence":"High","gaps":["Residue-level mechanistic roles in substrate or donor binding not resolved"]},{"year":2000,"claim":"Established FUT3 as a rate-limiting enzyme for sialyl-Lewis antigen synthesis that drives E-selectin adhesion and metastasis, defining its cancer-relevant function.","evidence":"Antisense suppression in BxPC-3 cells, flow cytometry, E-selectin adhesion assay, nude mouse metastasis model","pmids":["11058871"],"confidence":"High","gaps":["Antisense rather than genetic knockout","Downstream protein substrates carrying the sLe antigens not identified at this stage"]},{"year":2006,"claim":"Showed FUT3 transcription is directly suppressed by promoter methylation, identifying an epigenetic control of Lewis antigen output.","evidence":"5-aza-2'-deoxycytidine treatment, RT-PCR, enzyme activity, IHC, methylated luciferase reporters","pmids":["16427187"],"confidence":"High","gaps":["Trans-acting factors and signals controlling FUT3 promoter methylation unknown"]},{"year":2009,"claim":"Defined PKR as the primary viral RNA sensor mediating HSV-1 induction of the FUT3/5/6 cluster, linking innate viral sensing to fucosyltransferase expression.","evidence":"PKR inhibitor treatment, siRNA knockdown, flow cytometry for sLe(x), RT-PCR","pmids":["19349624"],"confidence":"Medium","gaps":["Pharmacological inhibition with partial siRNA validation","Cluster-level readout does not isolate FUT3-specific regulation"]},{"year":2017,"claim":"Identified NF-κB/p65 as the downstream effector of HSV-1-driven FUT3 cluster transcription, refining the viral induction pathway.","evidence":"NF-κB inhibitor panepoxydone, p65 siRNA, RT-PCR for FUT3/5/6","pmids":["28973293"],"confidence":"Medium","gaps":["Direct p65 binding to FUT3 promoter not demonstrated by ChIP","Whether all three cluster genes share identical regulatory elements unresolved"]},{"year":2018,"claim":"Linked FUT3 to TGF-β-induced EMT and demonstrated bidirectional control of proliferation, invasion, and E-selectin adhesion via gain- and loss-of-function.","evidence":"shRNA knockdown and overexpression, migration/invasion assays, E-selectin adhesion, xenograft","pmids":["29963165"],"confidence":"Medium","gaps":["Molecular substrate of FUT3 in the TGF-β axis not identified here","Single cell line and single lab"]},{"year":2021,"claim":"Established the DDX39B→FUT3→TGFβR-I fucosylation axis, providing both an upstream RNA-processing regulator and a direct fucosylated substrate driving EMT and metastasis.","evidence":"RIP-seq, minigene splicing assay, nuclear/cytoplasmic fractionation, gain/loss-of-function, in vivo metastasis","pmids":["33436563"],"confidence":"High","gaps":["Glycosite on TGFβR-I not mapped","How fucosylation alters receptor signaling structurally unresolved"]},{"year":2023,"claim":"Connected FUT3 to glucose metabolism and NF-κB signaling in lung adenocarcinoma, broadening its oncogenic phenotype beyond adhesion.","evidence":"siRNA knockdown, immunofluorescence, metabolite assays, western blot for NF-κB markers, xenograft, GSEA","pmids":["37946130"],"confidence":"Medium","gaps":["NF-κB regulation inferred from pathway markers, not direct mechanism","Fucosylation substrate mediating metabolic effect unidentified"]},{"year":2024,"claim":"Identified ITGA6 and GLG1 as direct FUT3 glycosylation substrates with mapped Lewis-a glycosites, linking FUT3 to integrin distribution and migration control.","evidence":"Lea-antibody capture mass spectrometry with glycosite mapping, immunofluorescence, siRNA, migration assays","pmids":["39477144"],"confidence":"High","gaps":["Mechanism connecting integrin α6β4 aggregation to migration not fully resolved","Single gastric cancer model"]},{"year":2025,"claim":"Showed FUT3 binds and fucosylates GRP78 to activate PERK/ATF4/STC2 ER-stress survival signaling, defining a metabolic stress-adaptation function.","evidence":"Co-immunoprecipitation, western blot, glycosylation assay, pathway inhibition, proliferation assay","pmids":["41392296"],"confidence":"Medium","gaps":["Single Co-IP-based interaction without reciprocal structural validation","GRP78 glycosite not mapped","Single lab, single paper"]},{"year":2025,"claim":"Identified a physical FUT3–B3GNT3 interaction activating NF-κB to drive autophagy and gemcitabine chemoresistance in pancreatic cancer.","evidence":"Co-immunoprecipitation, western blot, RT-qPCR, electron microscopy, xenograft, proliferation/migration assays","pmids":["41366466"],"confidence":"Medium","gaps":["Co-IP interaction without reciprocal or structural validation","Whether the interaction requires FUT3 catalytic activity unknown","Single lab, single paper"]},{"year":null,"claim":"How FUT3 selects its protein substrates and whether its non-canonical signaling roles (NF-κB activation, B3GNT3 interaction) depend on its fucosyltransferase activity remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model defining substrate-recognition determinants","Catalytic dependence of protein–protein interaction functions untested","Mechanism coupling fucosylation to NF-κB transcriptional output unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,9,11,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,11,12]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,11]}],"complexes":[],"partners":["TGFBR1","GRP78","ITGA6","GLG1","B3GNT3","DDX39B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21217","full_name":"3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3","aliases":["4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase","Alpha-3-fucosyltransferase FUT3","Blood group Lewis alpha-4-fucosyltransferase","Lewis FT","Fucosyltransferase 3","Fucosyltransferase III","FucT-III"],"length_aa":361,"mass_kda":42.1,"function":"Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to both the subterminal N-acetyl glucosamine (GlcNAc) of type 1 chain (beta-D-Gal-(1->3)-beta-D-GlcNAc) glycolipids and oligosaccharides via an alpha(1,4) linkage, and the subterminal glucose (Glc) or GlcNAc of type 2 chain (beta-D-Gal-(1->4)-beta-D-GlcNAc) oligosaccharides via an alpha(1,3) linkage, independently of the presence of terminal alpha-L-fucosyl-(1,2) moieties on the terminal galactose of these acceptors (PubMed:11058871, PubMed:12668675, PubMed:1977660). Through its catalytic activity, participates in the synthesis of antigens of the Lewis blood group system, i.e. Lewis a (Le(a)), lewis b (Le(b)), Lewis x/SSEA-1 (Le(x)) and lewis y (Le(y)) antigens (PubMed:11058871, PubMed:12668675, PubMed:1977660). Also catalyzes the transfer of L-fucose to subterminal GlcNAc of sialyl- and disialyl-lactotetraosylceramide to produce sialyl Lewis a (sLe(a)) and disialyl Lewis a via an alpha(1,4) linkage and therefore may regulate cell surface sLe(a) expression and consequently regulates adhesive properties to E-selectin, cell proliferation and migration (PubMed:11058871, PubMed:12668675, PubMed:27453266). Catalyzes the transfer of an L-fucose to 3'-sialyl-N-acetyllactosamine by an alpha(1,3) linkage, which allows the formation of sialyl-Lewis x structure and therefore may regulate the sialyl-Lewis x surface antigen expression and consequently adhesive properties to E-selectin (PubMed:11058871, PubMed:29593094). Prefers type 1 chain over type 2 acceptors (PubMed:7721776). Type 1 tetrasaccharide is a better acceptor than type 1 disaccharide suggesting that a beta anomeric configuration of GlcNAc in the substrate is preferred (PubMed:7721776). Lewis-positive (Le(+)) individuals have an active enzyme while Lewis-negative (Le(-)) individuals have an inactive enzyme (PubMed:1977660)","subcellular_location":"Golgi apparatus, Golgi stack membrane","url":"https://www.uniprot.org/uniprotkb/P21217/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FUT3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FUT3","total_profiled":1310},"omim":[{"mim_id":"618983","title":"BLOOD GROUP, LEWIS SYSTEM; LE","url":"https://www.omim.org/entry/618983"},{"mim_id":"616932","title":"PROTEIN O-FUCOSYLTRANSFERASE 4; POFUT4","url":"https://www.omim.org/entry/616932"},{"mim_id":"616931","title":"PROTEIN O-FUCOSYLTRANSFERASE 3; POFUT3","url":"https://www.omim.org/entry/616931"},{"mim_id":"616754","title":"BOMBAY PHENOTYPE","url":"https://www.omim.org/entry/616754"},{"mim_id":"602030","title":"FUCOSYLTRANSFERASE 7; FUT7","url":"https://www.omim.org/entry/602030"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":150.8},{"tissue":"intestine","ntpm":67.6},{"tissue":"retina","ntpm":76.2},{"tissue":"salivary gland","ntpm":79.3}],"url":"https://www.proteinatlas.org/search/FUT3"},"hgnc":{"alias_symbol":["CD174"],"prev_symbol":["LE"]},"alphafold":{"accession":"P21217","domains":[{"cath_id":"3.40.50.11660","chopping":"171-329","consensus_level":"high","plddt":94.9424,"start":171,"end":329},{"cath_id":"3.40.50","chopping":"63-167_332-359","consensus_level":"high","plddt":95.8362,"start":63,"end":359}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21217","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21217-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21217-F1-predicted_aligned_error_v6.png","plddt_mean":89.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FUT3","jax_strain_url":"https://www.jax.org/strain/search?query=FUT3"},"sequence":{"accession":"P21217","fasta_url":"https://rest.uniprot.org/uniprotkb/P21217.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21217/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21217"}},"corpus_meta":[{"pmid":"8063716","id":"PMC_8063716","title":"Molecular basis for Lewis alpha(1,3/1,4)-fucosyltransferase gene deficiency (FUT3) found in Lewis-negative Indonesian pedigrees.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8063716","citation_count":111,"is_preprint":false},{"pmid":"16107962","id":"PMC_16107962","title":"Influence of the combined ABO, FUT2, and FUT3 polymorphism on susceptibility to Norwalk virus attachment.","date":"2005","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16107962","citation_count":100,"is_preprint":false},{"pmid":"9079712","id":"PMC_9079712","title":"Molecular cloning and expression of a bovine alpha(1,3)-fucosyltransferase gene homologous to a putative ancestor gene of the human FUT3-FUT5-FUT6 cluster.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9079712","citation_count":64,"is_preprint":false},{"pmid":"7656588","id":"PMC_7656588","title":"Relative positions of two clusters of human alpha-L-fucosyltransferases in 19q (FUT1-FUT2) and 19p (FUT6-FUT3-FUT5) within the microsatellite genetic map of chromosome 19.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7656588","citation_count":63,"is_preprint":false},{"pmid":"33436563","id":"PMC_33436563","title":"The DDX39B/FUT3/TGFβR-I axis promotes tumor metastasis and EMT in colorectal cancer.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33436563","citation_count":55,"is_preprint":false},{"pmid":"26766790","id":"PMC_26766790","title":"Association of Ulcerative Colitis with FUT2 and FUT3 Polymorphisms in Patients from Southeast China.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26766790","citation_count":44,"is_preprint":false},{"pmid":"9268337","id":"PMC_9268337","title":"Significance of individual point mutations, T202C and C314T, in the human Lewis (FUT3) gene for expression of Lewis antigens by the human alpha(1,3/1,4)-fucosyltransferase, Fuc-TIII.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9268337","citation_count":43,"is_preprint":false},{"pmid":"8801770","id":"PMC_8801770","title":"DNA sequencing and screening for point mutations in the human Lewis (FUT3) gene enables molecular genotyping of the human Lewis blood group system.","date":"1996","source":"Vox sanguinis","url":"https://pubmed.ncbi.nlm.nih.gov/8801770","citation_count":43,"is_preprint":false},{"pmid":"7782074","id":"PMC_7782074","title":"Physical maps of human alpha (1,3)fucosyltransferase genes FUT3-FUT6 on chromosomes 19p13.3 and 11q21.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7782074","citation_count":42,"is_preprint":false},{"pmid":"11479278","id":"PMC_11479278","title":"The fucosylated histo-blood group antigens H type 2 (blood group O, CD173) and Lewis Y (CD174) are expressed on CD34+ hematopoietic progenitors but absent on mature lymphocytes.","date":"2001","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/11479278","citation_count":41,"is_preprint":false},{"pmid":"9703429","id":"PMC_9703429","title":"Five novel missense mutations of the Lewis gene (FUT3) in African (Xhosa) and Caucasian populations in South Africa.","date":"1998","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9703429","citation_count":39,"is_preprint":false},{"pmid":"21978830","id":"PMC_21978830","title":"Down-regulation of FUT3 and FUT5 by shRNA alters Lewis antigens expression and reduces the adhesion capacities of gastric cancer cells.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21978830","citation_count":38,"is_preprint":false},{"pmid":"16427187","id":"PMC_16427187","title":"Expression of Lea in gastric cancer cell lines depends on FUT3 expression regulated by promoter methylation.","date":"2006","source":"Cancer 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c.314C>T in FUT3.","date":"2023","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36900072","citation_count":6,"is_preprint":false},{"pmid":"34936845","id":"PMC_34936845","title":"Correlations of FUT3 gene polymorphisms with colon polyps.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34936845","citation_count":5,"is_preprint":false},{"pmid":"32218479","id":"PMC_32218479","title":"Systematic sequence analysis of the FUT3 gene identifies 11 novel alleles in the Sindhi and Punjabi populations from Pakistan.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32218479","citation_count":5,"is_preprint":false},{"pmid":"30929162","id":"PMC_30929162","title":"The challenge of determining the impact of FUT3 tumor-associated polymorphism rs2306969 (-6951 C> T) in invasive breast cancer cells.","date":"2019","source":"Molecular biology 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The L2 mutation (Ile-356→Lys) in the catalytic domain completely inactivates the enzyme.\",\n      \"method\": \"Site-directed mutagenesis, COS-7 cell transfection, enzyme activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzyme activity assays combined with mutagenesis and transfection, two distinct mutations characterized with orthogonal readouts (activity + protein levels)\",\n      \"pmids\": [\"8063716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The T202C mutation (Trp68→Arg) in FUT3 is the principal inactivating change responsible for the Le(a-b-) phenotype, reducing enzyme activity to <1% of wild type. The C314T mutation (Thr105→Met) alone does not reduce enzyme activity; only in combination with T202C is enzyme activity abolished.\",\n      \"method\": \"Chimeric FUT3 constructs, COS-7 cell transfection, enzyme activity assay, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with chimeric constructs, enzyme activity quantification, and immunofluorescence, with clear separation of individual mutation contributions\",\n      \"pmids\": [\"9268337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The G667A (Gly223→Arg) and G808A (Val270→Met) missense mutations each independently abolish FUT3 α(1,3/1,4)fucosyltransferase activity, while G484A (Asp162→Asn) alone retains ~20% of wild-type activity.\",\n      \"method\": \"Chimeric FUT3 constructs, COS-7 cell transfection, enzyme activity assay, Lewis antigen expression\",\n      \"journal\": \"Glycoconjugate journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — individual mutations tested in reconstitution assay with enzymatic readout and antigen expression, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10211701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Antisense suppression of FUT3 in BxPC-3 pancreatic cancer cells reduces cell-surface sialyl-Lewis a and sialyl-Lewis x antigen expression, inhibits adhesion to E-selectin, and decreases metastatic capacity in nude mice, establishing FUT3 as a rate-limiting enzyme for sialyl-Lewis antigen synthesis and E-selectin–mediated adhesion.\",\n      \"method\": \"Antisense cDNA transfection, flow cytometry, E-selectin adhesion assay, nude mouse metastasis model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotype, multiple orthogonal readouts (antigen expression, adhesion, metastasis)\",\n      \"pmids\": [\"11058871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FUT3 promoter hypomethylation is required for FUT3 expression in gastric cancer cells; treatment with 5-aza-2'-deoxycytidine increases FUT3 mRNA, α-1,4 fucosyltransferase activity, and Le(a) antigen expression. Luciferase reporter assays with methylated vs. unmethylated FUT3 promoter deletion constructs confirmed that methylation directly suppresses FUT3 transcription.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment, RT-PCR, enzyme activity assay, immunohistochemistry, luciferase reporter assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — luciferase reporter with methylated constructs plus functional enzymatic and antigen expression readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16427187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HSV-1 activates transcription of the FUT3/FUT5/FUT6 gene cluster via Protein Kinase R (PKR) as the primary viral RNA target; PKR inhibitors (2-AP, C16) suppress FUT3, FUT5, FUT6 expression and HSV-1-induced sLe(x) surface expression. The downstream pathway involves an IKK-2-independent but IMD-0354-sensitive mechanism distinct from classical NF-κB activation.\",\n      \"method\": \"PKR inhibitor treatment, siRNA knockdown, flow cytometry for sLe(x), RT-PCR\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition and partial siRNA validation, single lab, mechanistic pathway defined for FUT3 transcriptional regulation\",\n      \"pmids\": [\"19349624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"shRNA-mediated knockdown of FUT3 (alone or with FUT5) in gastric cancer cell lines reduces sialyl-Lewis antigen surface expression, decreases adhesion to endothelial cells via E-selectin binding, and reduces binding to hyaluronic acid, without changing CD44 protein levels.\",\n      \"method\": \"Lentiviral shRNA knockdown, qRT-PCR, flow cytometry, E-selectin adhesion assay, hyaluronic acid binding assay, western blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"21978830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HSV-1 activates transcription of the FUT3/FUT5/FUT6 cluster on chromosome 19 specifically via NF-κB/p65 signaling; panepoxydone treatment and p65 siRNA knockdown significantly reduce viral induction of FUT3, FUT5, and FUT6, while direct interferon-mediated NF-κB stimulation alone is insufficient to activate the cluster in uninfected cells.\",\n      \"method\": \"NF-κB inhibitor (panepoxydone), siRNA targeting p65, RT-PCR for FUT3/5/6 transcription\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and siRNA epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"28973293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FUT3 knockdown in pancreatic cancer cells (Capan-1) inhibits cell proliferation, reduces migration and invasion, impairs adhesion to E-selectin, and suppresses TGF-β-induced epithelial-mesenchymal transition (EMT); overexpression has the opposite effects.\",\n      \"method\": \"shRNA knockdown, overexpression, wound healing assay, transwell invasion assay, E-selectin adhesion assay, in vivo xenograft\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple functional readouts, single lab\",\n      \"pmids\": [\"29963165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX39B RNA helicase binds directly to FUT3 pre-mRNA, promotes its splicing and mRNA nuclear export, thereby upregulating FUT3 expression; elevated FUT3 increases fucosylation of TGFβR-I, activating the TGF-β signaling pathway to drive EMT and colorectal cancer metastasis.\",\n      \"method\": \"RIP-seq, RNA-seq, Minigene splicing assay, nuclear/cytoplasmic RNA fractionation, gain/loss-of-function, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RIP-seq, Minigene assay, fractionation) establishing the DDX39B→FUT3→TGFβR-I fucosylation→EMT axis\",\n      \"pmids\": [\"33436563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT3 knockdown in lung adenocarcinoma cells suppresses tumor proliferation, migration, and glucose metabolism; GSEA and western blot indicate FUT3 positively regulates NF-κB signaling, and FUT3 downregulation inactivates NF-κB pathway markers in vitro and suppresses tumorigenesis in vivo.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, metabolite activity assay, western blot (NF-κB markers), subcutaneous tumor model, GSEA\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with in vitro and in vivo readouts and NF-κB pathway markers, single lab\",\n      \"pmids\": [\"37946130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT3 directly synthesizes Lea glycans on ITGA6 (integrin α6) and GLG1; mass spectrometry identified Lea structures at specific N-glycosylation sites on both proteins. FUT3 silencing causes integrin α6β4 aggregation at the plasma membrane (associated with focal adhesion/hemidesmosome formation) and reduces GLG1 distribution in intracellular vesicles, thereby promoting gastric cancer cell migration.\",\n      \"method\": \"Lea-antibody capture coupled with mass spectrometry (glycosite identification), immunofluorescence, siRNA silencing, cell migration/invasion assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct substrate identification by mass spectrometry with glycosite mapping, combined with functional loss-of-function experiments, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39477144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT3 directly binds GRP78 and fucosylates it; this fucosylation activates the PERK/ATF4/STC2 ER stress signaling pathway, enhancing survival and proliferation of colorectal cancer cells under glucose-deficient conditions.\",\n      \"method\": \"Co-immunoprecipitation, western blot, glycosylation assay, pathway inhibition, cell proliferation assay\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP establishing FUT3–GRP78 interaction with downstream pathway readout, single lab, single paper\",\n      \"pmids\": [\"41392296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT3 physically interacts with B3GNT3 (β-1,3-N-acetylglucosaminyltransferase 3) via co-immunoprecipitation; this interaction activates NF-κB signaling to drive autophagy, pancreatic cancer progression, and gemcitabine chemoresistance. FUT3 knockdown suppresses these effects in cells and mouse xenografts.\",\n      \"method\": \"Co-immunoprecipitation, western blot, RT-qPCR, electron microscopy (autophagy), xenograft model, CCK-8/MTT/wound healing/transwell assays\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP for interaction, multiple functional readouts, single lab, single paper\",\n      \"pmids\": [\"41366466\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FUT3 encodes an α(1,3/1,4)-fucosyltransferase that localizes to the Golgi and catalyzes the addition of fucose to type 1 and type 2 chain precursors to synthesize Lewis a, Lewis b, sialyl-Lewis a, and sialyl-Lewis x antigens; specific missense mutations in its transmembrane (e.g., Leu-20→Arg, reducing Golgi anchoring) or catalytic domain (e.g., Ile-356→Lys, Gly223→Arg) abolish activity; its expression is regulated by promoter methylation and, during HSV-1 infection, by PKR- and NF-κB/p65-dependent transcriptional activation; in cancer contexts, FUT3 fucosylates substrates including TGFβR-I (activating TGF-β/EMT signaling), GRP78 (activating PERK/ATF4/STC2 ER stress survival), ITGA6, and GLG1, and physically interacts with B3GNT3 to activate NF-κB, collectively driving E-selectin–mediated adhesion, metastasis, chemoresistance, and glucose metabolism reprogramming.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FUT3 encodes an α(1,3/1,4)-fucosyltransferase that synthesizes Lewis-type glycan antigens, and it serves as a rate-limiting enzyme for sialyl-Lewis antigen production that drives E-selectin–mediated adhesion and metastasis in epithelial cancers [#3]. Structure–function studies define discrete determinants of activity: a transmembrane mutation (Leu-20→Arg) lowers enzyme levels by disrupting Golgi anchoring without affecting substrate affinity, whereas catalytic-domain substitutions (Ile-356→Lys, Gly223→Arg, Val270→Met, and Trp68→Arg) abolish activity, the last accounting for the Lewis-negative phenotype [#0, #1, #2]. FUT3 expression is controlled at multiple levels — promoter hypomethylation is required for transcription [#4], and viral infection by HSV-1 induces the FUT3/FUT5/FUT6 cluster through a PKR- and NF-κB/p65-dependent transcriptional mechanism [#5, #7], while DDX39B binds FUT3 pre-mRNA to promote its splicing and nuclear export [#9]. In cancer, FUT3 fucosylates specific protein substrates to rewire signaling: it modifies TGFβR-I to activate TGF-β/EMT signaling [#9], binds and fucosylates GRP78 to activate PERK/ATF4/STC2 ER-stress survival signaling under glucose deprivation [#12], and synthesizes Lewis-a glycans on ITGA6 (integrin α6) and GLG1, controlling integrin α6β4 surface distribution and cell migration [#11]. FUT3 additionally promotes proliferation, invasion, glucose metabolism, and chemoresistance, acting in part through NF-κB activation and a physical interaction with B3GNT3 [#8, #10, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Separated which structural regions of FUT3 govern protein stability versus catalysis, establishing that distinct mutations impair Golgi anchoring or enzymatic function.\",\n      \"evidence\": \"Site-directed mutagenesis with COS-7 transfection and enzyme activity assays\",\n      \"pmids\": [\"8063716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure or atomic model of the catalytic domain\", \"Mechanism by which Leu-20→Arg destabilizes Golgi anchoring inferred, not directly imaged\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the principal inactivating mutation underlying the Lewis-negative phenotype and showed mutation combinations determine activity loss.\",\n      \"evidence\": \"Chimeric FUT3 constructs, COS-7 transfection, enzyme activity assay, immunofluorescence\",\n      \"pmids\": [\"9268337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population frequency and physiological consequences of Le(a-b-) not addressed in this corpus\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended the mutational map of FUT3 catalytic residues by quantifying the activity impact of individual missense changes.\",\n      \"evidence\": \"Chimeric constructs, COS-7 transfection, enzyme activity and Lewis antigen expression\",\n      \"pmids\": [\"10211701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level mechanistic roles in substrate or donor binding not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Established FUT3 as a rate-limiting enzyme for sialyl-Lewis antigen synthesis that drives E-selectin adhesion and metastasis, defining its cancer-relevant function.\",\n      \"evidence\": \"Antisense suppression in BxPC-3 cells, flow cytometry, E-selectin adhesion assay, nude mouse metastasis model\",\n      \"pmids\": [\"11058871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Antisense rather than genetic knockout\", \"Downstream protein substrates carrying the sLe antigens not identified at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed FUT3 transcription is directly suppressed by promoter methylation, identifying an epigenetic control of Lewis antigen output.\",\n      \"evidence\": \"5-aza-2'-deoxycytidine treatment, RT-PCR, enzyme activity, IHC, methylated luciferase reporters\",\n      \"pmids\": [\"16427187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors and signals controlling FUT3 promoter methylation unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined PKR as the primary viral RNA sensor mediating HSV-1 induction of the FUT3/5/6 cluster, linking innate viral sensing to fucosyltransferase expression.\",\n      \"evidence\": \"PKR inhibitor treatment, siRNA knockdown, flow cytometry for sLe(x), RT-PCR\",\n      \"pmids\": [\"19349624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibition with partial siRNA validation\", \"Cluster-level readout does not isolate FUT3-specific regulation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified NF-κB/p65 as the downstream effector of HSV-1-driven FUT3 cluster transcription, refining the viral induction pathway.\",\n      \"evidence\": \"NF-κB inhibitor panepoxydone, p65 siRNA, RT-PCR for FUT3/5/6\",\n      \"pmids\": [\"28973293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p65 binding to FUT3 promoter not demonstrated by ChIP\", \"Whether all three cluster genes share identical regulatory elements unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked FUT3 to TGF-β-induced EMT and demonstrated bidirectional control of proliferation, invasion, and E-selectin adhesion via gain- and loss-of-function.\",\n      \"evidence\": \"shRNA knockdown and overexpression, migration/invasion assays, E-selectin adhesion, xenograft\",\n      \"pmids\": [\"29963165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate of FUT3 in the TGF-β axis not identified here\", \"Single cell line and single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the DDX39B→FUT3→TGFβR-I fucosylation axis, providing both an upstream RNA-processing regulator and a direct fucosylated substrate driving EMT and metastasis.\",\n      \"evidence\": \"RIP-seq, minigene splicing assay, nuclear/cytoplasmic fractionation, gain/loss-of-function, in vivo metastasis\",\n      \"pmids\": [\"33436563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosite on TGFβR-I not mapped\", \"How fucosylation alters receptor signaling structurally unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected FUT3 to glucose metabolism and NF-κB signaling in lung adenocarcinoma, broadening its oncogenic phenotype beyond adhesion.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, metabolite assays, western blot for NF-κB markers, xenograft, GSEA\",\n      \"pmids\": [\"37946130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-κB regulation inferred from pathway markers, not direct mechanism\", \"Fucosylation substrate mediating metabolic effect unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ITGA6 and GLG1 as direct FUT3 glycosylation substrates with mapped Lewis-a glycosites, linking FUT3 to integrin distribution and migration control.\",\n      \"evidence\": \"Lea-antibody capture mass spectrometry with glycosite mapping, immunofluorescence, siRNA, migration assays\",\n      \"pmids\": [\"39477144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting integrin α6β4 aggregation to migration not fully resolved\", \"Single gastric cancer model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FUT3 binds and fucosylates GRP78 to activate PERK/ATF4/STC2 ER-stress survival signaling, defining a metabolic stress-adaptation function.\",\n      \"evidence\": \"Co-immunoprecipitation, western blot, glycosylation assay, pathway inhibition, proliferation assay\",\n      \"pmids\": [\"41392296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP-based interaction without reciprocal structural validation\", \"GRP78 glycosite not mapped\", \"Single lab, single paper\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a physical FUT3–B3GNT3 interaction activating NF-κB to drive autophagy and gemcitabine chemoresistance in pancreatic cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, western blot, RT-qPCR, electron microscopy, xenograft, proliferation/migration assays\",\n      \"pmids\": [\"41366466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP interaction without reciprocal or structural validation\", \"Whether the interaction requires FUT3 catalytic activity unknown\", \"Single lab, single paper\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FUT3 selects its protein substrates and whether its non-canonical signaling roles (NF-κB activation, B3GNT3 interaction) depend on its fucosyltransferase activity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model defining substrate-recognition determinants\", \"Catalytic dependence of protein–protein interaction functions untested\", \"Mechanism coupling fucosylation to NF-κB transcriptional output unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 11, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TGFBR1\",\n      \"GRP78\",\n      \"ITGA6\",\n      \"GLG1\",\n      \"B3GNT3\",\n      \"DDX39B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}