FUT3

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).

1. 1994 High

   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

   PMID:8063716

   Open questions at the time

   • No crystal structure or atomic model of the catalytic domain
   • Mechanism by which Leu-20→Arg destabilizes Golgi anchoring inferred, not directly imaged
2. 1997 High

   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

   PMID:9268337

   Open questions at the time

   • Population frequency and physiological consequences of Le(a-b-) not addressed in this corpus
3. 1998 High

   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

   PMID:10211701

   Open questions at the time

   • Residue-level mechanistic roles in substrate or donor binding not resolved
4. 2000 High

   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

   PMID:11058871

   Open questions at the time

   • Antisense rather than genetic knockout
   • Downstream protein substrates carrying the sLe antigens not identified at this stage
5. 2006 High

   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

   PMID:16427187

   Open questions at the time

   • Trans-acting factors and signals controlling FUT3 promoter methylation unknown
6. 2009 Medium

   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

   PMID:19349624

   Open questions at the time

   • Pharmacological inhibition with partial siRNA validation
   • Cluster-level readout does not isolate FUT3-specific regulation
7. 2017 Medium

   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

   PMID:28973293

   Open questions at the time

   • Direct p65 binding to FUT3 promoter not demonstrated by ChIP
   • Whether all three cluster genes share identical regulatory elements unresolved
8. 2018 Medium

   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

   PMID:29963165

   Open questions at the time

   • Molecular substrate of FUT3 in the TGF-β axis not identified here
   • Single cell line and single lab
9. 2021 High

   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

   PMID:33436563

   Open questions at the time

   • Glycosite on TGFβR-I not mapped
   • How fucosylation alters receptor signaling structurally unresolved
10. 2023 Medium

    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

    PMID:37946130

    Open questions at the time

    • NF-κB regulation inferred from pathway markers, not direct mechanism
    • Fucosylation substrate mediating metabolic effect unidentified
11. 2024 High

    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

    PMID:39477144

    Open questions at the time

    • Mechanism connecting integrin α6β4 aggregation to migration not fully resolved
    • Single gastric cancer model
12. 2025 Medium

    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

    PMID:41392296

    Open questions at the time

    • Single Co-IP-based interaction without reciprocal structural validation
    • GRP78 glycosite not mapped
    • Single lab, single paper
13. 2025 Medium

    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

    PMID:41366466

    Open questions at the time

    • Co-IP interaction without reciprocal or structural validation
    • Whether the interaction requires FUT3 catalytic activity unknown
    • Single lab, single paper

• 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.
• No structural model defining substrate-recognition determinants
• Catalytic dependence of protein–protein interaction functions untested
• Mechanism coupling fucosylation to NF-κB transcriptional output unknown