{"gene":"ST3GAL1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2020,"finding":"ST3GAL1 is transcriptionally induced by the oncogenic SOX2-GLI1 transcriptional complex in melanoma, and ST3GAL1 promotes melanoma invasion by sialylating the receptor tyrosine kinase AXL, inducing AXL dimerization and activation.","method":"In vitro and in vivo silencing studies, glycosylated protein analysis, AXL dimerization/activation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, in vivo, protein glycosylation analysis, receptor activation assays), single lab but strong mechanistic resolution","pmids":["33203881"],"is_preprint":false},{"year":2019,"finding":"ST3GAL1 sialylates vasorin (VASN) with α2,3-linked sialic acid on O-glycans; this sialylation reduces VASN binding to TGF-β1 by 2–3 fold, thereby dampening TGF-β1/Smad2/Smad3 signaling and angiogenesis. TGF-β1 in turn transcriptionally upregulates ST3Gal1, forming a feedback regulatory loop.","method":"LC-MS/MS O-glycan analysis, neuraminidase treatment, HUVEC tube formation assay, Smad2/3 activation assays, ST3GAL1 silencing in MCF7 xenografts","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic substrate identification by mass spectrometry, functional angiogenesis assays, and in vivo xenograft validation with multiple orthogonal methods","pmids":["30252131"],"is_preprint":false},{"year":2020,"finding":"ST3GAL1 mediates O-linked sialylation of CD55, shifting O-glycan profile to disialylated core 2 structures; this sialylation protects cancer cells from complement-mediated lysis and reduces antibody-dependent cell-mediated cytotoxicity, functioning as an immune checkpoint mechanism.","method":"ST3GAL1 siRNA knockdown, tandem mass spectrometry of N- and O-linked oligosaccharides of CD55, C3 deposition assay, complement-mediated lysis assay, ADCC assay","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 1-2 — substrate identified by MS glycan profiling, functional immune evasion assays with specific mechanistic readouts","pmids":["33177111"],"is_preprint":false},{"year":2018,"finding":"ST3GAL1 mediates O-linked sialylation of GFRA1, which is required for GDNF-induced RET, AKT, and ERα phosphorylation in ER-positive breast cancer cells; GDNF also transcriptionally induces ST3GAL1, forming a positive feedback loop.","method":"ST3GAL1 silencing, phosphorylation assays (RET, AKT, ERα), GDNF-stimulation, GDNF-induced ST3GAL1 transcription measurement","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined signaling phenotype and feedback loop established, single lab","pmids":["30040982"],"is_preprint":false},{"year":2023,"finding":"ST3GAL1 glycosylates CD18 in activated CD8+ T cells, and ST3GAL1-mediated glycosylation of CD18 alters LFA-1 endocytic recycling, causing nonspecific tissue sequestration of T cells and impairing cancer-targeting migration of CAR T cells. βII-spectrin, a central LFA-1-associated cytoskeletal molecule, reverses this effect.","method":"CRISPR-Cas9 pooled in vivo loss-of-function screen, glycosylated protein analysis, LFA-1 endocytic recycling assays, CAR T cell in vivo tumor homing experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo CRISPR screen, substrate identification by glycoprotein analysis, mechanistic endocytic recycling assay, multiple orthogonal approaches","pmids":["37069398"],"is_preprint":false},{"year":2018,"finding":"ST3GAL1 overexpression in ovarian cancer cells increases cell migration, invasion, and resistance to paclitaxel; TGF-β1 increases ST3GAL1 expression and induces EMT, while ST3GAL1 knockdown inhibits EMT markers.","method":"ST3GAL1 overexpression/knockdown in ovarian cancer cell lines, in vitro migration/invasion assays, mouse xenograft model, EMT marker analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO/OE with defined cellular phenotype, in vivo validation, but no direct molecular substrate identified","pmids":["30375371"],"is_preprint":false},{"year":2020,"finding":"The lncRNA MEG3 suppresses ST3Gal1 transcription via modulation of the transcription factor c-Jun; ST3Gal1 sialylates EGFR to inhibit EGFR phosphorylation, thereby suppressing PI3K-AKT pathway activation in renal cell carcinoma.","method":"MEG3 overexpression/knockdown, bioinformatics identification of c-Jun binding to ST3Gal1 promoter, EGFR sialylation and phosphorylation assays, PI3K-AKT pathway analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — substrate (EGFR) and pathway (PI3K-AKT) identified with mechanistic follow-up, single lab","pmids":["32737220"],"is_preprint":false},{"year":2022,"finding":"Both ST3GAL1 and ST3GAL2 function as cellular O-glycan sialyltransferases, transferring sialic acid to Galβ1,3GalNAc; CD34, CD43, and GPIbα are major glycoprotein substrates for both enzymes in hematopoietic progenitor cells and megakaryocytes, while GPIIb O-sialylation relies predominantly on ST3GAL2. Loss of both enzymes dramatically impairs megakaryocyte proplatelet formation.","method":"ST3GAL1/ST3GAL2 double-knockout human iPSC lines, peanut agglutinin lectin binding assay, differentiation into HPCs and megakaryocytes, identification of GP substrates","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with substrate identification in living cells and specific functional phenotype (proplatelet formation), multiple orthogonal methods","pmids":["35507766"],"is_preprint":false},{"year":2016,"finding":"Human ST3GAL1 is a disulfide-containing type II transmembrane glycoprotein that catalyzes transfer of sialic acid from CMP-sialic acid to β-d-galactoside substrates including lactose, N-acetyllactosamine, and benzyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside. Active enzyme requires native disulfide bonds for proper folding.","method":"Recombinant expression in E. coli, co-expression with sulfhydryl oxidase/PDI/DsbC, in vitro sialylation assays with defined substrates","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic assay with defined substrates and mutagenesis/folding studies","pmids":["27166796"],"is_preprint":false},{"year":2016,"finding":"miR-4701-5p directly targets ST3GAL1 to reduce CML cell resistance to multiple chemotherapeutics; altered ST3GAL1 expression corresponds to the drug-resistant phenotype, and miR-4701-5p-mediated ST3GAL1 suppression converts adriamycin-resistant cells to susceptible in vivo.","method":"miRNA target validation, differential ST3GAL1 expression in drug-resistant vs. -sensitive CML cell lines, in vitro and in vivo drug resistance assays","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 — direct miRNA-target relationship with functional phenotype, single lab, limited mechanistic depth","pmids":["27088512"],"is_preprint":false},{"year":2024,"finding":"ST3Gal1 synthesizes sialoglycans that act as ligands for Siglec-7 and Siglec-9 immunoreceptors in prostate cancer, enabling immune evasion; ST3Gal1 levels are negatively regulated by androgen signaling, and this glyco-immune checkpoint can be modulated by enzalutamide.","method":"Siglec-7/9 ligand expression analysis, ST3Gal1 manipulation in prostate cancer cells, androgen signaling modulation, enzalutamide treatment","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Siglec ligand synthesis by ST3Gal1 established, functional immune evasion readout, androgen regulation demonstrated, single lab","pmids":["38448753"],"is_preprint":false},{"year":2025,"finding":"ST3GAL1-mediated sialylation of NRP1 increases NRP1 binding affinity toward EGFR; ST3GAL1 silencing impairs cell migration and wound healing through reduced CAPN2 activity downstream of diminished EGF/EGFR signaling, and sensitizes cells to cetuximab.","method":"ST3GAL1 silencing, identification of NRP1 as ST3GAL1 substrate, EGFR-NRP1 binding affinity measurements, CAPN2 activity assays, wound healing and migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — substrate identified with functional consequence on EGFR signaling, migration assays, and therapeutic sensitivity, single lab","pmids":["40024474"],"is_preprint":false},{"year":2026,"finding":"RANKL activates c-FOS to drive ST3GAL1 transcription in osteoclasts, whereas estrogen-bound ERα competes with TRAF6 and suppresses c-FOS-dependent ST3GAL1 induction; sialidase treatment in estrogen-deficient models reduces osteoclast-mediated bone loss, mimicking estradiol effects.","method":"RANKL stimulation, c-FOS and ERα binding studies, single-cell RNA sequencing of human bone, sialidase treatment in vivo estrogen-deficient models","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulatory mechanism identified with in vivo functional validation, single lab","pmids":["41680135"],"is_preprint":false},{"year":2024,"finding":"ST3GAL1 promotes iCCA malignancy through O-glycosylation changes that activate the NF-κB signaling pathway; miR-320b acts as a post-transcriptional repressor of ST3GAL1, suppressing ST3GAL1 expression and reducing iCCA cell proliferation, migration, and invasion.","method":"ST3GAL1 overexpression, proteomic analysis, glycoproteomics of O-glycosylation, miR-320b target validation, NF-κB pathway analysis","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway identified by proteomics with functional KD data and post-transcriptional regulation, single lab","pmids":["39069074"],"is_preprint":false},{"year":2025,"finding":"ST3GAL1 directly glycosylates VEGF-A and activates FAK/paxillin signaling in endometrial cancer, promoting VEGF-A expression and EMT; ST3GAL1 inhibition with soyasaponin I reduced VEGF-A signaling and tumor growth in vivo, with enhanced effect in combination with bevacizumab.","method":"Duolink proximity ligation assay, co-immunoprecipitation, ST3GAL1 genetic inhibition and pharmacological inhibition (soyasaponin I), xenograft models, FAK/paxillin pathway analysis","journal":"International journal of gynaecology and obstetrics","confidence":"Medium","confidence_rationale":"Tier 2 — VEGF-A identified as substrate by PLA and Co-IP, downstream FAK/paxillin pathway and in vivo validation, single lab","pmids":["40497576"],"is_preprint":false},{"year":2026,"finding":"ST3GAL1 directly binds to MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, and invasion; treatment with the sialyltransferase inhibitor Lith-O-Asp or MUCL1 knockdown reverses these protumorigenic phenotypes.","method":"Co-IP, sialylation assays, ST3GAL1 KD/OE with MUCL1 stability and degradation assays, in vivo tumor and lung metastasis models","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding and sialylation of MUCL1 established by Co-IP, functional rescue experiments, in vivo validation, single lab","pmids":["41770470"],"is_preprint":false},{"year":2024,"finding":"A continuous universal glycosyltransferase assay (UGC) established kinetic parameters for ST3GAL1; soyasaponin1 exhibits time-dependent inhibition of ST3GAL1 with an IC50 of 37 μM, making ST3GAL1 the most responsive of the tested enzymes (ST3GAL1 > FUT1 > C1GALT1).","method":"Fluorescence spectrophotometry-based continuous enzymatic assay with kinase coupling, dose-response inhibition measurements","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro kinetic assay with inhibitor characterization, single study","pmids":["38645360"],"is_preprint":false},{"year":2017,"finding":"Androgen-androgen receptor (AR) signaling negatively regulates ST3GAL1 (and ST3GAL4) expression in the submandibular gland, modulating MUC10 sialylation; this influences sex differences in oral commensal microbiota composition.","method":"Androgen/AR signaling manipulation, neuraminidase treatment, SDS-PAGE mobility shift of MUC10, ST3GAL1 expression analysis, microbiota profiling","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — androgen-AR regulation of ST3GAL1 shown, functional consequence on mucin sialylation demonstrated, but mechanistic depth limited","pmids":["39572079"],"is_preprint":false}],"current_model":"ST3GAL1 is a type II transmembrane sialyltransferase that catalyzes the transfer of α2,3-linked sialic acid from CMP-sialic acid to Galβ1,3GalNAc (core 1 O-glycan) structures on multiple glycoprotein substrates including AXL, CD55, GFRA1, EGFR, NRP1, VASN, CD18, CD34, CD43, GPIbα, MUCL1, and VEGF-A; substrate sialylation modulates downstream signaling (AXL dimerization/activation, EGFR/NRP1 interaction, GDNF/GFRA1/RET pathway, TGF-β/VASN axis), immune evasion (Siglec-7/9 ligand presentation, CD55-mediated complement resistance, LFA-1 recycling in T cells), and cancer malignancy, with transcription regulated by SOX2-GLI1, c-FOS/RANKL, TGF-β1, GDNF, and androgen-AR signaling."},"narrative":{"teleology":[{"year":2016,"claim":"Establishing the core enzymatic identity of ST3GAL1: recombinant ST3GAL1 was shown to require native disulfide bonds for activity and to transfer sialic acid from CMP-sialic acid to β-d-galactoside substrates including lactose and N-acetyllactosamine in vitro, defining it as a bona fide sialyltransferase with characterized substrate preferences.","evidence":"Recombinant expression in E. coli with oxidative folding chaperones, in vitro sialylation assays with defined substrates","pmids":["27166796"],"confidence":"High","gaps":["No crystal structure of human ST3GAL1 available","Kinetic parameters for physiological O-glycan substrates not determined in this study","Catalytic mechanism at atomic resolution unresolved"]},{"year":2018,"claim":"Linking ST3GAL1 to specific receptor signaling cascades: ST3GAL1 was found to sialylate GFRA1, enabling GDNF-induced RET/AKT/ERα activation in breast cancer, with GDNF transcriptionally inducing ST3GAL1 to form a positive feedback loop — establishing the paradigm that ST3GAL1 modifies individual receptor glycoproteins to control ligand-driven signaling.","evidence":"ST3GAL1 silencing with phosphorylation assays for RET, AKT, ERα in ER+ breast cancer cells; GDNF stimulation and ST3GAL1 transcript measurement","pmids":["30040982"],"confidence":"Medium","gaps":["Specific O-glycan sites on GFRA1 modified by ST3GAL1 not mapped","Whether sialylation alters GFRA1-GDNF binding affinity not directly measured"]},{"year":2019,"claim":"Demonstrating that ST3GAL1 sialylation can attenuate rather than enhance signaling: sialylation of vasorin (VASN) reduced its binding to TGF-β1 by 2–3 fold, dampening Smad2/3 signaling and angiogenesis, while TGF-β1 itself transcriptionally induced ST3GAL1, revealing a negative feedback loop distinct from the positive feedback with GDNF/GFRA1.","evidence":"LC-MS/MS O-glycan analysis, neuraminidase treatment, HUVEC tube formation, Smad activation assays, MCF7 xenografts","pmids":["30252131"],"confidence":"High","gaps":["Whether VASN sialylation affects other TGF-β superfamily ligands unknown","Structural basis for how sialylation reduces VASN-TGF-β1 binding not determined"]},{"year":2020,"claim":"Expanding substrate repertoire to immune regulators and oncogenic receptors: ST3GAL1 was shown to sialylate CD55 (generating disialyl core 2 O-glycans that protect cancer cells from complement lysis and ADCC) and AXL (inducing dimerization/activation downstream of SOX2-GLI1), broadening the functional scope from growth factor signaling to immune evasion and oncogene activation.","evidence":"Mass spectrometry of CD55 O-glycans after ST3GAL1 knockdown, complement lysis/ADCC assays; AXL dimerization assays with in vivo melanoma models","pmids":["33177111","33203881"],"confidence":"High","gaps":["Whether CD55 sialylation also affects complement regulatory function beyond protecting from lysis not tested","Whether other sialyltransferases compensate for ST3GAL1 loss on AXL or CD55 not examined"]},{"year":2020,"claim":"Revealing context-dependent signaling outcomes: in renal cell carcinoma, ST3GAL1-mediated sialylation of EGFR inhibited EGFR phosphorylation and suppressed PI3K-AKT signaling, contrasting with contexts where ST3GAL1 promotes oncogenic signaling, and ST3GAL1 transcription was regulated by the lncRNA MEG3 via c-Jun.","evidence":"MEG3 overexpression/knockdown, c-Jun binding to ST3GAL1 promoter, EGFR sialylation and phosphorylation assays","pmids":["32737220"],"confidence":"Medium","gaps":["Whether EGFR inhibition by sialylation is specific to the O-glycan versus N-glycan context not resolved","Apparent contradiction with studies showing ST3GAL1 promotes oncogenic EGFR signaling in other contexts not mechanistically reconciled"]},{"year":2022,"claim":"Establishing physiological hematopoietic substrates and functional redundancy with ST3GAL2: double knockout of ST3GAL1/ST3GAL2 in iPSC-derived megakaryocytes identified CD34, CD43, and GPIbα as major O-glycan substrates and revealed that both enzymes are required for proplatelet formation, defining a non-cancer physiological role.","evidence":"ST3GAL1/ST3GAL2 double-KO iPSC lines, PNA lectin binding, megakaryocyte differentiation, substrate identification","pmids":["35507766"],"confidence":"High","gaps":["Individual contributions of ST3GAL1 versus ST3GAL2 to each substrate not fully deconvolved","In vivo platelet phenotype in animal models not reported"]},{"year":2023,"claim":"Discovering a T cell-intrinsic role: an in vivo CRISPR screen identified ST3GAL1 as a glycosylation modifier of CD18 in CD8+ T cells; ST3GAL1-mediated CD18 sialylation altered LFA-1 endocytic recycling, causing nonspecific tissue sequestration and impairing CAR T cell tumor homing, establishing ST3GAL1 as a cell-autonomous regulator of T cell trafficking.","evidence":"Pooled in vivo CRISPR-Cas9 loss-of-function screen, glycoprotein analysis, LFA-1 recycling assays, CAR T cell homing experiments","pmids":["37069398"],"confidence":"High","gaps":["Whether ST3GAL1 deletion improves human CAR T cell efficacy in clinical settings unknown","Mechanism by which βII-spectrin reverses ST3GAL1-dependent LFA-1 mislocalization not fully elucidated"]},{"year":2024,"claim":"Connecting ST3GAL1 to inhibitory Siglec ligand synthesis and androgen regulation: ST3GAL1-synthesized sialoglycans serve as ligands for Siglec-7/9 in prostate cancer, with androgen-AR signaling negatively regulating ST3GAL1 expression, providing a mechanistic link between hormone signaling and glyco-immune evasion.","evidence":"Siglec-7/9 ligand expression analysis, ST3GAL1 manipulation, androgen signaling modulation, enzalutamide treatment in prostate cancer cells","pmids":["38448753"],"confidence":"Medium","gaps":["Specific glycoprotein carriers of Siglec-7/9 ligands generated by ST3GAL1 not identified","Whether enzalutamide-mediated ST3GAL1 induction enhances immune evasion in patients not tested"]},{"year":2025,"claim":"Identifying NRP1 and VEGF-A as ST3GAL1 substrates with distinct signaling outputs: sialylation of NRP1 increased its affinity for EGFR and activated downstream CAPN2/migration signaling, while sialylation of VEGF-A activated FAK/paxillin signaling in endometrial cancer, further expanding the substrate-to-pathway map.","evidence":"ST3GAL1 silencing, NRP1-EGFR binding affinity measurements, CAPN2 activity assays; Duolink PLA and Co-IP for VEGF-A, xenograft models with soyasaponin I inhibitor","pmids":["40024474","40497576"],"confidence":"Medium","gaps":["Whether NRP1 sialylation by ST3GAL1 occurs at O-glycan or N-glycan sites not resolved","Specificity of soyasaponin I for ST3GAL1 over other sialyltransferases in vivo not established"]},{"year":2026,"claim":"Resolving transcriptional regulation in osteoclasts and identifying MUCL1 as a stability-modulating substrate: RANKL/c-FOS drives ST3GAL1 transcription in osteoclasts with estrogen-ERα opposing this via TRAF6 competition, linking ST3GAL1 to bone homeostasis; separately, ST3GAL1 sialylation of MUCL1 stabilizes the protein to promote breast cancer metastasis.","evidence":"RANKL stimulation with c-FOS/ERα binding studies, scRNA-seq of human bone, sialidase treatment in estrogen-deficient models; Co-IP, MUCL1 stability/degradation assays, in vivo metastasis models","pmids":["41680135","41770470"],"confidence":"Medium","gaps":["Whether ST3GAL1 sialylation of specific osteoclast substrates mediates the bone loss phenotype not determined","Degradation pathway (proteasomal vs. lysosomal) for desialylated MUCL1 not identified"]},{"year":null,"claim":"A high-resolution structural model of human ST3GAL1 with bound substrate/donor, a comprehensive map of the O-glycosites it modifies on each substrate, and in vivo genetic studies distinguishing ST3GAL1 from compensating sialyltransferases in normal tissue homeostasis remain outstanding gaps.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of human ST3GAL1","Site-specific O-glycan modification mapping incomplete for most substrates","Conditional knockout phenotypes in non-cancer tissues largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,4,7,8,11,14,15]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3,6,11,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,15]}],"complexes":[],"partners":["AXL","VASN","GFRA1","CD55","ITGB2","NRP1","MUCL1","VEGFA"],"other_free_text":[]},"mechanistic_narrative":"ST3GAL1 is a type II transmembrane sialyltransferase that transfers α2,3-linked sialic acid from CMP-sialic acid to Galβ1,3GalNAc (core 1) O-glycan structures on a broad range of glycoprotein substrates, thereby modulating receptor signaling, immune recognition, and cell adhesion. Identified substrates include AXL, VASN, GFRA1, EGFR, NRP1, CD55, CD18, CD34, CD43, GPIbα, MUCL1, and VEGF-A; sialylation of these targets controls diverse downstream pathways including AXL dimerization/activation, TGF-β1/Smad signaling, GDNF/RET/AKT signaling, EGFR/PI3K-AKT signaling, FAK/paxillin signaling, NF-κB activation, and LFA-1 endocytic recycling in T cells [PMID:27166796, PMID:33203881, PMID:30040982, PMID:30252131, PMID:37069398, PMID:40024474, PMID:39069074, PMID:40497576]. ST3GAL1 also generates Siglec-7/9 ligands and modifies CD55 to confer complement resistance, establishing it as a glyco-immune checkpoint that promotes immune evasion [PMID:33177111, PMID:38448753]. ST3GAL1 transcription is regulated by SOX2-GLI1, c-FOS/RANKL, TGF-β1, GDNF, and androgen-AR signaling, and is post-transcriptionally repressed by miR-4701-5p and miR-320b, integrating ST3GAL1 into multiple oncogenic and physiological feedback circuits [PMID:33203881, PMID:30252131, PMID:30040982, PMID:41680135, PMID:27088512, PMID:39069074]."},"prefetch_data":{"uniprot":{"accession":"Q11201","full_name":"CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1","aliases":["Gal-NAc6S","Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase","Monosialoganglioside sialyltransferase","SIATFL","ST3Gal I","ST3GalI","ST3GalA.1","ST3O","Sialyltransferase 4A","SIAT4-A"],"length_aa":340,"mass_kda":39.1,"function":"A beta-galactoside alpha2->3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids (PubMed:31784620, PubMed:8027041). Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc-terminated glycoconjugates through an alpha2-3 linkage (PubMed:31784620, PubMed:8027041, PubMed:31719620). Adds sialic acid to the core 1 O-glycan, Galbeta-(1->3)-GalNAc-O-Ser/Thr, which is a major structure of mucin-type O-glycans. As part of a homeostatic mechanism that regulates CD8-positive T cell numbers, sialylates core 1 O-glycans of T cell glycoproteins, SPN/CD43 and PTPRC/CD45. Prevents premature apoptosis of thymic CD8-positive T cells prior to peripheral emigration, whereas in the secondary lymphoid organs controls the survival of CD8-positive memory T cells generated following a successful immune response (By similarity). Transfers sialic acid to asialofetuin, presumably onto Galbeta-(1->3)-GalNAc-O-Ser (By similarity). Sialylates GM1a, GA1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively (By similarity) (PubMed:8027041)","subcellular_location":"Golgi apparatus, Golgi stack membrane; Golgi apparatus, trans-Golgi network membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q11201/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ST3GAL1","classification":"Not Classified","n_dependent_lines":101,"n_total_lines":1208,"dependency_fraction":0.0836092715231788},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ST3GAL1","total_profiled":1310},"omim":[{"mim_id":"607188","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 2; ST3GAL2","url":"https://www.omim.org/entry/607188"},{"mim_id":"607187","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 1; ST3GAL1","url":"https://www.omim.org/entry/607187"},{"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":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ST3GAL1"},"hgnc":{"alias_symbol":["ST3O","SIATFL","ST3GalA.1"],"prev_symbol":["SIAT4A"]},"alphafold":{"accession":"Q11201","domains":[{"cath_id":"3.90.1480.20","chopping":"71-336","consensus_level":"high","plddt":95.0817,"start":71,"end":336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11201","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q11201-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q11201-F1-predicted_aligned_error_v6.png","plddt_mean":90.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ST3GAL1","jax_strain_url":"https://www.jax.org/strain/search?query=ST3GAL1"},"sequence":{"accession":"Q11201","fasta_url":"https://rest.uniprot.org/uniprotkb/Q11201.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q11201/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11201"}},"corpus_meta":[{"pmid":"30375371","id":"PMC_30375371","title":"Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-β1-induced EMT and confers paclitaxel resistance in ovarian cancer.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30375371","citation_count":152,"is_preprint":false},{"pmid":"33203881","id":"PMC_33203881","title":"ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33203881","citation_count":76,"is_preprint":false},{"pmid":"30252131","id":"PMC_30252131","title":"Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30252131","citation_count":59,"is_preprint":false},{"pmid":"33177111","id":"PMC_33177111","title":"Sialylation of CD55 by ST3GAL1 Facilitates Immune Evasion in Cancer.","date":"2020","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/33177111","citation_count":48,"is_preprint":false},{"pmid":"37069398","id":"PMC_37069398","title":"ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors.","date":"2023","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37069398","citation_count":40,"is_preprint":false},{"pmid":"30040982","id":"PMC_30040982","title":"Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30040982","citation_count":39,"is_preprint":false},{"pmid":"38448753","id":"PMC_38448753","title":"ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38448753","citation_count":26,"is_preprint":false},{"pmid":"32737220","id":"PMC_32737220","title":"The lncRNA MEG3 mediates renal cell cancer progression by regulating ST3Gal1 transcription and EGFR sialylation.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32737220","citation_count":24,"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":24,"is_preprint":false},{"pmid":"27088512","id":"PMC_27088512","title":"Alpha-2, 3-sialyltransferases regulate the multidrug resistance of chronic myeloid leukemia through miR-4701-5p targeting ST3GAL1.","date":"2016","source":"Laboratory investigation; a journal of technical methods and 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cells","date":"2024-05-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.13.593990","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18646,"output_tokens":4643,"usd":0.062792},"stage2":{"model":"claude-opus-4-6","input_tokens":8185,"output_tokens":3609,"usd":0.196725},"total_usd":0.259517,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"ST3GAL1 is transcriptionally induced by the oncogenic SOX2-GLI1 transcriptional complex in melanoma, and ST3GAL1 promotes melanoma invasion by sialylating the receptor tyrosine kinase AXL, inducing AXL dimerization and activation.\",\n      \"method\": \"In vitro and in vivo silencing studies, glycosylated protein analysis, AXL dimerization/activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, in vivo, protein glycosylation analysis, receptor activation assays), single lab but strong mechanistic resolution\",\n      \"pmids\": [\"33203881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST3GAL1 sialylates vasorin (VASN) with α2,3-linked sialic acid on O-glycans; this sialylation reduces VASN binding to TGF-β1 by 2–3 fold, thereby dampening TGF-β1/Smad2/Smad3 signaling and angiogenesis. TGF-β1 in turn transcriptionally upregulates ST3Gal1, forming a feedback regulatory loop.\",\n      \"method\": \"LC-MS/MS O-glycan analysis, neuraminidase treatment, HUVEC tube formation assay, Smad2/3 activation assays, ST3GAL1 silencing in MCF7 xenografts\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic substrate identification by mass spectrometry, functional angiogenesis assays, and in vivo xenograft validation with multiple orthogonal methods\",\n      \"pmids\": [\"30252131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ST3GAL1 mediates O-linked sialylation of CD55, shifting O-glycan profile to disialylated core 2 structures; this sialylation protects cancer cells from complement-mediated lysis and reduces antibody-dependent cell-mediated cytotoxicity, functioning as an immune checkpoint mechanism.\",\n      \"method\": \"ST3GAL1 siRNA knockdown, tandem mass spectrometry of N- and O-linked oligosaccharides of CD55, C3 deposition assay, complement-mediated lysis assay, ADCC assay\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — substrate identified by MS glycan profiling, functional immune evasion assays with specific mechanistic readouts\",\n      \"pmids\": [\"33177111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST3GAL1 mediates O-linked sialylation of GFRA1, which is required for GDNF-induced RET, AKT, and ERα phosphorylation in ER-positive breast cancer cells; GDNF also transcriptionally induces ST3GAL1, forming a positive feedback loop.\",\n      \"method\": \"ST3GAL1 silencing, phosphorylation assays (RET, AKT, ERα), GDNF-stimulation, GDNF-induced ST3GAL1 transcription measurement\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined signaling phenotype and feedback loop established, single lab\",\n      \"pmids\": [\"30040982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ST3GAL1 glycosylates CD18 in activated CD8+ T cells, and ST3GAL1-mediated glycosylation of CD18 alters LFA-1 endocytic recycling, causing nonspecific tissue sequestration of T cells and impairing cancer-targeting migration of CAR T cells. βII-spectrin, a central LFA-1-associated cytoskeletal molecule, reverses this effect.\",\n      \"method\": \"CRISPR-Cas9 pooled in vivo loss-of-function screen, glycosylated protein analysis, LFA-1 endocytic recycling assays, CAR T cell in vivo tumor homing experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo CRISPR screen, substrate identification by glycoprotein analysis, mechanistic endocytic recycling assay, multiple orthogonal approaches\",\n      \"pmids\": [\"37069398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ST3GAL1 overexpression in ovarian cancer cells increases cell migration, invasion, and resistance to paclitaxel; TGF-β1 increases ST3GAL1 expression and induces EMT, while ST3GAL1 knockdown inhibits EMT markers.\",\n      \"method\": \"ST3GAL1 overexpression/knockdown in ovarian cancer cell lines, in vitro migration/invasion assays, mouse xenograft model, EMT marker analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/OE with defined cellular phenotype, in vivo validation, but no direct molecular substrate identified\",\n      \"pmids\": [\"30375371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA MEG3 suppresses ST3Gal1 transcription via modulation of the transcription factor c-Jun; ST3Gal1 sialylates EGFR to inhibit EGFR phosphorylation, thereby suppressing PI3K-AKT pathway activation in renal cell carcinoma.\",\n      \"method\": \"MEG3 overexpression/knockdown, bioinformatics identification of c-Jun binding to ST3Gal1 promoter, EGFR sialylation and phosphorylation assays, PI3K-AKT pathway analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — substrate (EGFR) and pathway (PI3K-AKT) identified with mechanistic follow-up, single lab\",\n      \"pmids\": [\"32737220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Both ST3GAL1 and ST3GAL2 function as cellular O-glycan sialyltransferases, transferring sialic acid to Galβ1,3GalNAc; CD34, CD43, and GPIbα are major glycoprotein substrates for both enzymes in hematopoietic progenitor cells and megakaryocytes, while GPIIb O-sialylation relies predominantly on ST3GAL2. Loss of both enzymes dramatically impairs megakaryocyte proplatelet formation.\",\n      \"method\": \"ST3GAL1/ST3GAL2 double-knockout human iPSC lines, peanut agglutinin lectin binding assay, differentiation into HPCs and megakaryocytes, identification of GP substrates\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with substrate identification in living cells and specific functional phenotype (proplatelet formation), multiple orthogonal methods\",\n      \"pmids\": [\"35507766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human ST3GAL1 is a disulfide-containing type II transmembrane glycoprotein that catalyzes transfer of sialic acid from CMP-sialic acid to β-d-galactoside substrates including lactose, N-acetyllactosamine, and benzyl 2-acetamido-2-deoxy-3-O-(β-d-galactopyranosyl)-α-d-galactopyranoside. Active enzyme requires native disulfide bonds for proper folding.\",\n      \"method\": \"Recombinant expression in E. coli, co-expression with sulfhydryl oxidase/PDI/DsbC, in vitro sialylation assays with defined substrates\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay with defined substrates and mutagenesis/folding studies\",\n      \"pmids\": [\"27166796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-4701-5p directly targets ST3GAL1 to reduce CML cell resistance to multiple chemotherapeutics; altered ST3GAL1 expression corresponds to the drug-resistant phenotype, and miR-4701-5p-mediated ST3GAL1 suppression converts adriamycin-resistant cells to susceptible in vivo.\",\n      \"method\": \"miRNA target validation, differential ST3GAL1 expression in drug-resistant vs. -sensitive CML cell lines, in vitro and in vivo drug resistance assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct miRNA-target relationship with functional phenotype, single lab, limited mechanistic depth\",\n      \"pmids\": [\"27088512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ST3Gal1 synthesizes sialoglycans that act as ligands for Siglec-7 and Siglec-9 immunoreceptors in prostate cancer, enabling immune evasion; ST3Gal1 levels are negatively regulated by androgen signaling, and this glyco-immune checkpoint can be modulated by enzalutamide.\",\n      \"method\": \"Siglec-7/9 ligand expression analysis, ST3Gal1 manipulation in prostate cancer cells, androgen signaling modulation, enzalutamide treatment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Siglec ligand synthesis by ST3Gal1 established, functional immune evasion readout, androgen regulation demonstrated, single lab\",\n      \"pmids\": [\"38448753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL1-mediated sialylation of NRP1 increases NRP1 binding affinity toward EGFR; ST3GAL1 silencing impairs cell migration and wound healing through reduced CAPN2 activity downstream of diminished EGF/EGFR signaling, and sensitizes cells to cetuximab.\",\n      \"method\": \"ST3GAL1 silencing, identification of NRP1 as ST3GAL1 substrate, EGFR-NRP1 binding affinity measurements, CAPN2 activity assays, wound healing and migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate identified with functional consequence on EGFR signaling, migration assays, and therapeutic sensitivity, single lab\",\n      \"pmids\": [\"40024474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RANKL activates c-FOS to drive ST3GAL1 transcription in osteoclasts, whereas estrogen-bound ERα competes with TRAF6 and suppresses c-FOS-dependent ST3GAL1 induction; sialidase treatment in estrogen-deficient models reduces osteoclast-mediated bone loss, mimicking estradiol effects.\",\n      \"method\": \"RANKL stimulation, c-FOS and ERα binding studies, single-cell RNA sequencing of human bone, sialidase treatment in vivo estrogen-deficient models\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulatory mechanism identified with in vivo functional validation, single lab\",\n      \"pmids\": [\"41680135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ST3GAL1 promotes iCCA malignancy through O-glycosylation changes that activate the NF-κB signaling pathway; miR-320b acts as a post-transcriptional repressor of ST3GAL1, suppressing ST3GAL1 expression and reducing iCCA cell proliferation, migration, and invasion.\",\n      \"method\": \"ST3GAL1 overexpression, proteomic analysis, glycoproteomics of O-glycosylation, miR-320b target validation, NF-κB pathway analysis\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway identified by proteomics with functional KD data and post-transcriptional regulation, single lab\",\n      \"pmids\": [\"39069074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ST3GAL1 directly glycosylates VEGF-A and activates FAK/paxillin signaling in endometrial cancer, promoting VEGF-A expression and EMT; ST3GAL1 inhibition with soyasaponin I reduced VEGF-A signaling and tumor growth in vivo, with enhanced effect in combination with bevacizumab.\",\n      \"method\": \"Duolink proximity ligation assay, co-immunoprecipitation, ST3GAL1 genetic inhibition and pharmacological inhibition (soyasaponin I), xenograft models, FAK/paxillin pathway analysis\",\n      \"journal\": \"International journal of gynaecology and obstetrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — VEGF-A identified as substrate by PLA and Co-IP, downstream FAK/paxillin pathway and in vivo validation, single lab\",\n      \"pmids\": [\"40497576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ST3GAL1 directly binds to MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, and invasion; treatment with the sialyltransferase inhibitor Lith-O-Asp or MUCL1 knockdown reverses these protumorigenic phenotypes.\",\n      \"method\": \"Co-IP, sialylation assays, ST3GAL1 KD/OE with MUCL1 stability and degradation assays, in vivo tumor and lung metastasis models\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding and sialylation of MUCL1 established by Co-IP, functional rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"41770470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A continuous universal glycosyltransferase assay (UGC) established kinetic parameters for ST3GAL1; soyasaponin1 exhibits time-dependent inhibition of ST3GAL1 with an IC50 of 37 μM, making ST3GAL1 the most responsive of the tested enzymes (ST3GAL1 > FUT1 > C1GALT1).\",\n      \"method\": \"Fluorescence spectrophotometry-based continuous enzymatic assay with kinase coupling, dose-response inhibition measurements\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinetic assay with inhibitor characterization, single study\",\n      \"pmids\": [\"38645360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Androgen-androgen receptor (AR) signaling negatively regulates ST3GAL1 (and ST3GAL4) expression in the submandibular gland, modulating MUC10 sialylation; this influences sex differences in oral commensal microbiota composition.\",\n      \"method\": \"Androgen/AR signaling manipulation, neuraminidase treatment, SDS-PAGE mobility shift of MUC10, ST3GAL1 expression analysis, microbiota profiling\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — androgen-AR regulation of ST3GAL1 shown, functional consequence on mucin sialylation demonstrated, but mechanistic depth limited\",\n      \"pmids\": [\"39572079\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ST3GAL1 is a type II transmembrane sialyltransferase that catalyzes the transfer of α2,3-linked sialic acid from CMP-sialic acid to Galβ1,3GalNAc (core 1 O-glycan) structures on multiple glycoprotein substrates including AXL, CD55, GFRA1, EGFR, NRP1, VASN, CD18, CD34, CD43, GPIbα, MUCL1, and VEGF-A; substrate sialylation modulates downstream signaling (AXL dimerization/activation, EGFR/NRP1 interaction, GDNF/GFRA1/RET pathway, TGF-β/VASN axis), immune evasion (Siglec-7/9 ligand presentation, CD55-mediated complement resistance, LFA-1 recycling in T cells), and cancer malignancy, with transcription regulated by SOX2-GLI1, c-FOS/RANKL, TGF-β1, GDNF, and androgen-AR signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ST3GAL1 is a type II transmembrane sialyltransferase that transfers α2,3-linked sialic acid from CMP-sialic acid to Galβ1,3GalNAc (core 1) O-glycan structures on a broad range of glycoprotein substrates, thereby modulating receptor signaling, immune recognition, and cell adhesion. Identified substrates include AXL, VASN, GFRA1, EGFR, NRP1, CD55, CD18, CD34, CD43, GPIbα, MUCL1, and VEGF-A; sialylation of these targets controls diverse downstream pathways including AXL dimerization/activation, TGF-β1/Smad signaling, GDNF/RET/AKT signaling, EGFR/PI3K-AKT signaling, FAK/paxillin signaling, NF-κB activation, and LFA-1 endocytic recycling in T cells [PMID:27166796, PMID:33203881, PMID:30040982, PMID:30252131, PMID:37069398, PMID:40024474, PMID:39069074, PMID:40497576]. ST3GAL1 also generates Siglec-7/9 ligands and modifies CD55 to confer complement resistance, establishing it as a glyco-immune checkpoint that promotes immune evasion [PMID:33177111, PMID:38448753]. ST3GAL1 transcription is regulated by SOX2-GLI1, c-FOS/RANKL, TGF-β1, GDNF, and androgen-AR signaling, and is post-transcriptionally repressed by miR-4701-5p and miR-320b, integrating ST3GAL1 into multiple oncogenic and physiological feedback circuits [PMID:33203881, PMID:30252131, PMID:30040982, PMID:41680135, PMID:27088512, PMID:39069074].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing the core enzymatic identity of ST3GAL1: recombinant ST3GAL1 was shown to require native disulfide bonds for activity and to transfer sialic acid from CMP-sialic acid to β-d-galactoside substrates including lactose and N-acetyllactosamine in vitro, defining it as a bona fide sialyltransferase with characterized substrate preferences.\",\n      \"evidence\": \"Recombinant expression in E. coli with oxidative folding chaperones, in vitro sialylation assays with defined substrates\",\n      \"pmids\": [\"27166796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of human ST3GAL1 available\", \"Kinetic parameters for physiological O-glycan substrates not determined in this study\", \"Catalytic mechanism at atomic resolution unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking ST3GAL1 to specific receptor signaling cascades: ST3GAL1 was found to sialylate GFRA1, enabling GDNF-induced RET/AKT/ERα activation in breast cancer, with GDNF transcriptionally inducing ST3GAL1 to form a positive feedback loop — establishing the paradigm that ST3GAL1 modifies individual receptor glycoproteins to control ligand-driven signaling.\",\n      \"evidence\": \"ST3GAL1 silencing with phosphorylation assays for RET, AKT, ERα in ER+ breast cancer cells; GDNF stimulation and ST3GAL1 transcript measurement\",\n      \"pmids\": [\"30040982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific O-glycan sites on GFRA1 modified by ST3GAL1 not mapped\", \"Whether sialylation alters GFRA1-GDNF binding affinity not directly measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that ST3GAL1 sialylation can attenuate rather than enhance signaling: sialylation of vasorin (VASN) reduced its binding to TGF-β1 by 2–3 fold, dampening Smad2/3 signaling and angiogenesis, while TGF-β1 itself transcriptionally induced ST3GAL1, revealing a negative feedback loop distinct from the positive feedback with GDNF/GFRA1.\",\n      \"evidence\": \"LC-MS/MS O-glycan analysis, neuraminidase treatment, HUVEC tube formation, Smad activation assays, MCF7 xenografts\",\n      \"pmids\": [\"30252131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VASN sialylation affects other TGF-β superfamily ligands unknown\", \"Structural basis for how sialylation reduces VASN-TGF-β1 binding not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanding substrate repertoire to immune regulators and oncogenic receptors: ST3GAL1 was shown to sialylate CD55 (generating disialyl core 2 O-glycans that protect cancer cells from complement lysis and ADCC) and AXL (inducing dimerization/activation downstream of SOX2-GLI1), broadening the functional scope from growth factor signaling to immune evasion and oncogene activation.\",\n      \"evidence\": \"Mass spectrometry of CD55 O-glycans after ST3GAL1 knockdown, complement lysis/ADCC assays; AXL dimerization assays with in vivo melanoma models\",\n      \"pmids\": [\"33177111\", \"33203881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD55 sialylation also affects complement regulatory function beyond protecting from lysis not tested\", \"Whether other sialyltransferases compensate for ST3GAL1 loss on AXL or CD55 not examined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing context-dependent signaling outcomes: in renal cell carcinoma, ST3GAL1-mediated sialylation of EGFR inhibited EGFR phosphorylation and suppressed PI3K-AKT signaling, contrasting with contexts where ST3GAL1 promotes oncogenic signaling, and ST3GAL1 transcription was regulated by the lncRNA MEG3 via c-Jun.\",\n      \"evidence\": \"MEG3 overexpression/knockdown, c-Jun binding to ST3GAL1 promoter, EGFR sialylation and phosphorylation assays\",\n      \"pmids\": [\"32737220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EGFR inhibition by sialylation is specific to the O-glycan versus N-glycan context not resolved\", \"Apparent contradiction with studies showing ST3GAL1 promotes oncogenic EGFR signaling in other contexts not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing physiological hematopoietic substrates and functional redundancy with ST3GAL2: double knockout of ST3GAL1/ST3GAL2 in iPSC-derived megakaryocytes identified CD34, CD43, and GPIbα as major O-glycan substrates and revealed that both enzymes are required for proplatelet formation, defining a non-cancer physiological role.\",\n      \"evidence\": \"ST3GAL1/ST3GAL2 double-KO iPSC lines, PNA lectin binding, megakaryocyte differentiation, substrate identification\",\n      \"pmids\": [\"35507766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of ST3GAL1 versus ST3GAL2 to each substrate not fully deconvolved\", \"In vivo platelet phenotype in animal models not reported\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovering a T cell-intrinsic role: an in vivo CRISPR screen identified ST3GAL1 as a glycosylation modifier of CD18 in CD8+ T cells; ST3GAL1-mediated CD18 sialylation altered LFA-1 endocytic recycling, causing nonspecific tissue sequestration and impairing CAR T cell tumor homing, establishing ST3GAL1 as a cell-autonomous regulator of T cell trafficking.\",\n      \"evidence\": \"Pooled in vivo CRISPR-Cas9 loss-of-function screen, glycoprotein analysis, LFA-1 recycling assays, CAR T cell homing experiments\",\n      \"pmids\": [\"37069398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ST3GAL1 deletion improves human CAR T cell efficacy in clinical settings unknown\", \"Mechanism by which βII-spectrin reverses ST3GAL1-dependent LFA-1 mislocalization not fully elucidated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting ST3GAL1 to inhibitory Siglec ligand synthesis and androgen regulation: ST3GAL1-synthesized sialoglycans serve as ligands for Siglec-7/9 in prostate cancer, with androgen-AR signaling negatively regulating ST3GAL1 expression, providing a mechanistic link between hormone signaling and glyco-immune evasion.\",\n      \"evidence\": \"Siglec-7/9 ligand expression analysis, ST3GAL1 manipulation, androgen signaling modulation, enzalutamide treatment in prostate cancer cells\",\n      \"pmids\": [\"38448753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific glycoprotein carriers of Siglec-7/9 ligands generated by ST3GAL1 not identified\", \"Whether enzalutamide-mediated ST3GAL1 induction enhances immune evasion in patients not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying NRP1 and VEGF-A as ST3GAL1 substrates with distinct signaling outputs: sialylation of NRP1 increased its affinity for EGFR and activated downstream CAPN2/migration signaling, while sialylation of VEGF-A activated FAK/paxillin signaling in endometrial cancer, further expanding the substrate-to-pathway map.\",\n      \"evidence\": \"ST3GAL1 silencing, NRP1-EGFR binding affinity measurements, CAPN2 activity assays; Duolink PLA and Co-IP for VEGF-A, xenograft models with soyasaponin I inhibitor\",\n      \"pmids\": [\"40024474\", \"40497576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NRP1 sialylation by ST3GAL1 occurs at O-glycan or N-glycan sites not resolved\", \"Specificity of soyasaponin I for ST3GAL1 over other sialyltransferases in vivo not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolving transcriptional regulation in osteoclasts and identifying MUCL1 as a stability-modulating substrate: RANKL/c-FOS drives ST3GAL1 transcription in osteoclasts with estrogen-ERα opposing this via TRAF6 competition, linking ST3GAL1 to bone homeostasis; separately, ST3GAL1 sialylation of MUCL1 stabilizes the protein to promote breast cancer metastasis.\",\n      \"evidence\": \"RANKL stimulation with c-FOS/ERα binding studies, scRNA-seq of human bone, sialidase treatment in estrogen-deficient models; Co-IP, MUCL1 stability/degradation assays, in vivo metastasis models\",\n      \"pmids\": [\"41680135\", \"41770470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ST3GAL1 sialylation of specific osteoclast substrates mediates the bone loss phenotype not determined\", \"Degradation pathway (proteasomal vs. lysosomal) for desialylated MUCL1 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of human ST3GAL1 with bound substrate/donor, a comprehensive map of the O-glycosites it modifies on each substrate, and in vivo genetic studies distinguishing ST3GAL1 from compensating sialyltransferases in normal tissue homeostasis remain outstanding gaps.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of human ST3GAL1\", \"Site-specific O-glycan modification mapping incomplete for most substrates\", \"Conditional knockout phenotypes in non-cancer tissues largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 8, 11, 14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 6, 11, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AXL\",\n      \"VASN\",\n      \"GFRA1\",\n      \"CD55\",\n      \"ITGB2\",\n      \"NRP1\",\n      \"MUCL1\",\n      \"VEGFA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}