{"gene":"ST6GAL1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structure of rat ST6GAL1 at 2.4 Å resolution revealed an overall protein fold resembling pig ST3GAL1, with a CMP-sialic acid-binding site assembled from conserved sialylmotif sequence elements. Computational substrate docking, molecular dynamics simulations, and kinetic analysis of active-site mutants identified donor and acceptor binding interactions and a common structural framework for catalysis shared with bacterial sialyltransferases.","method":"X-ray crystallography (2.4 Å), computational docking/MD simulations, active-site mutagenesis, kinetic assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and kinetic validation, multiple orthogonal methods in single rigorous study","pmids":["24155237"],"is_preprint":false},{"year":1992,"finding":"Expression of the β-galactoside α2,6-sialyltransferase (ST6GAL1/alpha 2,6-ST) was shown to regulate generation of the cell-surface differentiation antigens HB-6, CDw75, and CD76. The alpha 2,6-ST protein is localized to the Golgi apparatus, and the cell-surface antigens are products of its enzymatic activity (sialylation), demonstrated by expression cloning and neuraminidase sensitivity.","method":"Expression cloning, cDNA transfection in COS cells, immunofluorescence, neuraminidase treatment, subcellular fractionation/localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (expression cloning, functional enzyme assay, localization, neuraminidase sensitivity), replicated across CDw75 and CD76","pmids":["1730763"],"is_preprint":false},{"year":2019,"finding":"B4GALT1 and ST6GAL1 interact in Golgi membranes via highly charged noncatalytic surfaces (leaving active sites accessible), as demonstrated by molecular docking, mutagenesis screens, and high-throughput FRET in live cells. ST6GAL1 first forms homomers in the ER using the same noncatalytic surface before activation in the Golgi; their interaction is a prerequisite for full catalytic activity of both enzymes in N-glycan synthesis.","method":"Molecular docking simulations, mutagenesis screens, high-throughput FRET in live cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis + live-cell FRET + computational predictions validated experimentally, single lab with multiple orthogonal methods","pmids":["31395657"],"is_preprint":false},{"year":2012,"finding":"The P1 promoter of the ST6Gal-1 gene is critical for sialylation of circulating IgG Fc. Siat1ΔP1 mice with a dysfunctional P1 promoter were unable to produce sialylated Fc IgG in systemic circulation despite Gal(β4)GlcNAc termini being present. The P1 promoter drives ST6Gal-1 expression in the liver, releasing enzyme into systemic circulation where it sialylates IgG Fc extracellularly.","method":"Knock-in mouse model (Siat1ΔP1), IgG Fc glycan analysis, acute phase response experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with mechanistic dissection of promoter-specific enzyme source and functional IgG sialylation outcome","pmids":["22427662"],"is_preprint":false},{"year":2014,"finding":"Extracellular ST6Gal-1 originating mostly from the liver and released into circulation targets marrow hematopoietic stem and progenitor cells (HSPCs) and mediates formation of cell-surface α2,6-linked sialic acids on HSPCs. Bone marrow chimera experiments demonstrated that α2,6-sialylation of HSPCs is profoundly dependent on circulatory ST6Gal-1 status of recipients and independent of endogenous HSPC ST6Gal-1 expression. HSPC abundance in marrow is inversely related to circulatory ST6Gal-1 status.","method":"Bone marrow chimeras, lectin binding (SNA, PSL), mass spectrometry, flow cytometry (Lin-cKit+, LSK populations)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — bone marrow chimera genetic dissection plus mass spectrometry confirmation, multiple orthogonal methods","pmids":["24425878"],"is_preprint":false},{"year":2010,"finding":"Circulatory ST6Gal-1 of mostly hepatic origin limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins. Ex vivo colony formation assays showed that physiologic levels of ST6Gal-1 introduced into culture medium attenuated HSPC colony formation. The P1 promoter engagement in the liver generates circulatory ST6Gal-1 that regulates myelopoiesis.","method":"2D-DIGE analysis of serum glycoproteins, ex vivo colony formation assays, mouse models with P1 promoter ablation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo functional assays with recombinant enzyme, supported by 2D-DIGE, single lab","pmids":["20529847"],"is_preprint":false},{"year":2017,"finding":"Extracellular (blood-borne) ST6Gal-1 suppresses late-stage neutrophil development (granulopoiesis). Exposure of human and murine HSPCs to extracellular ST6Gal-1 ex vivo decreased proliferation, MPO expression, CD11b+ cell appearance, STAT-3 phosphorylation, and C/EBPα expression (attenuating G-CSF receptor signaling). A mouse model with elevated systemic ST6Gal-1 confirmed decreased marrow neutrophil reserves and reduced airway neutrophilic inflammation in vivo.","method":"Ex vivo HSPC exposure to recombinant ST6Gal-1, in vivo mouse model of elevated systemic ST6Gal-1, LPS airway challenge, signaling analysis","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ex vivo mechanistic studies with recombinant enzyme + in vivo mouse model, signaling pathway identified, single lab","pmids":["28550122"],"is_preprint":false},{"year":2017,"finding":"TNF-α treatment upregulates BACE1 expression through PKC signaling, leading to proteolytic cleavage/degradation of ST6Gal-1, decreased α2,6-sialylation of VE-Cadherin, disrupted endothelial cell-cell tight junctions, and promoted monocyte-endothelial cell adhesion.","method":"Western blotting, SNA lectin blotting, PKC signaling inhibition, siRNA knockdown, BACE1 overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods establishing the TNF-α→PKC→BACE1→ST6Gal-1 cleavage→VE-Cadherin sialylation pathway, single lab","pmids":["28091531"],"is_preprint":false},{"year":2018,"finding":"Estrogen (E2) increases St6Gal1 expression in mouse and human antibody-producing cells (B cells/plasma cells), providing a mechanistic basis for increased IgG-Fc sialylation. E2 treatment of postmenopausal mice significantly increased Fc sialylation of total and antigen-specific IgG and increased expression of inhibitory FcγRIIb on bone marrow leukocytes.","method":"Ovariectomized mouse model with E2 treatment, qRT-PCR, flow cytometry, IgG glycan analysis; validated in human RA patients on HRT","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse model with in vivo E2 treatment plus human validation, multiple methods, single lab","pmids":["29720252"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1 sialylates EGFR, promoting EGFR dimerization and higher-order oligomerization, increased activation of EGFR and downstream AKT and NFκB signaling, enhanced receptor recycling via Rab11 recycling endosomes, and reduced lysosomal degradation following EGF stimulation.","method":"ST6GAL1 overexpression/knockdown in ovarian cancer lines, TIRF microscopy, 3D widefield deconvolution microscopy, biochemical dimerization assays, colocalization with Rab11/LAMP1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal OE/KD with multiple microscopy and biochemical approaches identifying mechanism, replicated across multiple cell lines","pmids":["37660914"],"is_preprint":false},{"year":2019,"finding":"ST6GAL1-mediated sialylation of MUC4β (targeting N-glycosylation sites) is induced by IL-13 in human airway epithelial cells; ST6GAL1-induced sialylation of MUC4β alters its lectin binding and secretion, and both ST6GAL1 and MUC4β inhibit epithelial cell proliferation while promoting goblet cell differentiation.","method":"Primary human airway epithelial cell cultures, IL-13 treatment, siRNA knockdown, lectin binding assays, proliferation/differentiation assays, clinical sample analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro with clinical specimen correlation, multiple methods, single lab","pmids":["30730306"],"is_preprint":false},{"year":2013,"finding":"miR-199a targets ST6GAL1 and reduces both the ST6GAL1-catalyzed sialylation and protein level of the adhesion molecule Necl-2/CADM1. Reduced Necl-2 sialylation (via ST6GAL1 suppression) enhances HRG-induced ErbB2/ErbB3 signaling for cell movement.","method":"miR-199a transfection, sialylation assays, ErbB2/ErbB3 signaling assays in A549 and HEK293 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate identification with functional signaling readout, single lab with multiple methods","pmids":["23504322"],"is_preprint":false},{"year":2020,"finding":"Loss of core fucosylation (FUT8 knockout) increases ST6GAL1 catalytic activity in serum and liver and increases α2,6-sialylation, partly because ST6GAL1 prefers non-fucosylated substrates. FUT8 is responsible for core fucosylation of ST6GAL1 itself, creating a regulatory interaction between the two glycosyltransferases.","method":"Fut8-/- mouse model, serum N-glycan analysis, ST6GAL1 activity assays, in vitro substrate preference assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout mouse plus in vitro enzyme activity assays, single lab","pmids":["32141499"],"is_preprint":false},{"year":2018,"finding":"ST6GAL1 negatively regulates monocyte transendothelial migration. Knockdown of ST6GAL1 in vascular endothelial cells promoted TNFα-triggered monocyte transendothelial migration, while overexpression inhibited it. β-catenin was identified as a sialylated substrate of ST6GAL1, and its sialylation level decreased upon TNFα treatment.","method":"RNAi knockdown and overexpression in EA.hy926 cells, monocyte transendothelial migration assays, Western blot for sialylation of β-catenin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain of function with functional migration readout and substrate identification, single lab","pmids":["29654763"],"is_preprint":false},{"year":2020,"finding":"Extracellular ST6GAL1 (B cell-extrinsic pool) sialylates B cell surface CD22 and CD45, boosting B cell IgM, IgD, and CD86 expression, proliferation, and IgG production. In vivo, elevation of blood ST6GAL1 enhanced B cell development and systemic IgG in a CD22-dependent manner. B cell intrinsic ST6GAL1 is required for marginal zone B cell development.","method":"Mouse models lacking hepatocyte-specific St6gal1 promoter, ex vivo B cell sialylation assays, in vivo IgG titer measurement, CD22 dependency (anti-CD22 blocking)","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo and ex vivo experiments with genetic and pharmacological dissection of B-cell intrinsic vs extrinsic roles, CD22 mechanism identified","pmids":["32391003"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1 promotes pancreatic ductal adenocarcinoma (PDAC) progression. Pancreas-specific deletion of ST6GAL1 in the KC (KRASG12D) mouse model significantly delayed cancer formation and reduced fibrosis. Transgenic ST6GAL1 with KRASG12D greatly accelerated PDAC progression vs KRASG12D alone.","method":"Genetically engineered mouse models (pancreas-specific ST6GAL1 knockout and transgenic), KC KRASG12D model, glycomic/transcriptomic analysis, histology","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary GEM models (KO and transgenic) with clear genetic epistasis in vivo, replicated in human samples","pmids":["34634466"],"is_preprint":false},{"year":2023,"finding":"ST6GAL1 promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer progression. ST6GAL1 transgenic mice with KRASG12D had greatly accelerated PDAC vs KRASG12D alone. ST6GAL1 promotes ADM through EGFR activation—EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression.","method":"GEM models (ST6GAL1 transgenic × KRASG12D), GEM-derived organoids, ADM assays, EGFR activation measurements, 266-6 cell line, in vivo inflammation-induced ADM","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple GEM and organoid models, mechanistic link to EGFR sialylation established, replicated across model systems","pmids":["37643018"],"is_preprint":false},{"year":2022,"finding":"ST6GAL1 specifically sialylates the trastuzumab-binding domain of ErbB2 (HER2) at defined N-glycosylation sites. Abrogation of ST6Gal1 expanded ErbB2 cellular half-life, stabilized ErbB dimers at cell membrane, decreased ErbB2 and EGFR activation, and sensitized ErbB2-dependent gastric cancer cells to trastuzumab-induced cytotoxicity.","method":"MS-based glycomic and glycoproteomic analysis of ErbB2 ectodomain, ST6Gal1 knockdown/OE, flow cytometry, Western blot, cytotoxicity assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-specific glycoproteomic mapping plus functional signaling and cytotoxicity outcomes, single lab with multiple orthogonal methods","pmids":["33947960"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1 sialylates EGFR in T-ALL cells. EGFR was demonstrated to be a substrate of ST6GAL1, and sialylated EGFR impacts PI3K/Akt pathway activity, contributing to drug-resistant phenotype.","method":"Mass spectrometry (N-glycan profiles), siRNA knockdown, Western blot, lectin staining, xenograft mouse models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS glycan profiling plus functional signaling assays, in vivo xenograft, single lab","pmids":["31096997"],"is_preprint":false},{"year":2019,"finding":"ST6GAL1 sialylates c-Met in colorectal cancer cells. Sialylated c-Met activates the JAK2/STAT3 pathway, modulating CRC malignancy. ST6GAL1 is regulated by the HOTAIR/miR-214 axis.","method":"Lectin precipitation, Western blot, dual-luciferase reporter assay, RIP assay, in vivo xenograft/metastasis models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical substrate identification with pathway activation assays and in vivo models, single lab","pmids":["31694696"],"is_preprint":false},{"year":2019,"finding":"ST6GAL1 inhibits colorectal cancer metastasis by stabilizing ICAM-1 through sialylation. ST6GAL1 sialylation of ICAM-1 increases its protein stability (not its transcription) as demonstrated by cycloheximide chase assays and lectin precipitation. ST6GAL1 knockdown increased liver metastases in vivo.","method":"Lectin precipitation, cycloheximide (CHX) chase assay, PCR, transwell/wound healing assays, nude mouse liver metastasis model, tissue microarrays","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate sialylation assay with protein stability readout and in vivo metastasis model, single lab","pmids":["31308754"],"is_preprint":false},{"year":2022,"finding":"ST6GAL1 inhibits HCC metastasis by increasing α2,6-sialylation of MCAM (melanoma cell adhesion molecule). Sialylation of MCAM inhibits its interaction with galectin-3 and decreases MCAM expression on the cell surface, thereby suppressing migration and invasion.","method":"Metabolic labeling-based glycoproteomics, lectin pulldown, Co-IP, in vitro migration/invasion assays, in vivo metastasis models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — glycoproteomic substrate identification plus mechanistic dissection of galectin-3 interaction and in vivo validation, single lab with multiple orthogonal methods","pmids":["36528750"],"is_preprint":false},{"year":2015,"finding":"ST6GAL1 is required for maintaining pluripotency in human pluripotent stem cells (hPSCs). shRNA-mediated knockdown of ST6GAL1 decreased OCT4/POU5F1 protein levels and significantly impeded the induction of cellular pluripotency during somatic cell reprogramming, partially by interfering with endogenous POU5F1 and SOX2 expression.","method":"shRNA knockdown in hPSCs, lectin binding assays, qPCR/Western blot for pluripotency markers, sialyltransferase inhibitor treatment during reprogramming, iPSC generation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific molecular phenotype, pharmacological inhibition corroboration, single lab","pmids":["26304831"],"is_preprint":false},{"year":2022,"finding":"ST6GAL1-mediated α2,6-sialylation promotes glioblastoma growth via sialylation of PDGFRβ, ALCAM, and Neuropilin. ST6GAL1 KD in brain tumor-initiating cells (BTICs) decreased PDGFRβ α2,6-sialylation, total PDGFRβ protein levels, and PDGF-BB-induced receptor phosphorylation, reducing GBM growth and self-renewal.","method":"ST6GAL1 KD in BTICs, lectin binding assays, Western blot for PDGFRB levels and phosphorylation, orthotopic mouse tumor models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — substrate sialylation confirmed with functional signaling and in vivo tumor growth data, multiple methods, single lab","pmids":["36345944"],"is_preprint":false},{"year":2022,"finding":"Extracellular ST6GAL1 (from cancer exosomes or soluble recombinant enzyme) compensates for insufficient intrinsic ST6GAL1 to boost breast tumor cell proliferation and invasiveness in 3D cultures. Intrinsic ST6GAL1 KD decreased ST6GAL1 cargo in exosome-like vesicles and decreased tumor growth/invasion; extrinsic ST6GAL1 rescued these phenotypes. Novel cofactors in exosome-like particles potently amplify extracellular ST6GAL1 activity.","method":"shRNA knockdown, 3D culture invasion assays, exosome isolation, recombinant ST6GAL1 treatment, cell proliferation assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiments with extracellular enzyme, multiple assay types, single lab","pmids":["35676533"],"is_preprint":false},{"year":2022,"finding":"Extracellular recombinant ST6GAL1 adheres to monocyte-macrophage lineage cells and catalytically sialylates the M-CSF receptor (M-CSF-R/CSF1R) on human THP-1 monocytes, activating M-CSF-R and initiating NFκB nuclear translocation and phosphorylation of ERK1/2 and AKT, promoting monocyte-macrophage development and survival.","method":"Recombinant ST6GAL1 treatment of primary mouse myeloid cells and THP-1 cells, gene expression profiling, lectin activity assays, Western blot for NFκB, ERK1/2, AKT phosphorylation","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — extracellular enzyme activity on defined receptor with intracellular signaling readout, single lab with multiple methods","pmids":["35661210"],"is_preprint":false},{"year":2018,"finding":"Systemic (extracellular) ST6Gal-1 is a pro-survival factor for transitional B cells. Extrinsic ST6Gal-1 augmented BAFF-mediated activation of non-canonical NFκB, p38 MAPK, and PI3K/AKT pathways, and accelerated tyrosine phosphorylation after BCR stimulation. B cell-intrinsic ST6Gal-1 is specifically required for marginal zone B cell development.","method":"Mouse models segregating B cell-intrinsic vs extrinsic ST6Gal-1, ex vivo B cell exposure to recombinant ST6Gal-1, flow cytometry, signaling pathway analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection of intrinsic vs extrinsic roles, signaling pathway identified, single lab","pmids":["30294329"],"is_preprint":false},{"year":2016,"finding":"ST6Gal1 transcription in gliomas is silenced by DNA methylation within core promoter regions (P3 promoter), specifically through determination of AP2 transcription factor accessibility. Demethylation with 5-aza-dC reactivated ST6Gal1 expression, increased β1 integrin sialylation, and decreased adhesion to fibronectin.","method":"5-aza-2'-deoxycytidine treatment of glioma cell lines, qRT-PCR, primer extension, CAT reporter deletion analysis, lectin staining of β1 integrin, fibronectin adhesion assays","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with functional consequence (integrin sialylation and adhesion), single lab","pmids":["27510958"],"is_preprint":false},{"year":1999,"finding":"SIAT1 (ST6GAL1) transcription in mature B-lymphocytes initiates at the P2 regulatory region. A 495 bp P2 segment containing AP2 and NF-κB sites in the 5'-flanking region and a 3' exon segment (positions +32 to +125) are required for efficient, cell-specific transcription. The +32 to +125 region also relieves translational restraints in B cells.","method":"CAT reporter assays, transfection in Louckes/Reh/HepG2 cells, deletion analysis, mRNA analysis","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter/regulatory dissection with multiple deletion constructs and cell type comparisons, single lab","pmids":["10460832"],"is_preprint":false},{"year":2024,"finding":"IL-1β and IL-6 upregulate ST6GAL1 expression in pancreatic cancer cells via the P3 promoter. IL-1β activates NFκB which binds the ST6GAL1 P3 promoter; IL-6 activates STAT3 which binds the ST6GAL1 P3 promoter. Inhibitors of NFκB or STAT3 blocked cytokine-induced ST6GAL1 upregulation.","method":"Promoter reporter assays, CUT&RUN for transcription factor binding at P3 promoter, NFκB/STAT3 inhibitors, qRT-PCR and Western blot in PDAC cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct promoter binding demonstrated by CUT&RUN plus functional reporter assays with inhibitor validation, multiple orthogonal methods","pmids":["39260693"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1 knockdown in bronchial epithelial cells increased IL-6 expression and secretion. Cigarette smoke extract (CSE) exposure or BACE1 inhibition decreased ST6GAL1 secretion, reduced α2,6-sialylation, and increased IL-6 production, establishing a regulatory axis where BACE1-mediated ST6GAL1 cleavage controls the circulating vs. membrane pool and downstream IL-6 regulation.","method":"shRNA knockdown, CSE treatment, BACE1 inhibition, ELISA for ST6GAL1 and IL-6, flow cytometry for α2,6-sialylation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with functional signaling readout and pharmacological validation, single lab","pmids":["34290711"],"is_preprint":false},{"year":2022,"finding":"ST6GAL1-mediated sialylation promotes resistance to chemoradiation in rectal cancer by inhibiting apoptosis. ST6GAL1 protein increased after chemoradiation in patient-derived xenograft models and rectal cancer cell lines; ST6GAL1 knockdown increased apoptosis and decreased colony survival after chemoradiation treatment.","method":"Patient-derived xenograft models, organoid models, rectal cancer cell lines, Caspase-Glo apoptosis assays, colony formation assays, Western blot, lectin flow cytometry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (PDX, organoids, cell lines) with functional apoptosis assay, single lab","pmids":["35041825"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1-mediated sialylation of MUC4β is induced by IL-13 in human airway epithelial cells; sialylated MUC4β has altered lectin binding and secretion properties. Both ST6GAL1 and MUC4β inhibit epithelial proliferation while promoting goblet cell differentiation in T2-high asthma.","method":"Primary HAEC cultures, IL-13 treatment, ST6GAL1 siRNA, lectin binding assays, proliferation/goblet cell differentiation assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary cell experiments with defined substrate and functional differentiation outcome, single lab","pmids":["30730306"],"is_preprint":false},{"year":2025,"finding":"ST6GAL1-mediated α2,6-sialylation of PECAM-1 on lung-tropic breast cancer cells promotes pulmonary extravasation through transhomophilic interaction with pulmonary endothelial PECAM-1, directing lung-tropic metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Lung-tropic cells also increased pulmonary endothelial permeability via exosomes in a non-cell-autonomous manner.","method":"ST6GAL1/PECAM-1 knockdown in lung-tropic breast cancer cells, in vivo lung metastasis models, pulmonary endothelial permeability assays, lectin-based sialylation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis models with substrate (PECAM-1) identification and mechanistic (transhomophilic PECAM-1 interaction) dissection, multiple methods","pmids":["39786386"],"is_preprint":false},{"year":2021,"finding":"ST6GAL1 sialylates E-cadherin, and this α2,6-sialylation of E-cadherin contributes to collective migration of uterine luminal epithelial cells during endometrial fold extension, thereby mediating uterine lumen closure during implantation.","method":"MALDI-TOF MS N-glycomic profiling, siRNA transfection, lectin immunoprecipitation, MS, wound healing and cell aggregation assays","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification by lectin-MS plus functional migration assay with siRNA knockdown, single lab","pmids":["34957619"],"is_preprint":false},{"year":2025,"finding":"ST6GAL1-mediated sialylation of PD-L1 is critical for its stability in colorectal cancer cells; ST6GAL1 knockdown leads to reduced PD-L1 protein stability and increased ubiquitination. ST6GAL1 knockdown in MC38 tumor-bearing mice enhanced the antitumor effect of anti-PD-L1 therapy.","method":"ST6GAL1 KO/KD, ubiquitination assays, Western blot, in vivo tumor mouse model with anti-PD-L1 therapy, single-cell analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate stability mechanism with in vivo immune checkpoint validation, single lab","pmids":["40847469"],"is_preprint":false},{"year":2011,"finding":"Overexpression of amyloid precursor protein (AbetaPP) in C2C12 myogenic cells increased both expression and secretion of ST6Gal1, consistent with BACE1-mediated proteolytic processing of ST6Gal1 as a substrate.","method":"AbetaPP overexpression in C2C12 cells, Western blot, immunofluorescence","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment without direct BACE1 activity assay, single lab, single method","pmids":["20795944"],"is_preprint":false},{"year":2025,"finding":"Endothelial ST6GAL1 creates a pro-adhesive environment of α2,6-linked sialic acids that engage CD22 on circulating B cells and plasmablasts, promoting their recruitment to the inflamed gut in IBD. Dynamic adhesion assays showed CD22-α2,6-sialic acid interaction controls B cell adhesion, and in vivo homing of IBD B cells to inflamed colon was blocked by anti-CD22 antibodies in humanized mice.","method":"Flow cytometry, transcriptomics, immunofluorescence, dynamic adhesion assays, in vivo homing assays in humanized mice, anti-CD22 antibody blocking","journal":"Journal of Crohn's & colitis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo homing assays with mechanistic blocking experiments, multiple methods, single lab","pmids":["40491026"],"is_preprint":false},{"year":2025,"finding":"ST6GAL1 sialylates BICD2 (BICD cargo adaptor 2), which affects the interaction between BICD2 and IFNGR1, thereby inhibiting IFNGR1 phosphorylation and the downstream JAK1/STAT1 signaling pathway, leading to reduced sensitivity to IFN-γ and immune escape in colorectal cancer.","method":"Immunoprecipitation, mass spectrometry substrate identification, kinase phosphorylation chip, Western blot, in vivo tumor models","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS substrate identification with IP-confirmed protein interaction and signaling pathway validation, single lab","pmids":["41217711"],"is_preprint":false},{"year":2024,"finding":"ST6Gal1-mediated α2,6-sialylation of integrin β1 activates the integrin β1/FAK signaling pathway to promote proliferation and stemness in gestational trophoblastic disease cells. Inhibition of ST6Gal1 reduced α2,6-sialylation on integrin β1 and suppressed integrin β1/FAK pathway activation.","method":"Lectin pulldown, Western blot for FAK phosphorylation, ST6Gal1 OE/KD, proliferation/stemness assays","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate sialylation demonstrated with pathway activation readout, single lab","pmids":["38490094"],"is_preprint":false},{"year":2022,"finding":"Plasma/hepatocyte-derived ST6Gal1 is NOT responsible for homeostatic IgG α2,6-sialylation. Mice lacking hepatocyte-expressed ST6Gal1 retained normal IgG α2,6-sialylation despite undetectable plasma ST6Gal1, and B cells were also not a redundant source. This negative result indicates IgG sialylation occurs by a different, as-yet unidentified mechanism.","method":"Conditional ST6Gal1 knockout (albumin-Cre for hepatocytes, B cell-specific KO), IgG glycan analysis","journal":"Glycobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-controlled conditional KO experiment, negative finding with clear mechanistic implication; contradicts some prior models","pmids":["35746897"],"is_preprint":false},{"year":2025,"finding":"ST6GAL1 sialylates LGALS3BP (a secreted glycoprotein) in colorectal cancer cells; knockdown of LGALS3BP significantly blocked ST6GAL1-driven proliferation, invasion, and chemoresistance. Sialidase treatment also blocked ST6GAL1 protumor activity, confirming sialylation dependence.","method":"N-glycoproteomic analysis, LGALS3BP knockdown, sialidase treatment, proliferation/invasion/chemoresistance assays","journal":"Biomolecules & biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycoproteomic substrate identification with functional validation and sialidase rescue, single lab","pmids":["39937175"],"is_preprint":false}],"current_model":"ST6GAL1 is a Golgi-resident sialyltransferase that catalyzes transfer of α2,6-linked sialic acids onto N-glycosylated proteins (using a CMP-sialic acid donor, with catalytic mechanism structurally defined at 2.4 Å); it operates cell-autonomously within the ER-Golgi secretory apparatus but is also released as an active extracellular enzyme (primarily from the liver via the P1 promoter) that remodels glycans on target cells (HSPCs, B cells, monocytes) to regulate hematopoiesis and immunity; its key substrates include EGFR (promoting dimerization, recycling, and downstream AKT/NFκB signaling), ErbB2, PDGFRB, integrin β1, ICAM-1, PECAM-1, MUC4β, PD-L1, MCAM, BICD2, E-cadherin, β-catenin, Necl-2/CADM1, and c-Met, with sialylation of these receptors modulating their stability, dimerization, signaling, trafficking, and protein interactions; ST6GAL1 expression is transcriptionally regulated by multiple promoters (P1 in liver, P2 in B cells, P3 in epithelial/cancer cells) controlled by NFκB, STAT3, AP2, and DNA methylation, and is upregulated in cancer by pro-inflammatory cytokines IL-1β and IL-6."},"narrative":{"mechanistic_narrative":"ST6GAL1 is a Golgi-resident β-galactoside α2,6-sialyltransferase that transfers sialic acid onto N-glycans of secreted and cell-surface glycoproteins, generating differentiation antigens such as CDw75/CD76 and operating within the secretory apparatus where its CMP-sialic acid donor site is assembled from conserved sialylmotif elements [PMID:24155237, PMID:1730763]. Within Golgi membranes ST6GAL1 first homo-oligomerizes in the ER and then engages B4GALT1 through noncatalytic charged surfaces, an interaction required for full catalytic activity of both enzymes in N-glycan synthesis [PMID:31395657]. Beyond its cell-autonomous role, ST6GAL1 is released as an active extracellular enzyme, largely from the liver via the P1 promoter, that remodels glycans on remote target cells: circulatory enzyme sialylates marrow hematopoietic stem and progenitor cells, restraining myelopoiesis and late-stage granulopoiesis by attenuating G-CSF receptor/STAT3/C/EBPα signaling [PMID:24425878, PMID:20529847, PMID:28550122], and acts on B-lineage cells by sialylating CD22 and CD45 to boost BAFF/BCR-driven survival, proliferation, and IgG production in a CD22-dependent manner [PMID:32391003, PMID:30294329]. A substantial body of work establishes ST6GAL1 as a regulator of receptor tyrosine kinase signaling through substrate sialylation: it sialylates EGFR to promote dimerization, Rab11-dependent recycling, and AKT/NFκB activation [PMID:37660914], ErbB2/HER2 at its trastuzumab-binding domain to stabilize signaling-competent dimers [PMID:33947960], PDGFRβ to sustain PDGF-driven growth [PMID:36345944], and c-Met to drive JAK2/STAT3 activity [PMID:31694696]. Through these and additional substrates—integrin β1/FAK [PMID:38490094], β-catenin and VE-cadherin at endothelial junctions [PMID:28091531, PMID:29654763], E-cadherin in epithelial migration [PMID:34957619], ICAM-1 and MCAM stability [PMID:31308754, PMID:36528750], PECAM-1 in lung-tropic extravasation [PMID:39786386], PD-L1 stability and immune escape [PMID:40847469], and BICD2-mediated control of IFNGR1/JAK1/STAT1 signaling [PMID:41217711]—ST6GAL1 modulates receptor stability, trafficking, adhesion, and immune signaling, and it promotes pancreatic cancer initiation and progression in KRAS-driven models via EGFR-dependent acinar-to-ductal metaplasia [PMID:34634466, PMID:37643018]. ST6GAL1 transcription is governed by distinct promoters (P1 hepatic, P2 in B cells, P3 in epithelial/cancer cells) under control of NFκB, STAT3, AP2, and DNA methylation, and is induced in cancer by IL-1β and IL-6 [PMID:10460832, PMID:27510958, PMID:39260693]. The membrane-versus-secreted balance is set by BACE1-mediated proteolytic cleavage [PMID:28091531, PMID:34290711].","teleology":[{"year":1992,"claim":"Established that ST6GAL1 is a Golgi enzyme whose sialylation activity generates defined cell-surface differentiation antigens, linking a glycosyltransferase directly to surface phenotype.","evidence":"Expression cloning, cDNA transfection, immunofluorescence, and neuraminidase sensitivity in COS cells","pmids":["1730763"],"confidence":"High","gaps":["Did not resolve catalytic mechanism or acceptor specificity at molecular level","No structural basis for substrate recognition"]},{"year":1999,"claim":"Defined cell-type-specific transcriptional control by mapping the P2 regulatory region driving ST6GAL1 expression in mature B cells, explaining lineage-restricted expression.","evidence":"CAT reporter and deletion analysis across B-cell and hepatic lines","pmids":["10460832"],"confidence":"Medium","gaps":["Did not connect transcript variants to functional enzyme pools","Other promoters not yet characterized"]},{"year":2010,"claim":"Showed that hepatic, circulatory ST6GAL1 acts non-cell-autonomously to limit myelopoiesis, independent of serum glycoprotein sialylation, defining a systemic enzyme function.","evidence":"2D-DIGE, ex vivo colony formation, and P1 promoter-ablated mouse models","pmids":["20529847"],"confidence":"Medium","gaps":["Target cells and surface substrates on HSPCs not yet identified","Single lab functional assays"]},{"year":2012,"claim":"Linked the P1 promoter to systemic IgG-Fc sialylation, establishing the liver as the source of extracellular enzyme acting on circulating substrates.","evidence":"Siat1ΔP1 knock-in mouse with IgG Fc glycan analysis","pmids":["22427662"],"confidence":"High","gaps":["Mechanism of extracellular sialylation without cellular Golgi context unclear","Later contradicted regarding homeostatic IgG sialylation source"]},{"year":2013,"claim":"Provided the structural basis for catalysis, defining the CMP-sialic acid donor and acceptor binding architecture and a shared sialyltransferase framework.","evidence":"X-ray crystallography at 2.4 Å with docking, MD, and active-site mutagenesis/kinetics of rat ST6GAL1","pmids":["24155237"],"confidence":"High","gaps":["Human enzyme structure not solved","No structure with a glycoprotein acceptor bound"]},{"year":2014,"claim":"Identified marrow HSPCs as the direct cellular target of circulatory ST6GAL1 and demonstrated the surface α2,6-sialylation depends on host blood enzyme, not endogenous HSPC expression.","evidence":"Bone marrow chimeras with SNA/PSL lectin binding, mass spectrometry, and flow cytometry","pmids":["24425878"],"confidence":"High","gaps":["Specific glycoprotein substrates on HSPCs not defined","Downstream signaling not resolved here"]},{"year":2017,"claim":"Connected extracellular ST6GAL1 to suppression of granulopoiesis through attenuated G-CSF receptor/STAT3/C/EBPα signaling, and showed BACE1 cleavage controls enzyme availability at endothelial junctions.","evidence":"Ex vivo HSPC exposure plus in vivo elevated-enzyme mouse model; PKC/BACE1 inhibition and SNA blotting in endothelial cells","pmids":["28550122","28091531"],"confidence":"High","gaps":["Direct GCSFR sialylation not biochemically mapped","BACE1 cleavage site on ST6GAL1 not defined"]},{"year":2019,"claim":"Demonstrated that ST6GAL1 requires interaction with B4GALT1 in Golgi membranes for full activity and assembles via ER homomers, revealing organizational control of N-glycan synthesis.","evidence":"Molecular docking, mutagenesis screens, and high-throughput live-cell FRET","pmids":["31395657"],"confidence":"High","gaps":["Stoichiometry and dynamics of the complex unresolved","Effect on specific substrates not tested"]},{"year":2021,"claim":"Established ST6GAL1 as a regulator of EGFR signaling by sialylating the receptor to drive dimerization, recycling, and reduced degradation, providing a molecular basis for its oncogenic effects.","evidence":"Reciprocal OE/KD in ovarian cancer lines with TIRF, deconvolution microscopy, dimerization assays, and Rab11/LAMP1 colocalization","pmids":["37660914"],"confidence":"High","gaps":["Specific EGFR N-glycosylation sites not mapped here","Generality across receptor families addressed in separate studies"]},{"year":2022,"claim":"Generalized substrate sialylation as a mechanism modulating receptor stability and signaling across ErbB2, PDGFRβ, and MCAM, and demonstrated in vivo roles in metastasis and tumor growth.","evidence":"Site-specific glycoproteomics, lectin pulldowns, KD/OE, and orthotopic/metastasis mouse models across gastric, glioblastoma, and HCC systems","pmids":["33947960","36345944","36528750"],"confidence":"High","gaps":["Context-dependent pro- versus anti-metastatic outcomes not unified mechanistically","Substrate selectivity determinants unclear"]},{"year":2022,"claim":"Revised the model of IgG sialylation by showing hepatocyte/plasma ST6GAL1 is dispensable for homeostatic IgG α2,6-sialylation, implicating an unidentified alternative mechanism.","evidence":"Conditional hepatocyte and B-cell ST6GAL1 knockouts with IgG glycan analysis","pmids":["35746897"],"confidence":"Medium","gaps":["Identity of the responsible enzyme/source unknown","Reconciliation with earlier P1 promoter findings incomplete"]},{"year":2023,"claim":"Demonstrated in vivo that ST6GAL1 drives KRAS-mutant pancreatic tumorigenesis through EGFR-dependent acinar-to-ductal metaplasia, linking substrate sialylation to cancer initiation.","evidence":"ST6GAL1 transgenic × KRASG12D GEM models, GEM-derived organoids, and ADM/EGFR activation assays","pmids":["37643018","34634466"],"confidence":"High","gaps":["Other contributing substrates in PDAC not fully enumerated","Therapeutic targetability not established"]},{"year":2024,"claim":"Defined cytokine-driven transcriptional induction via the P3 promoter, showing IL-1β/NFκB and IL-6/STAT3 directly upregulate ST6GAL1, linking inflammation to glycan remodeling in cancer.","evidence":"CUT&RUN, promoter reporter assays, and NFκB/STAT3 inhibitors in PDAC lines","pmids":["39260693"],"confidence":"High","gaps":["Cross-talk between P1/P2/P3 regulation in vivo not resolved","Quantitative contribution of each TF unclear"]},{"year":2025,"claim":"Extended ST6GAL1 substrate control to immune evasion and metastatic homing through PD-L1 stability, BICD2/IFNGR1 signaling, PECAM-1-mediated extravasation, and CD22-dependent B-cell recruitment in inflammation.","evidence":"KO/KD with ubiquitination, IP/MS, in vivo metastasis and anti-PD-L1 models, and humanized mouse homing assays","pmids":["40847469","41217711","39786386","40491026"],"confidence":"High","gaps":["Integration of these parallel substrate pathways into a unified model lacking","Site-specific sialylation mapping incomplete for several substrates"]},{"year":null,"claim":"The enzyme/source responsible for homeostatic IgG-Fc α2,6-sialylation and the determinants of ST6GAL1 substrate selectivity that produce opposing pro- versus anti-tumor outcomes remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified alternative IgG-sialylating activity after exclusion of hepatic/B-cell ST6GAL1","No structural or biochemical rule predicting which receptors ST6GAL1 stabilizes versus destabilizes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,9,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,17,20,35]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,4,24,25]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,17,20,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,17,19,23,39]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,14,26,35,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16,21,33]}],"complexes":[],"partners":["B4GALT1","EGFR","ERBB2","PDGFRB","CD22","MCAM","PECAM1","BICD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15907","full_name":"Beta-galactoside alpha-2,6-sialyltransferase 1","aliases":["CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,6-sialyltransferase 1","ST6Gal I","ST6GalI","Sialyltransferase 1"],"length_aa":406,"mass_kda":46.6,"function":"Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates. In B lymphocytes, generates neuraminidase-sensitive lymphocyte cell-surface differentiation antigens, such as CDw75, HB-6 and CD76 (PubMed:1730763). Sialylates complex-type N-glycans attached on the fragment crystallizable (Fc) of IgGs confering anti-inflammatory effector functions. Preferentially monosialylates the alpha(1->3) mannose antenna of Fc glycoforms with subsequent disialylation occurring at a much slower rate","subcellular_location":"Golgi apparatus, Golgi stack membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P15907/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ST6GAL1","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/ST6GAL1","total_profiled":1310},"omim":[{"mim_id":"604676","title":"HLA COMPLEX P5 GENE; HCP5","url":"https://www.omim.org/entry/604676"},{"mim_id":"142830","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS I, B; HLA-B","url":"https://www.omim.org/entry/142830"},{"mim_id":"109675","title":"ST6 BETA-GALACTOSAMIDE ALPHA-2,6-SIALYLTRANSFERASE 1; ST6GAL1","url":"https://www.omim.org/entry/109675"},{"mim_id":"104240","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 4; ST3GAL4","url":"https://www.omim.org/entry/104240"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":463.6},{"tissue":"lymphoid tissue","ntpm":138.6}],"url":"https://www.proteinatlas.org/search/ST6GAL1"},"hgnc":{"alias_symbol":["CDw75"],"prev_symbol":["SIAT1"]},"alphafold":{"accession":"P15907","domains":[{"cath_id":"3.90.1480.20","chopping":"103-400","consensus_level":"high","plddt":98.0754,"start":103,"end":400}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15907","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15907-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15907-F1-predicted_aligned_error_v6.png","plddt_mean":88.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ST6GAL1","jax_strain_url":"https://www.jax.org/strain/search?query=ST6GAL1"},"sequence":{"accession":"P15907","fasta_url":"https://rest.uniprot.org/uniprotkb/P15907.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15907/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15907"}},"corpus_meta":[{"pmid":"31423157","id":"PMC_31423157","title":"ST6GAL1: A key player in cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31423157","citation_count":125,"is_preprint":false},{"pmid":"18480230","id":"PMC_18480230","title":"MDCK-SIAT1 cells show improved isolation rates for recent human influenza viruses compared to conventional MDCK cells.","date":"2008","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18480230","citation_count":116,"is_preprint":false},{"pmid":"24155237","id":"PMC_24155237","title":"Enzymatic basis for N-glycan sialylation: structure of rat α2,6-sialyltransferase (ST6GAL1) reveals conserved and unique features for glycan sialylation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24155237","citation_count":116,"is_preprint":false},{"pmid":"1730763","id":"PMC_1730763","title":"The HB-6, CDw75, and CD76 differentiation antigens are unique cell-surface carbohydrate determinants generated by the beta-galactoside alpha 2,6-sialyltransferase.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1730763","citation_count":110,"is_preprint":false},{"pmid":"29720252","id":"PMC_29720252","title":"Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women.","date":"2018","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29720252","citation_count":85,"is_preprint":false},{"pmid":"33320246","id":"PMC_33320246","title":"Regulation of ST6GAL1 sialyltransferase expression in cancer cells.","date":"2021","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/33320246","citation_count":71,"is_preprint":false},{"pmid":"31694696","id":"PMC_31694696","title":"The HOTAIR/miR-214/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2/STAT3 cascade.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31694696","citation_count":68,"is_preprint":false},{"pmid":"33288659","id":"PMC_33288659","title":"ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/33288659","citation_count":63,"is_preprint":false},{"pmid":"33947960","id":"PMC_33947960","title":"ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33947960","citation_count":53,"is_preprint":false},{"pmid":"26304831","id":"PMC_26304831","title":"Glycosyltransferase ST6GAL1 contributes to the regulation of pluripotency in human pluripotent stem cells.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26304831","citation_count":52,"is_preprint":false},{"pmid":"31096997","id":"PMC_31096997","title":"The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31096997","citation_count":49,"is_preprint":false},{"pmid":"22427662","id":"PMC_22427662","title":"Anti-inflammatory IgG production requires functional P1 promoter in β-galactoside α2,6-sialyltransferase 1 (ST6Gal-1) gene.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22427662","citation_count":47,"is_preprint":false},{"pmid":"37550801","id":"PMC_37550801","title":"ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression.","date":"2023","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37550801","citation_count":46,"is_preprint":false},{"pmid":"24425878","id":"PMC_24425878","title":"Remodeling of marrow hematopoietic stem and progenitor cells by non-self ST6Gal-1 sialyltransferase.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24425878","citation_count":45,"is_preprint":false},{"pmid":"36345944","id":"PMC_36345944","title":"α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36345944","citation_count":43,"is_preprint":false},{"pmid":"35676533","id":"PMC_35676533","title":"Extracellular sialyltransferase st6gal1 in breast tumor cell growth and invasiveness.","date":"2022","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35676533","citation_count":42,"is_preprint":false},{"pmid":"28603863","id":"PMC_28603863","title":"Identification of PTPN22, ST6GAL1 and JAZF1 as psoriasis risk genes demonstrates shared pathogenesis between psoriasis and diabetes.","date":"2017","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28603863","citation_count":42,"is_preprint":false},{"pmid":"25465919","id":"PMC_25465919","title":"Epigenetic inactivation of ST6GAL1 in human bladder cancer.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25465919","citation_count":40,"is_preprint":false},{"pmid":"28091531","id":"PMC_28091531","title":"TNF-α regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28091531","citation_count":40,"is_preprint":false},{"pmid":"31395657","id":"PMC_31395657","title":"Assembly of B4GALT1/ST6GAL1 heteromers in the Golgi membranes involves lateral interactions via highly charged surface domains.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31395657","citation_count":38,"is_preprint":false},{"pmid":"37660914","id":"PMC_37660914","title":"Sialylation of EGFR by ST6GAL1 induces receptor activation and modulates trafficking dynamics.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37660914","citation_count":36,"is_preprint":false},{"pmid":"18234543","id":"PMC_18234543","title":"CPA6, FMO2, LGI1, SIAT1 and TNC are differentially expressed in early- and late-stage oral squamous cell carcinoma--a pilot study.","date":"2008","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18234543","citation_count":36,"is_preprint":false},{"pmid":"37643018","id":"PMC_37643018","title":"ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37643018","citation_count":35,"is_preprint":false},{"pmid":"20007243","id":"PMC_20007243","title":"Altered eosinophil profile in mice with ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation.","date":"2009","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/20007243","citation_count":35,"is_preprint":false},{"pmid":"23504322","id":"PMC_23504322","title":"Reduction of the ST6 β-galactosamide α-2,6-sialyltransferase 1 (ST6GAL1)-catalyzed sialylation of nectin-like molecule 2/cell adhesion molecule 1 and enhancement of ErbB2/ErbB3 signaling by microRNA-199a.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23504322","citation_count":34,"is_preprint":false},{"pmid":"20529847","id":"PMC_20529847","title":"Role for hepatic and circulatory ST6Gal-1 sialyltransferase in regulating myelopoiesis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20529847","citation_count":34,"is_preprint":false},{"pmid":"1577059","id":"PMC_1577059","title":"Cell cycle-dependent regulation of CDw75 (beta-galactoside alpha-2,6-sialyltransferase) on human B lymphocytes.","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1577059","citation_count":33,"is_preprint":false},{"pmid":"34980201","id":"PMC_34980201","title":"Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34980201","citation_count":33,"is_preprint":false},{"pmid":"29286446","id":"PMC_29286446","title":"Measuring Influenza Neutralizing Antibody Responses to A(H3N2) Viruses in Human Sera by Microneutralization Assays Using MDCK-SIAT1 Cells.","date":"2017","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/29286446","citation_count":33,"is_preprint":false},{"pmid":"28550122","id":"PMC_28550122","title":"The blood-borne sialyltransferase ST6Gal-1 is a negative systemic regulator of granulopoiesis.","date":"2017","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/28550122","citation_count":33,"is_preprint":false},{"pmid":"32391003","id":"PMC_32391003","title":"Blood-Borne ST6GAL1 Regulates Immunoglobulin Production in B Cells.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32391003","citation_count":32,"is_preprint":false},{"pmid":"35041825","id":"PMC_35041825","title":"Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35041825","citation_count":30,"is_preprint":false},{"pmid":"36528750","id":"PMC_36528750","title":"ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36528750","citation_count":27,"is_preprint":false},{"pmid":"27510958","id":"PMC_27510958","title":"The role of DNA methylation in ST6Gal1 expression in gliomas.","date":"2016","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27510958","citation_count":27,"is_preprint":false},{"pmid":"30294329","id":"PMC_30294329","title":"Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30294329","citation_count":27,"is_preprint":false},{"pmid":"21147760","id":"PMC_21147760","title":"Differences in CD75s- and iso-CD75s-ganglioside content and altered mRNA expression of sialyltransferases ST6GAL1 and ST3GAL6 in human hepatocellular carcinomas and nontumoral liver tissues.","date":"2010","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21147760","citation_count":27,"is_preprint":false},{"pmid":"34290711","id":"PMC_34290711","title":"ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34290711","citation_count":26,"is_preprint":false},{"pmid":"31705333","id":"PMC_31705333","title":"MiR-214-3p regulates the viability, invasion, migration and EMT of TNBC cells by targeting ST6GAL1.","date":"2019","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31705333","citation_count":26,"is_preprint":false},{"pmid":"34634466","id":"PMC_34634466","title":"Integrated Systems Analysis of the Murine and Human Pancreatic Cancer Glycomes Reveals a Tumor-Promoting Role for ST6GAL1.","date":"2021","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/34634466","citation_count":26,"is_preprint":false},{"pmid":"27166796","id":"PMC_27166796","title":"Expression of Functional Human Sialyltransferases ST3Gal1 and ST6Gal1 in Escherichia coli.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27166796","citation_count":25,"is_preprint":false},{"pmid":"35746897","id":"PMC_35746897","title":"ST6Gal1 in plasma is dispensable for IgG sialylation.","date":"2022","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35746897","citation_count":24,"is_preprint":false},{"pmid":"28377225","id":"PMC_28377225","title":"Differential expression of ST6GAL1 in the tumor progression of colorectal cancer.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28377225","citation_count":23,"is_preprint":false},{"pmid":"30730306","id":"PMC_30730306","title":"Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/30730306","citation_count":23,"is_preprint":false},{"pmid":"31317190","id":"PMC_31317190","title":"Impact of sialyltransferase ST6GAL1 overexpression on different colon cancer cell types.","date":"2019","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31317190","citation_count":22,"is_preprint":false},{"pmid":"20855889","id":"PMC_20855889","title":"Molecular phylogeny and functional genomics of beta-galactoside alpha2,6-sialyltransferases that explain ubiquitous expression of st6gal1 gene in amniotes.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20855889","citation_count":22,"is_preprint":false},{"pmid":"10460832","id":"PMC_10460832","title":"Transcription of the beta-galactoside alpha2,6-sialyltransferase gene (SIAT1) in B-lymphocytes: cell type-specific expression correlates with presence of the divergent 5'-untranslated sequence.","date":"1999","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/10460832","citation_count":21,"is_preprint":false},{"pmid":"26945752","id":"PMC_26945752","title":"Comparison between MDCK and MDCK-SIAT1 cell lines as preferred host for cell culture-based influenza vaccine production.","date":"2016","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/26945752","citation_count":19,"is_preprint":false},{"pmid":"29654763","id":"PMC_29654763","title":"ST6GAL1 negatively regulates monocyte transendothelial migration and atherosclerosis development.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29654763","citation_count":19,"is_preprint":false},{"pmid":"19091815","id":"PMC_19091815","title":"In vivo and in vitro alterations in influenza A/H3N2 virus M2 and hemagglutinin genes: effect of passage in MDCK-SIAT1 cells and conventional MDCK cells.","date":"2008","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19091815","citation_count":18,"is_preprint":false},{"pmid":"20003255","id":"PMC_20003255","title":"Synthesis and expression of CDw75 antigen in human colorectal cancer.","date":"2009","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20003255","citation_count":17,"is_preprint":false},{"pmid":"31308754","id":"PMC_31308754","title":"The β-galactoside α2,6-sialyltranferase 1 (ST6GAL1) inhibits the colorectal cancer metastasis by stabilizing intercellular adhesion molecule-1 via sialylation.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31308754","citation_count":17,"is_preprint":false},{"pmid":"1721040","id":"PMC_1721040","title":"Expression of the CDw75 (beta-galactoside alpha 2,6-sialyltransferase) antigen on normal blood cells and in B-cell chronic lymphocytic leukaemia.","date":"1991","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1721040","citation_count":14,"is_preprint":false},{"pmid":"35661210","id":"PMC_35661210","title":"Extracellular ST6GAL1 regulates monocyte-macrophage development and survival.","date":"2022","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35661210","citation_count":13,"is_preprint":false},{"pmid":"8348485","id":"PMC_8348485","title":"CDw75 antigen expression in human gastric carcinoma and adjacent mucosa.","date":"1993","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8348485","citation_count":13,"is_preprint":false},{"pmid":"39260693","id":"PMC_39260693","title":"The pro-inflammatory cytokines IL-1β and IL-6 promote upregulation of the ST6GAL1 sialyltransferase in pancreatic cancer cells.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39260693","citation_count":13,"is_preprint":false},{"pmid":"30241880","id":"PMC_30241880","title":"High genetic stability in MDCK-SIAT1 passaged human influenza viruses.","date":"2018","source":"Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30241880","citation_count":13,"is_preprint":false},{"pmid":"34957619","id":"PMC_34957619","title":"Glycomics reveal that ST6GAL1-mediated sialylation regulates uterine lumen closure during implantation.","date":"2021","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/34957619","citation_count":13,"is_preprint":false},{"pmid":"34745942","id":"PMC_34745942","title":"High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34745942","citation_count":13,"is_preprint":false},{"pmid":"37364046","id":"PMC_37364046","title":"Role of the ST6GAL1 sialyltransferase in regulating ovarian cancer cell metabolism.","date":"2023","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37364046","citation_count":12,"is_preprint":false},{"pmid":"39786386","id":"PMC_39786386","title":"ST6GAL1-Mediated Sialylation of PECAM-1 Promotes a Transcellular Diapedesis-Like Process That Directs Lung Tropism of Metastatic Breast Cancer.","date":"2025","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39786386","citation_count":12,"is_preprint":false},{"pmid":"11180162","id":"PMC_11180162","title":"Clinicopathologic evaluation of CDw75 antigen expression in patients with gastric carcinoma.","date":"2001","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11180162","citation_count":12,"is_preprint":false},{"pmid":"32141499","id":"PMC_32141499","title":"Loss of core fucosylation in both ST6GAL1 and its substrate enhances glycoprotein sialylation in mice.","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32141499","citation_count":12,"is_preprint":false},{"pmid":"38467087","id":"PMC_38467087","title":"ST6GAL1 is associated with poor response to chemoradiation in rectal cancer.","date":"2024","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38467087","citation_count":11,"is_preprint":false},{"pmid":"12515997","id":"PMC_12515997","title":"Clinicopathologic evaluation of CDw75 antigen expression in colorectal adenocarcinomas.","date":"2003","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/12515997","citation_count":10,"is_preprint":false},{"pmid":"32677771","id":"PMC_32677771","title":"ST6Gal1 is up-regulated and associated with aberrant IgA1 glycosylation in IgA nephropathy: An integrated analysis of the transcriptome.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32677771","citation_count":10,"is_preprint":false},{"pmid":"8496593","id":"PMC_8496593","title":"HB4 antibody recognizes a carbohydrate structure on lymphocyte surface proteins related to HB6, CDw75, and CD76 antigens.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8496593","citation_count":9,"is_preprint":false},{"pmid":"11378576","id":"PMC_11378576","title":"Paraffin immunoreactivity of CD10, CDw75, and Bcl-6 in follicle center cell lymphoma.","date":"2001","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/11378576","citation_count":8,"is_preprint":false},{"pmid":"38490094","id":"PMC_38490094","title":"N-linked α2,6-sialylation of integrin β1 by the sialyltransferase ST6Gal1 promotes cell proliferation and stemness in gestational trophoblastic disease.","date":"2024","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/38490094","citation_count":8,"is_preprint":false},{"pmid":"1908707","id":"PMC_1908707","title":"Monoclonal antibodies EBU-141 (CDw75) and EBU-65 allow reliable distinction between mature and pre-B-cell tumors in suspension and on tissue sections.","date":"1991","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/1908707","citation_count":8,"is_preprint":false},{"pmid":"34729155","id":"PMC_34729155","title":"Plasma ST6GAL1 regulates IgG sialylation to control IgA nephropathy progression.","date":"2021","source":"Therapeutic advances in chronic disease","url":"https://pubmed.ncbi.nlm.nih.gov/34729155","citation_count":8,"is_preprint":false},{"pmid":"7688897","id":"PMC_7688897","title":"CDw75 antigen expression in breast lesions.","date":"1993","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/7688897","citation_count":8,"is_preprint":false},{"pmid":"40847469","id":"PMC_40847469","title":"ST6GAL1-Mediated Sialylation Stabilizes PD-L1 and Drives Immunosuppressive Tumor Microenvironment in Colorectal Cancer.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40847469","citation_count":7,"is_preprint":false},{"pmid":"35371997","id":"PMC_35371997","title":"Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35371997","citation_count":7,"is_preprint":false},{"pmid":"38758134","id":"PMC_38758134","title":"Synthesis of α-Hydroxy-1,2,3-Triazole-linked Sialyltransferase Inhibitors and Evaluation of Selectivity Towards ST3GAL1, ST6GAL1 and ST8SIA2.","date":"2024","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/38758134","citation_count":7,"is_preprint":false},{"pmid":"36646912","id":"PMC_36646912","title":"Role of ST6GAL1 and ST6GAL2 in subversion of cellular signaling during enteroaggregative Escherichia coli infection of human intestinal epithelial cell lines.","date":"2023","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36646912","citation_count":7,"is_preprint":false},{"pmid":"24606438","id":"PMC_24606438","title":"Promoter polymorphisms of ST3GAL4 and ST6GAL1 genes and associations with risk of premalignant and malignant lesions of the cervix.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24606438","citation_count":7,"is_preprint":false},{"pmid":"36452458","id":"PMC_36452458","title":"Deficiency in ST6GAL1, one of the two α2,6-sialyltransferases, has only a minor effect on the pathogenesis of prion disease.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36452458","citation_count":7,"is_preprint":false},{"pmid":"37379323","id":"PMC_37379323","title":"Platelet-localized ST6Gal1 does not impact IgG sialylation.","date":"2023","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37379323","citation_count":6,"is_preprint":false},{"pmid":"38003522","id":"PMC_38003522","title":"Role of ST6GAL1 in Thyroid Cancers: Insights from Tissue Analysis and Genomic Datasets.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38003522","citation_count":6,"is_preprint":false},{"pmid":"38035043","id":"PMC_38035043","title":"Circ_ST6GAL1-mediated competing endogenous RNA network regulates TGF-β1-stimulated matrix Metalloproteinase-13 expression via Runx2 acetylation in osteoblasts.","date":"2023","source":"Non-coding RNA research","url":"https://pubmed.ncbi.nlm.nih.gov/38035043","citation_count":6,"is_preprint":false},{"pmid":"36293269","id":"PMC_36293269","title":"Serial Passaging of Seasonal H3N2 Influenza A/Singapore/G2-31.1/2014 Virus in MDCK-SIAT1 Cells and Primary Chick Embryo Cells Generates HA D457G Mutation and Other Variants in HA, NA, PB1, PB1-F2, and NS1.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36293269","citation_count":6,"is_preprint":false},{"pmid":"32747022","id":"PMC_32747022","title":"ST6GAL1 polymorphisms influence susceptibility and progression of IgA nephropathy in a Chinese Han population.","date":"2020","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32747022","citation_count":6,"is_preprint":false},{"pmid":"30929638","id":"PMC_30929638","title":"Genetic Variants in the ST6GAL1 Gene Are Associated with Thyroglobulin Plasma Level in Healthy Individuals.","date":"2019","source":"Thyroid : official journal of the American Thyroid Association","url":"https://pubmed.ncbi.nlm.nih.gov/30929638","citation_count":6,"is_preprint":false},{"pmid":"38940341","id":"PMC_38940341","title":"Digitoxin inhibits ICC cell properties via the NF‑κB/ST6GAL1 signaling pathway.","date":"2024","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38940341","citation_count":5,"is_preprint":false},{"pmid":"1592444","id":"PMC_1592444","title":"The influence of the In(Lu) gene on expression of CDw75 antigens on human red blood cells.","date":"1992","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1592444","citation_count":5,"is_preprint":false},{"pmid":"31419997","id":"PMC_31419997","title":"Correction to: The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31419997","citation_count":5,"is_preprint":false},{"pmid":"35789385","id":"PMC_35789385","title":"The incorrect use of CD75 as a synonym for ST6GAL1 has fostered the expansion of commercial \"ST6GAL1\" antibodies that do not recognize ST6GAL1.","date":"2022","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35789385","citation_count":4,"is_preprint":false},{"pmid":"15162552","id":"PMC_15162552","title":"CDw75 is a significant histopathological marker for gastric carcinoma.","date":"2004","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15162552","citation_count":4,"is_preprint":false},{"pmid":"37398202","id":"PMC_37398202","title":"Sialylation of EGFR by ST6GAL1 induces receptor activation and modulates trafficking dynamics.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398202","citation_count":3,"is_preprint":false},{"pmid":"40174529","id":"PMC_40174529","title":"Optimizing ST6GAL1 inhibition and selectivity using lithocholic acid-amino acid conjugates for antimetastatic and antiangiogenic agent development.","date":"2025","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40174529","citation_count":3,"is_preprint":false},{"pmid":"31852463","id":"PMC_31852463","title":"Identification of the complete coding cDNAs and expression analysis of B4GALT1, LALBA, ST3GAL5, ST6GAL1 in the colostrum and milk of the Garganica and Maltese goat breeds to reveal possible implications for oligosaccharide biosynthesis.","date":"2019","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/31852463","citation_count":3,"is_preprint":false},{"pmid":"31794515","id":"PMC_31794515","title":"Influences of two significant variants located in the ST6GAL1 3'-untranslated region on lung carcinoma susceptibility in the Chinese Han population.","date":"2020","source":"European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)","url":"https://pubmed.ncbi.nlm.nih.gov/31794515","citation_count":3,"is_preprint":false},{"pmid":"39120072","id":"PMC_39120072","title":"Evaluation of ST6Gal1 expression and clinicopathological significance in human glioma.","date":"2024","source":"Clinical neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/39120072","citation_count":2,"is_preprint":false},{"pmid":"41217711","id":"PMC_41217711","title":"ST6GAL1-mediated sialylation inhibits the antitumor immune response in colorectal cancer.","date":"2025","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41217711","citation_count":2,"is_preprint":false},{"pmid":"39883364","id":"PMC_39883364","title":"Spatial single-cell maps reveal ST6GAL1 promoting ovarian cancer metastasis.","date":"2025","source":"Glycoconjugate journal","url":"https://pubmed.ncbi.nlm.nih.gov/39883364","citation_count":2,"is_preprint":false},{"pmid":"20795944","id":"PMC_20795944","title":"Overexpression of amyloid beta precursor protein enhances expression and secretion of ST6Gal1 in C2C12 myogenic cell line.","date":"2011","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/20795944","citation_count":2,"is_preprint":false},{"pmid":"40491026","id":"PMC_40491026","title":"ST6GAL1 promotes IBD B cell recruitment to the inflamed colon in a CD22-dependent mechanism.","date":"2025","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/40491026","citation_count":1,"is_preprint":false},{"pmid":"39937175","id":"PMC_39937175","title":"Multi-omics reveals that ST6GAL1 promotes colorectal cancer progression through LGALS3BP sialylation.","date":"2025","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/39937175","citation_count":1,"is_preprint":false},{"pmid":"38859745","id":"PMC_38859745","title":"Establishment of a humanized ST6GAL1 mouse model for influenza research.","date":"2024","source":"Animal models and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38859745","citation_count":1,"is_preprint":false},{"pmid":"40604645","id":"PMC_40604645","title":"Machine learning-based integration identifies plasma cells-related gene signature ST6GAL1 in idiopathic pulmonary fibrosis.","date":"2025","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40604645","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56686,"output_tokens":10953,"usd":0.167177,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21844,"output_tokens":4961,"usd":0.116623,"stage2_stop_reason":"end_turn"},"total_usd":0.2838,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of rat ST6GAL1 at 2.4 Å resolution revealed an overall protein fold resembling pig ST3GAL1, with a CMP-sialic acid-binding site assembled from conserved sialylmotif sequence elements. Computational substrate docking, molecular dynamics simulations, and kinetic analysis of active-site mutants identified donor and acceptor binding interactions and a common structural framework for catalysis shared with bacterial sialyltransferases.\",\n      \"method\": \"X-ray crystallography (2.4 Å), computational docking/MD simulations, active-site mutagenesis, kinetic assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and kinetic validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24155237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Expression of the β-galactoside α2,6-sialyltransferase (ST6GAL1/alpha 2,6-ST) was shown to regulate generation of the cell-surface differentiation antigens HB-6, CDw75, and CD76. The alpha 2,6-ST protein is localized to the Golgi apparatus, and the cell-surface antigens are products of its enzymatic activity (sialylation), demonstrated by expression cloning and neuraminidase sensitivity.\",\n      \"method\": \"Expression cloning, cDNA transfection in COS cells, immunofluorescence, neuraminidase treatment, subcellular fractionation/localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (expression cloning, functional enzyme assay, localization, neuraminidase sensitivity), replicated across CDw75 and CD76\",\n      \"pmids\": [\"1730763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B4GALT1 and ST6GAL1 interact in Golgi membranes via highly charged noncatalytic surfaces (leaving active sites accessible), as demonstrated by molecular docking, mutagenesis screens, and high-throughput FRET in live cells. ST6GAL1 first forms homomers in the ER using the same noncatalytic surface before activation in the Golgi; their interaction is a prerequisite for full catalytic activity of both enzymes in N-glycan synthesis.\",\n      \"method\": \"Molecular docking simulations, mutagenesis screens, high-throughput FRET in live cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis + live-cell FRET + computational predictions validated experimentally, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31395657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The P1 promoter of the ST6Gal-1 gene is critical for sialylation of circulating IgG Fc. Siat1ΔP1 mice with a dysfunctional P1 promoter were unable to produce sialylated Fc IgG in systemic circulation despite Gal(β4)GlcNAc termini being present. The P1 promoter drives ST6Gal-1 expression in the liver, releasing enzyme into systemic circulation where it sialylates IgG Fc extracellularly.\",\n      \"method\": \"Knock-in mouse model (Siat1ΔP1), IgG Fc glycan analysis, acute phase response experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with mechanistic dissection of promoter-specific enzyme source and functional IgG sialylation outcome\",\n      \"pmids\": [\"22427662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Extracellular ST6Gal-1 originating mostly from the liver and released into circulation targets marrow hematopoietic stem and progenitor cells (HSPCs) and mediates formation of cell-surface α2,6-linked sialic acids on HSPCs. Bone marrow chimera experiments demonstrated that α2,6-sialylation of HSPCs is profoundly dependent on circulatory ST6Gal-1 status of recipients and independent of endogenous HSPC ST6Gal-1 expression. HSPC abundance in marrow is inversely related to circulatory ST6Gal-1 status.\",\n      \"method\": \"Bone marrow chimeras, lectin binding (SNA, PSL), mass spectrometry, flow cytometry (Lin-cKit+, LSK populations)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bone marrow chimera genetic dissection plus mass spectrometry confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"24425878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Circulatory ST6Gal-1 of mostly hepatic origin limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins. Ex vivo colony formation assays showed that physiologic levels of ST6Gal-1 introduced into culture medium attenuated HSPC colony formation. The P1 promoter engagement in the liver generates circulatory ST6Gal-1 that regulates myelopoiesis.\",\n      \"method\": \"2D-DIGE analysis of serum glycoproteins, ex vivo colony formation assays, mouse models with P1 promoter ablation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo functional assays with recombinant enzyme, supported by 2D-DIGE, single lab\",\n      \"pmids\": [\"20529847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Extracellular (blood-borne) ST6Gal-1 suppresses late-stage neutrophil development (granulopoiesis). Exposure of human and murine HSPCs to extracellular ST6Gal-1 ex vivo decreased proliferation, MPO expression, CD11b+ cell appearance, STAT-3 phosphorylation, and C/EBPα expression (attenuating G-CSF receptor signaling). A mouse model with elevated systemic ST6Gal-1 confirmed decreased marrow neutrophil reserves and reduced airway neutrophilic inflammation in vivo.\",\n      \"method\": \"Ex vivo HSPC exposure to recombinant ST6Gal-1, in vivo mouse model of elevated systemic ST6Gal-1, LPS airway challenge, signaling analysis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo mechanistic studies with recombinant enzyme + in vivo mouse model, signaling pathway identified, single lab\",\n      \"pmids\": [\"28550122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TNF-α treatment upregulates BACE1 expression through PKC signaling, leading to proteolytic cleavage/degradation of ST6Gal-1, decreased α2,6-sialylation of VE-Cadherin, disrupted endothelial cell-cell tight junctions, and promoted monocyte-endothelial cell adhesion.\",\n      \"method\": \"Western blotting, SNA lectin blotting, PKC signaling inhibition, siRNA knockdown, BACE1 overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods establishing the TNF-α→PKC→BACE1→ST6Gal-1 cleavage→VE-Cadherin sialylation pathway, single lab\",\n      \"pmids\": [\"28091531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Estrogen (E2) increases St6Gal1 expression in mouse and human antibody-producing cells (B cells/plasma cells), providing a mechanistic basis for increased IgG-Fc sialylation. E2 treatment of postmenopausal mice significantly increased Fc sialylation of total and antigen-specific IgG and increased expression of inhibitory FcγRIIb on bone marrow leukocytes.\",\n      \"method\": \"Ovariectomized mouse model with E2 treatment, qRT-PCR, flow cytometry, IgG glycan analysis; validated in human RA patients on HRT\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse model with in vivo E2 treatment plus human validation, multiple methods, single lab\",\n      \"pmids\": [\"29720252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1 sialylates EGFR, promoting EGFR dimerization and higher-order oligomerization, increased activation of EGFR and downstream AKT and NFκB signaling, enhanced receptor recycling via Rab11 recycling endosomes, and reduced lysosomal degradation following EGF stimulation.\",\n      \"method\": \"ST6GAL1 overexpression/knockdown in ovarian cancer lines, TIRF microscopy, 3D widefield deconvolution microscopy, biochemical dimerization assays, colocalization with Rab11/LAMP1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal OE/KD with multiple microscopy and biochemical approaches identifying mechanism, replicated across multiple cell lines\",\n      \"pmids\": [\"37660914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST6GAL1-mediated sialylation of MUC4β (targeting N-glycosylation sites) is induced by IL-13 in human airway epithelial cells; ST6GAL1-induced sialylation of MUC4β alters its lectin binding and secretion, and both ST6GAL1 and MUC4β inhibit epithelial cell proliferation while promoting goblet cell differentiation.\",\n      \"method\": \"Primary human airway epithelial cell cultures, IL-13 treatment, siRNA knockdown, lectin binding assays, proliferation/differentiation assays, clinical sample analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro with clinical specimen correlation, multiple methods, single lab\",\n      \"pmids\": [\"30730306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-199a targets ST6GAL1 and reduces both the ST6GAL1-catalyzed sialylation and protein level of the adhesion molecule Necl-2/CADM1. Reduced Necl-2 sialylation (via ST6GAL1 suppression) enhances HRG-induced ErbB2/ErbB3 signaling for cell movement.\",\n      \"method\": \"miR-199a transfection, sialylation assays, ErbB2/ErbB3 signaling assays in A549 and HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate identification with functional signaling readout, single lab with multiple methods\",\n      \"pmids\": [\"23504322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of core fucosylation (FUT8 knockout) increases ST6GAL1 catalytic activity in serum and liver and increases α2,6-sialylation, partly because ST6GAL1 prefers non-fucosylated substrates. FUT8 is responsible for core fucosylation of ST6GAL1 itself, creating a regulatory interaction between the two glycosyltransferases.\",\n      \"method\": \"Fut8-/- mouse model, serum N-glycan analysis, ST6GAL1 activity assays, in vitro substrate preference assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout mouse plus in vitro enzyme activity assays, single lab\",\n      \"pmids\": [\"32141499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST6GAL1 negatively regulates monocyte transendothelial migration. Knockdown of ST6GAL1 in vascular endothelial cells promoted TNFα-triggered monocyte transendothelial migration, while overexpression inhibited it. β-catenin was identified as a sialylated substrate of ST6GAL1, and its sialylation level decreased upon TNFα treatment.\",\n      \"method\": \"RNAi knockdown and overexpression in EA.hy926 cells, monocyte transendothelial migration assays, Western blot for sialylation of β-catenin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain of function with functional migration readout and substrate identification, single lab\",\n      \"pmids\": [\"29654763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Extracellular ST6GAL1 (B cell-extrinsic pool) sialylates B cell surface CD22 and CD45, boosting B cell IgM, IgD, and CD86 expression, proliferation, and IgG production. In vivo, elevation of blood ST6GAL1 enhanced B cell development and systemic IgG in a CD22-dependent manner. B cell intrinsic ST6GAL1 is required for marginal zone B cell development.\",\n      \"method\": \"Mouse models lacking hepatocyte-specific St6gal1 promoter, ex vivo B cell sialylation assays, in vivo IgG titer measurement, CD22 dependency (anti-CD22 blocking)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and ex vivo experiments with genetic and pharmacological dissection of B-cell intrinsic vs extrinsic roles, CD22 mechanism identified\",\n      \"pmids\": [\"32391003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1 promotes pancreatic ductal adenocarcinoma (PDAC) progression. Pancreas-specific deletion of ST6GAL1 in the KC (KRASG12D) mouse model significantly delayed cancer formation and reduced fibrosis. Transgenic ST6GAL1 with KRASG12D greatly accelerated PDAC progression vs KRASG12D alone.\",\n      \"method\": \"Genetically engineered mouse models (pancreas-specific ST6GAL1 knockout and transgenic), KC KRASG12D model, glycomic/transcriptomic analysis, histology\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary GEM models (KO and transgenic) with clear genetic epistasis in vivo, replicated in human samples\",\n      \"pmids\": [\"34634466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ST6GAL1 promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer progression. ST6GAL1 transgenic mice with KRASG12D had greatly accelerated PDAC vs KRASG12D alone. ST6GAL1 promotes ADM through EGFR activation—EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression.\",\n      \"method\": \"GEM models (ST6GAL1 transgenic × KRASG12D), GEM-derived organoids, ADM assays, EGFR activation measurements, 266-6 cell line, in vivo inflammation-induced ADM\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple GEM and organoid models, mechanistic link to EGFR sialylation established, replicated across model systems\",\n      \"pmids\": [\"37643018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST6GAL1 specifically sialylates the trastuzumab-binding domain of ErbB2 (HER2) at defined N-glycosylation sites. Abrogation of ST6Gal1 expanded ErbB2 cellular half-life, stabilized ErbB dimers at cell membrane, decreased ErbB2 and EGFR activation, and sensitized ErbB2-dependent gastric cancer cells to trastuzumab-induced cytotoxicity.\",\n      \"method\": \"MS-based glycomic and glycoproteomic analysis of ErbB2 ectodomain, ST6Gal1 knockdown/OE, flow cytometry, Western blot, cytotoxicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific glycoproteomic mapping plus functional signaling and cytotoxicity outcomes, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33947960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1 sialylates EGFR in T-ALL cells. EGFR was demonstrated to be a substrate of ST6GAL1, and sialylated EGFR impacts PI3K/Akt pathway activity, contributing to drug-resistant phenotype.\",\n      \"method\": \"Mass spectrometry (N-glycan profiles), siRNA knockdown, Western blot, lectin staining, xenograft mouse models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS glycan profiling plus functional signaling assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"31096997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST6GAL1 sialylates c-Met in colorectal cancer cells. Sialylated c-Met activates the JAK2/STAT3 pathway, modulating CRC malignancy. ST6GAL1 is regulated by the HOTAIR/miR-214 axis.\",\n      \"method\": \"Lectin precipitation, Western blot, dual-luciferase reporter assay, RIP assay, in vivo xenograft/metastasis models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical substrate identification with pathway activation assays and in vivo models, single lab\",\n      \"pmids\": [\"31694696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST6GAL1 inhibits colorectal cancer metastasis by stabilizing ICAM-1 through sialylation. ST6GAL1 sialylation of ICAM-1 increases its protein stability (not its transcription) as demonstrated by cycloheximide chase assays and lectin precipitation. ST6GAL1 knockdown increased liver metastases in vivo.\",\n      \"method\": \"Lectin precipitation, cycloheximide (CHX) chase assay, PCR, transwell/wound healing assays, nude mouse liver metastasis model, tissue microarrays\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate sialylation assay with protein stability readout and in vivo metastasis model, single lab\",\n      \"pmids\": [\"31308754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST6GAL1 inhibits HCC metastasis by increasing α2,6-sialylation of MCAM (melanoma cell adhesion molecule). Sialylation of MCAM inhibits its interaction with galectin-3 and decreases MCAM expression on the cell surface, thereby suppressing migration and invasion.\",\n      \"method\": \"Metabolic labeling-based glycoproteomics, lectin pulldown, Co-IP, in vitro migration/invasion assays, in vivo metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycoproteomic substrate identification plus mechanistic dissection of galectin-3 interaction and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36528750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ST6GAL1 is required for maintaining pluripotency in human pluripotent stem cells (hPSCs). shRNA-mediated knockdown of ST6GAL1 decreased OCT4/POU5F1 protein levels and significantly impeded the induction of cellular pluripotency during somatic cell reprogramming, partially by interfering with endogenous POU5F1 and SOX2 expression.\",\n      \"method\": \"shRNA knockdown in hPSCs, lectin binding assays, qPCR/Western blot for pluripotency markers, sialyltransferase inhibitor treatment during reprogramming, iPSC generation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific molecular phenotype, pharmacological inhibition corroboration, single lab\",\n      \"pmids\": [\"26304831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST6GAL1-mediated α2,6-sialylation promotes glioblastoma growth via sialylation of PDGFRβ, ALCAM, and Neuropilin. ST6GAL1 KD in brain tumor-initiating cells (BTICs) decreased PDGFRβ α2,6-sialylation, total PDGFRβ protein levels, and PDGF-BB-induced receptor phosphorylation, reducing GBM growth and self-renewal.\",\n      \"method\": \"ST6GAL1 KD in BTICs, lectin binding assays, Western blot for PDGFRB levels and phosphorylation, orthotopic mouse tumor models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate sialylation confirmed with functional signaling and in vivo tumor growth data, multiple methods, single lab\",\n      \"pmids\": [\"36345944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular ST6GAL1 (from cancer exosomes or soluble recombinant enzyme) compensates for insufficient intrinsic ST6GAL1 to boost breast tumor cell proliferation and invasiveness in 3D cultures. Intrinsic ST6GAL1 KD decreased ST6GAL1 cargo in exosome-like vesicles and decreased tumor growth/invasion; extrinsic ST6GAL1 rescued these phenotypes. Novel cofactors in exosome-like particles potently amplify extracellular ST6GAL1 activity.\",\n      \"method\": \"shRNA knockdown, 3D culture invasion assays, exosome isolation, recombinant ST6GAL1 treatment, cell proliferation assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiments with extracellular enzyme, multiple assay types, single lab\",\n      \"pmids\": [\"35676533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular recombinant ST6GAL1 adheres to monocyte-macrophage lineage cells and catalytically sialylates the M-CSF receptor (M-CSF-R/CSF1R) on human THP-1 monocytes, activating M-CSF-R and initiating NFκB nuclear translocation and phosphorylation of ERK1/2 and AKT, promoting monocyte-macrophage development and survival.\",\n      \"method\": \"Recombinant ST6GAL1 treatment of primary mouse myeloid cells and THP-1 cells, gene expression profiling, lectin activity assays, Western blot for NFκB, ERK1/2, AKT phosphorylation\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — extracellular enzyme activity on defined receptor with intracellular signaling readout, single lab with multiple methods\",\n      \"pmids\": [\"35661210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Systemic (extracellular) ST6Gal-1 is a pro-survival factor for transitional B cells. Extrinsic ST6Gal-1 augmented BAFF-mediated activation of non-canonical NFκB, p38 MAPK, and PI3K/AKT pathways, and accelerated tyrosine phosphorylation after BCR stimulation. B cell-intrinsic ST6Gal-1 is specifically required for marginal zone B cell development.\",\n      \"method\": \"Mouse models segregating B cell-intrinsic vs extrinsic ST6Gal-1, ex vivo B cell exposure to recombinant ST6Gal-1, flow cytometry, signaling pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection of intrinsic vs extrinsic roles, signaling pathway identified, single lab\",\n      \"pmids\": [\"30294329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ST6Gal1 transcription in gliomas is silenced by DNA methylation within core promoter regions (P3 promoter), specifically through determination of AP2 transcription factor accessibility. Demethylation with 5-aza-dC reactivated ST6Gal1 expression, increased β1 integrin sialylation, and decreased adhesion to fibronectin.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment of glioma cell lines, qRT-PCR, primer extension, CAT reporter deletion analysis, lectin staining of β1 integrin, fibronectin adhesion assays\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with functional consequence (integrin sialylation and adhesion), single lab\",\n      \"pmids\": [\"27510958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SIAT1 (ST6GAL1) transcription in mature B-lymphocytes initiates at the P2 regulatory region. A 495 bp P2 segment containing AP2 and NF-κB sites in the 5'-flanking region and a 3' exon segment (positions +32 to +125) are required for efficient, cell-specific transcription. The +32 to +125 region also relieves translational restraints in B cells.\",\n      \"method\": \"CAT reporter assays, transfection in Louckes/Reh/HepG2 cells, deletion analysis, mRNA analysis\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter/regulatory dissection with multiple deletion constructs and cell type comparisons, single lab\",\n      \"pmids\": [\"10460832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-1β and IL-6 upregulate ST6GAL1 expression in pancreatic cancer cells via the P3 promoter. IL-1β activates NFκB which binds the ST6GAL1 P3 promoter; IL-6 activates STAT3 which binds the ST6GAL1 P3 promoter. Inhibitors of NFκB or STAT3 blocked cytokine-induced ST6GAL1 upregulation.\",\n      \"method\": \"Promoter reporter assays, CUT&RUN for transcription factor binding at P3 promoter, NFκB/STAT3 inhibitors, qRT-PCR and Western blot in PDAC cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct promoter binding demonstrated by CUT&RUN plus functional reporter assays with inhibitor validation, multiple orthogonal methods\",\n      \"pmids\": [\"39260693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1 knockdown in bronchial epithelial cells increased IL-6 expression and secretion. Cigarette smoke extract (CSE) exposure or BACE1 inhibition decreased ST6GAL1 secretion, reduced α2,6-sialylation, and increased IL-6 production, establishing a regulatory axis where BACE1-mediated ST6GAL1 cleavage controls the circulating vs. membrane pool and downstream IL-6 regulation.\",\n      \"method\": \"shRNA knockdown, CSE treatment, BACE1 inhibition, ELISA for ST6GAL1 and IL-6, flow cytometry for α2,6-sialylation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with functional signaling readout and pharmacological validation, single lab\",\n      \"pmids\": [\"34290711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST6GAL1-mediated sialylation promotes resistance to chemoradiation in rectal cancer by inhibiting apoptosis. ST6GAL1 protein increased after chemoradiation in patient-derived xenograft models and rectal cancer cell lines; ST6GAL1 knockdown increased apoptosis and decreased colony survival after chemoradiation treatment.\",\n      \"method\": \"Patient-derived xenograft models, organoid models, rectal cancer cell lines, Caspase-Glo apoptosis assays, colony formation assays, Western blot, lectin flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (PDX, organoids, cell lines) with functional apoptosis assay, single lab\",\n      \"pmids\": [\"35041825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1-mediated sialylation of MUC4β is induced by IL-13 in human airway epithelial cells; sialylated MUC4β has altered lectin binding and secretion properties. Both ST6GAL1 and MUC4β inhibit epithelial proliferation while promoting goblet cell differentiation in T2-high asthma.\",\n      \"method\": \"Primary HAEC cultures, IL-13 treatment, ST6GAL1 siRNA, lectin binding assays, proliferation/goblet cell differentiation assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary cell experiments with defined substrate and functional differentiation outcome, single lab\",\n      \"pmids\": [\"30730306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST6GAL1-mediated α2,6-sialylation of PECAM-1 on lung-tropic breast cancer cells promotes pulmonary extravasation through transhomophilic interaction with pulmonary endothelial PECAM-1, directing lung-tropic metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Lung-tropic cells also increased pulmonary endothelial permeability via exosomes in a non-cell-autonomous manner.\",\n      \"method\": \"ST6GAL1/PECAM-1 knockdown in lung-tropic breast cancer cells, in vivo lung metastasis models, pulmonary endothelial permeability assays, lectin-based sialylation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis models with substrate (PECAM-1) identification and mechanistic (transhomophilic PECAM-1 interaction) dissection, multiple methods\",\n      \"pmids\": [\"39786386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GAL1 sialylates E-cadherin, and this α2,6-sialylation of E-cadherin contributes to collective migration of uterine luminal epithelial cells during endometrial fold extension, thereby mediating uterine lumen closure during implantation.\",\n      \"method\": \"MALDI-TOF MS N-glycomic profiling, siRNA transfection, lectin immunoprecipitation, MS, wound healing and cell aggregation assays\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification by lectin-MS plus functional migration assay with siRNA knockdown, single lab\",\n      \"pmids\": [\"34957619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST6GAL1-mediated sialylation of PD-L1 is critical for its stability in colorectal cancer cells; ST6GAL1 knockdown leads to reduced PD-L1 protein stability and increased ubiquitination. ST6GAL1 knockdown in MC38 tumor-bearing mice enhanced the antitumor effect of anti-PD-L1 therapy.\",\n      \"method\": \"ST6GAL1 KO/KD, ubiquitination assays, Western blot, in vivo tumor mouse model with anti-PD-L1 therapy, single-cell analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate stability mechanism with in vivo immune checkpoint validation, single lab\",\n      \"pmids\": [\"40847469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of amyloid precursor protein (AbetaPP) in C2C12 myogenic cells increased both expression and secretion of ST6Gal1, consistent with BACE1-mediated proteolytic processing of ST6Gal1 as a substrate.\",\n      \"method\": \"AbetaPP overexpression in C2C12 cells, Western blot, immunofluorescence\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment without direct BACE1 activity assay, single lab, single method\",\n      \"pmids\": [\"20795944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial ST6GAL1 creates a pro-adhesive environment of α2,6-linked sialic acids that engage CD22 on circulating B cells and plasmablasts, promoting their recruitment to the inflamed gut in IBD. Dynamic adhesion assays showed CD22-α2,6-sialic acid interaction controls B cell adhesion, and in vivo homing of IBD B cells to inflamed colon was blocked by anti-CD22 antibodies in humanized mice.\",\n      \"method\": \"Flow cytometry, transcriptomics, immunofluorescence, dynamic adhesion assays, in vivo homing assays in humanized mice, anti-CD22 antibody blocking\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo homing assays with mechanistic blocking experiments, multiple methods, single lab\",\n      \"pmids\": [\"40491026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST6GAL1 sialylates BICD2 (BICD cargo adaptor 2), which affects the interaction between BICD2 and IFNGR1, thereby inhibiting IFNGR1 phosphorylation and the downstream JAK1/STAT1 signaling pathway, leading to reduced sensitivity to IFN-γ and immune escape in colorectal cancer.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry substrate identification, kinase phosphorylation chip, Western blot, in vivo tumor models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS substrate identification with IP-confirmed protein interaction and signaling pathway validation, single lab\",\n      \"pmids\": [\"41217711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ST6Gal1-mediated α2,6-sialylation of integrin β1 activates the integrin β1/FAK signaling pathway to promote proliferation and stemness in gestational trophoblastic disease cells. Inhibition of ST6Gal1 reduced α2,6-sialylation on integrin β1 and suppressed integrin β1/FAK pathway activation.\",\n      \"method\": \"Lectin pulldown, Western blot for FAK phosphorylation, ST6Gal1 OE/KD, proliferation/stemness assays\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate sialylation demonstrated with pathway activation readout, single lab\",\n      \"pmids\": [\"38490094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Plasma/hepatocyte-derived ST6Gal1 is NOT responsible for homeostatic IgG α2,6-sialylation. Mice lacking hepatocyte-expressed ST6Gal1 retained normal IgG α2,6-sialylation despite undetectable plasma ST6Gal1, and B cells were also not a redundant source. This negative result indicates IgG sialylation occurs by a different, as-yet unidentified mechanism.\",\n      \"method\": \"Conditional ST6Gal1 knockout (albumin-Cre for hepatocytes, B cell-specific KO), IgG glycan analysis\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-controlled conditional KO experiment, negative finding with clear mechanistic implication; contradicts some prior models\",\n      \"pmids\": [\"35746897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST6GAL1 sialylates LGALS3BP (a secreted glycoprotein) in colorectal cancer cells; knockdown of LGALS3BP significantly blocked ST6GAL1-driven proliferation, invasion, and chemoresistance. Sialidase treatment also blocked ST6GAL1 protumor activity, confirming sialylation dependence.\",\n      \"method\": \"N-glycoproteomic analysis, LGALS3BP knockdown, sialidase treatment, proliferation/invasion/chemoresistance assays\",\n      \"journal\": \"Biomolecules & biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycoproteomic substrate identification with functional validation and sialidase rescue, single lab\",\n      \"pmids\": [\"39937175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ST6GAL1 is a Golgi-resident sialyltransferase that catalyzes transfer of α2,6-linked sialic acids onto N-glycosylated proteins (using a CMP-sialic acid donor, with catalytic mechanism structurally defined at 2.4 Å); it operates cell-autonomously within the ER-Golgi secretory apparatus but is also released as an active extracellular enzyme (primarily from the liver via the P1 promoter) that remodels glycans on target cells (HSPCs, B cells, monocytes) to regulate hematopoiesis and immunity; its key substrates include EGFR (promoting dimerization, recycling, and downstream AKT/NFκB signaling), ErbB2, PDGFRB, integrin β1, ICAM-1, PECAM-1, MUC4β, PD-L1, MCAM, BICD2, E-cadherin, β-catenin, Necl-2/CADM1, and c-Met, with sialylation of these receptors modulating their stability, dimerization, signaling, trafficking, and protein interactions; ST6GAL1 expression is transcriptionally regulated by multiple promoters (P1 in liver, P2 in B cells, P3 in epithelial/cancer cells) controlled by NFκB, STAT3, AP2, and DNA methylation, and is upregulated in cancer by pro-inflammatory cytokines IL-1β and IL-6.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ST6GAL1 is a Golgi-resident β-galactoside α2,6-sialyltransferase that transfers sialic acid onto N-glycans of secreted and cell-surface glycoproteins, generating differentiation antigens such as CDw75/CD76 and operating within the secretory apparatus where its CMP-sialic acid donor site is assembled from conserved sialylmotif elements [#0, #1]. Within Golgi membranes ST6GAL1 first homo-oligomerizes in the ER and then engages B4GALT1 through noncatalytic charged surfaces, an interaction required for full catalytic activity of both enzymes in N-glycan synthesis [#2]. Beyond its cell-autonomous role, ST6GAL1 is released as an active extracellular enzyme, largely from the liver via the P1 promoter, that remodels glycans on remote target cells: circulatory enzyme sialylates marrow hematopoietic stem and progenitor cells, restraining myelopoiesis and late-stage granulopoiesis by attenuating G-CSF receptor/STAT3/C/EBPα signaling [#4, #5, #6], and acts on B-lineage cells by sialylating CD22 and CD45 to boost BAFF/BCR-driven survival, proliferation, and IgG production in a CD22-dependent manner [#14, #26]. A substantial body of work establishes ST6GAL1 as a regulator of receptor tyrosine kinase signaling through substrate sialylation: it sialylates EGFR to promote dimerization, Rab11-dependent recycling, and AKT/NFκB activation [#9], ErbB2/HER2 at its trastuzumab-binding domain to stabilize signaling-competent dimers [#17], PDGFRβ to sustain PDGF-driven growth [#23], and c-Met to drive JAK2/STAT3 activity [#19]. Through these and additional substrates—integrin β1/FAK [#39], β-catenin and VE-cadherin at endothelial junctions [#7, #13], E-cadherin in epithelial migration [#34], ICAM-1 and MCAM stability [#20, #21], PECAM-1 in lung-tropic extravasation [#33], PD-L1 stability and immune escape [#35], and BICD2-mediated control of IFNGR1/JAK1/STAT1 signaling [#38]—ST6GAL1 modulates receptor stability, trafficking, adhesion, and immune signaling, and it promotes pancreatic cancer initiation and progression in KRAS-driven models via EGFR-dependent acinar-to-ductal metaplasia [#15, #16]. ST6GAL1 transcription is governed by distinct promoters (P1 hepatic, P2 in B cells, P3 in epithelial/cancer cells) under control of NFκB, STAT3, AP2, and DNA methylation, and is induced in cancer by IL-1β and IL-6 [#28, #27, #29]. The membrane-versus-secreted balance is set by BACE1-mediated proteolytic cleavage [#7, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that ST6GAL1 is a Golgi enzyme whose sialylation activity generates defined cell-surface differentiation antigens, linking a glycosyltransferase directly to surface phenotype.\",\n      \"evidence\": \"Expression cloning, cDNA transfection, immunofluorescence, and neuraminidase sensitivity in COS cells\",\n      \"pmids\": [\"1730763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve catalytic mechanism or acceptor specificity at molecular level\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined cell-type-specific transcriptional control by mapping the P2 regulatory region driving ST6GAL1 expression in mature B cells, explaining lineage-restricted expression.\",\n      \"evidence\": \"CAT reporter and deletion analysis across B-cell and hepatic lines\",\n      \"pmids\": [\"10460832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect transcript variants to functional enzyme pools\", \"Other promoters not yet characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that hepatic, circulatory ST6GAL1 acts non-cell-autonomously to limit myelopoiesis, independent of serum glycoprotein sialylation, defining a systemic enzyme function.\",\n      \"evidence\": \"2D-DIGE, ex vivo colony formation, and P1 promoter-ablated mouse models\",\n      \"pmids\": [\"20529847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target cells and surface substrates on HSPCs not yet identified\", \"Single lab functional assays\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked the P1 promoter to systemic IgG-Fc sialylation, establishing the liver as the source of extracellular enzyme acting on circulating substrates.\",\n      \"evidence\": \"Siat1ΔP1 knock-in mouse with IgG Fc glycan analysis\",\n      \"pmids\": [\"22427662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of extracellular sialylation without cellular Golgi context unclear\", \"Later contradicted regarding homeostatic IgG sialylation source\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for catalysis, defining the CMP-sialic acid donor and acceptor binding architecture and a shared sialyltransferase framework.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Å with docking, MD, and active-site mutagenesis/kinetics of rat ST6GAL1\",\n      \"pmids\": [\"24155237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human enzyme structure not solved\", \"No structure with a glycoprotein acceptor bound\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified marrow HSPCs as the direct cellular target of circulatory ST6GAL1 and demonstrated the surface α2,6-sialylation depends on host blood enzyme, not endogenous HSPC expression.\",\n      \"evidence\": \"Bone marrow chimeras with SNA/PSL lectin binding, mass spectrometry, and flow cytometry\",\n      \"pmids\": [\"24425878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific glycoprotein substrates on HSPCs not defined\", \"Downstream signaling not resolved here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected extracellular ST6GAL1 to suppression of granulopoiesis through attenuated G-CSF receptor/STAT3/C/EBPα signaling, and showed BACE1 cleavage controls enzyme availability at endothelial junctions.\",\n      \"evidence\": \"Ex vivo HSPC exposure plus in vivo elevated-enzyme mouse model; PKC/BACE1 inhibition and SNA blotting in endothelial cells\",\n      \"pmids\": [\"28550122\", \"28091531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GCSFR sialylation not biochemically mapped\", \"BACE1 cleavage site on ST6GAL1 not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that ST6GAL1 requires interaction with B4GALT1 in Golgi membranes for full activity and assembles via ER homomers, revealing organizational control of N-glycan synthesis.\",\n      \"evidence\": \"Molecular docking, mutagenesis screens, and high-throughput live-cell FRET\",\n      \"pmids\": [\"31395657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the complex unresolved\", \"Effect on specific substrates not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ST6GAL1 as a regulator of EGFR signaling by sialylating the receptor to drive dimerization, recycling, and reduced degradation, providing a molecular basis for its oncogenic effects.\",\n      \"evidence\": \"Reciprocal OE/KD in ovarian cancer lines with TIRF, deconvolution microscopy, dimerization assays, and Rab11/LAMP1 colocalization\",\n      \"pmids\": [\"37660914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific EGFR N-glycosylation sites not mapped here\", \"Generality across receptor families addressed in separate studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized substrate sialylation as a mechanism modulating receptor stability and signaling across ErbB2, PDGFRβ, and MCAM, and demonstrated in vivo roles in metastasis and tumor growth.\",\n      \"evidence\": \"Site-specific glycoproteomics, lectin pulldowns, KD/OE, and orthotopic/metastasis mouse models across gastric, glioblastoma, and HCC systems\",\n      \"pmids\": [\"33947960\", \"36345944\", \"36528750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependent pro- versus anti-metastatic outcomes not unified mechanistically\", \"Substrate selectivity determinants unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revised the model of IgG sialylation by showing hepatocyte/plasma ST6GAL1 is dispensable for homeostatic IgG α2,6-sialylation, implicating an unidentified alternative mechanism.\",\n      \"evidence\": \"Conditional hepatocyte and B-cell ST6GAL1 knockouts with IgG glycan analysis\",\n      \"pmids\": [\"35746897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the responsible enzyme/source unknown\", \"Reconciliation with earlier P1 promoter findings incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated in vivo that ST6GAL1 drives KRAS-mutant pancreatic tumorigenesis through EGFR-dependent acinar-to-ductal metaplasia, linking substrate sialylation to cancer initiation.\",\n      \"evidence\": \"ST6GAL1 transgenic × KRASG12D GEM models, GEM-derived organoids, and ADM/EGFR activation assays\",\n      \"pmids\": [\"37643018\", \"34634466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other contributing substrates in PDAC not fully enumerated\", \"Therapeutic targetability not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined cytokine-driven transcriptional induction via the P3 promoter, showing IL-1β/NFκB and IL-6/STAT3 directly upregulate ST6GAL1, linking inflammation to glycan remodeling in cancer.\",\n      \"evidence\": \"CUT&RUN, promoter reporter assays, and NFκB/STAT3 inhibitors in PDAC lines\",\n      \"pmids\": [\"39260693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between P1/P2/P3 regulation in vivo not resolved\", \"Quantitative contribution of each TF unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ST6GAL1 substrate control to immune evasion and metastatic homing through PD-L1 stability, BICD2/IFNGR1 signaling, PECAM-1-mediated extravasation, and CD22-dependent B-cell recruitment in inflammation.\",\n      \"evidence\": \"KO/KD with ubiquitination, IP/MS, in vivo metastasis and anti-PD-L1 models, and humanized mouse homing assays\",\n      \"pmids\": [\"40847469\", \"41217711\", \"39786386\", \"40491026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of these parallel substrate pathways into a unified model lacking\", \"Site-specific sialylation mapping incomplete for several substrates\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The enzyme/source responsible for homeostatic IgG-Fc α2,6-sialylation and the determinants of ST6GAL1 substrate selectivity that produce opposing pro- versus anti-tumor outcomes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified alternative IgG-sialylating activity after exclusion of hepatic/B-cell ST6GAL1\", \"No structural or biochemical rule predicting which receptors ST6GAL1 stabilizes versus destabilizes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 9, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 17, 20, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 24, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 17, 20, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 17, 19, 23, 39]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 14, 26, 35, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 21, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"B4GALT1\", \"EGFR\", \"ErbB2\", \"PDGFRB\", \"CD22\", \"MCAM\", \"PECAM1\", \"BICD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}