{"gene":"GALNT14","run_date":"2026-06-10T01:55:20","timeline":{"discoveries":[{"year":2003,"finding":"GALNT14 (pp-GalNAc-T14) is a type II membrane protein that transfers GalNAc to mucin-derived peptide substrates (Muc2, Muc5AC, Muc7, Muc13) in vitro, establishing it as a functional UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase initiating mucin-type O-glycosylation.","method":"Recombinant enzyme activity assay using mucin-derived peptide substrates; phylogenetic analysis showing subfamily with pp-GalNAc-T2","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrates, recombinant protein, foundational characterization paper","pmids":["12507512"],"is_preprint":false},{"year":2014,"finding":"GALNT14 overexpression in MCF-7 breast cancer cells increases MMP-2 enzymatic activity (demonstrated by gelatin zymography) through the AP-1-binding site in the MMP-2 promoter, and upregulates N-cadherin, vimentin, VEGF, TGF-β while downregulating E-cadherin, promoting EMT-related invasion and migration. GALNT14 knockdown reduces MUC1 expression.","method":"RNAi knockdown and overexpression in MCF-7 cells; gelatin zymography; RT-qPCR; Western blot; promoter analysis","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (zymography, promoter assay, Western blot), single lab","pmids":["24962947"],"is_preprint":false},{"year":2015,"finding":"GalNAc-T14 increases β-catenin protein stability and enhances WNT signaling sensitivity, leading to upregulation of HOXB9 expression, which drives invasion and metastasis in lung adenocarcinoma cells; pharmacological inhibition of β-catenin in GalNAc-T14-expressing cells suppressed HOXB9 and invasion.","method":"Microarray; biochemical analyses; pharmacological β-catenin inhibition; invasion assays; overexpression/knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (microarray, biochemical, pharmacological inhibition), single lab","pmids":["26544896"],"is_preprint":false},{"year":2016,"finding":"GALNT14 promotes lung-specific breast cancer metastasis by: (1) inhibiting the anti-metastatic BMP signaling from lung stroma to enhance metastasis initiation; (2) inducing macrophage infiltration and exploiting macrophage-derived FGFs for colony growth. Upstream, KRAS-PI3K-c-JUN signaling drives elevated GALNT14 expression in lung-metastatic breast cancer cells.","method":"In vitro and in vivo metastasis assays; signaling pathway analysis; macrophage co-culture; BMP pathway manipulation; genetic epistasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, defined signaling pathway placement, published in high-impact journal","pmids":["27982029"],"is_preprint":false},{"year":2016,"finding":"miR-125a directly targets GALNT14 (confirmed by luciferase reporter assay), reducing GALNT14 expression and thereby suppressing MMP2 and MMP9 activity in ovarian cancer cells.","method":"Luciferase reporter assay; gelatin zymography; miR-125a overexpression; siRNA knockdown of GALNT14","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter (direct target validation) plus functional readouts, single lab","pmids":["27133078"],"is_preprint":false},{"year":2018,"finding":"GALNT14 interacts with EFEMP2 (identified by yeast two-hybrid and confirmed by in vitro and in vivo binding assays), mediates O-glycosylation of EFEMP2, and this O-glycosylation stabilizes the EFEMP2 protein, thereby promoting breast cancer cell invasion.","method":"Yeast two-hybrid; Co-IP/pulldown (in vitro and in vivo binding assays); invasion assays with GALNT14 knockdown; Western blot for protein stability","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro/in vivo binding confirmation plus functional glycosylation readout, single lab","pmids":["29428518"],"is_preprint":false},{"year":2018,"finding":"GALNT14 regulates the stability of P-glycoprotein (P-gp), and higher GALNT14 levels correlate with and contribute to P-gp-mediated multidrug resistance in breast cancer cells.","method":"GALNT14 knockdown and overexpression; Western blot for P-gp; MTT drug sensitivity assay","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlation and knockdown/OE with Western blot but no direct glycosylation of P-gp demonstrated","pmids":["29702465"],"is_preprint":false},{"year":2019,"finding":"Oridonin upregulates GALNT14 expression, which mediates glycosylation of death receptor 5 (DR5); GALNT14 knockdown by siRNA and Endo H treatment both reduced oridonin-induced DR5 glycosylation, demonstrating that GALNT14-mediated DR5 glycosylation enhances DISC formation and TRAIL-induced apoptosis.","method":"siRNA knockdown; Endo H glycosylation inhibitor treatment; DISC formation assay; Western blot; co-treatment with benzyl-α-GalNAc glycosylation inhibitor","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (siRNA, enzymatic inhibitor, pharmacological glycosylation inhibitor) converging on same mechanism, single lab","pmids":["31336136"],"is_preprint":false},{"year":2019,"finding":"BORIS expression in fallopian tube secretory epithelial cells induces GALNT14 transcription via de novo CTCF binding at the GALNT14 locus (ChIP-seq), and GALNT14 knockdown abrogates BORIS-induced cell motility and invasion, placing GALNT14 downstream of BORIS/CTCF in an invasion pathway.","method":"ChIP-seq; GALNT14 knockdown; motility/invasion assays; RNA-seq; BORIS overexpression","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus functional rescue experiment, multiple orthogonal methods, single lab","pmids":["31292201"],"is_preprint":false},{"year":2020,"finding":"GALNT14 knockdown and bortezomib treatment both attenuate TGFβ-mediated gene expression and suppress TGFβ-dependent metastatic genes in lung cancer, placing GALNT14 as a regulator of TGFβ signaling in metastasis.","method":"GALNT14 knockdown; bortezomib treatment; in vitro and in vivo metastasis assays; gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent in vitro and in vivo data with genetic and pharmacological approaches, single lab","pmids":["32388539"],"is_preprint":false},{"year":2021,"finding":"GALNT14 modifies O-glycosylation of EGFR; GALNT14 downregulation suppresses EGFR-mediated mTOR pathway activity, thereby reducing apoptosis and ferroptosis in ovarian cancer cells.","method":"Western blotting; GALNT14 knockdown; mTOR pathway activity assay; cell death assays (apoptosis and ferroptosis)","journal":"Future oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, O-glycosylation of EGFR inferred from pathway activity rather than direct site mapping, single method set","pmids":["34643088"],"is_preprint":false},{"year":2022,"finding":"GALNT14 mediates O-glycosylation of PHB2 at serine-161 (identified by comparative lectin-capture glycoproteomics and confirmed by site-directed mutagenesis); this O-glycosylation is required for increased PHB2–IGFBP6 interaction, which activates IGF1R-mediated signaling to promote HCC cell growth, migration, and drug resistance.","method":"Lectin-capture glycoproteomic approach (LC-MS); site-directed mutagenesis (PHB2-S161); Co-IP for PHB2–IGFBP6 interaction; IGF1R signaling assays; cell functional assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct substrate identification by glycoproteomics, site confirmed by mutagenesis, downstream pathway and functional consequences established, multiple orthogonal methods in one study","pmids":["36376274"],"is_preprint":false},{"year":2023,"finding":"GALNT14 overexpression in the IgA1-producing Dakiki cell line enhances galactose deficiency of IgA1, while siRNA-mediated knockdown reduces galactose-deficient IgA1 production; GalNAc-T14 localizes to the trans-Golgi network.","method":"GALNT14 overexpression and siRNA knockdown in Dakiki cells; IgA1 O-glycan analysis; subcellular localization by immunofluorescence","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with direct glycan readout, localization confirmed, single lab","pmids":["37180502"],"is_preprint":false},{"year":2024,"finding":"GALNT14 O-glycosylates hnRNPUL1, which upregulates AKR1C2 expression, thereby reducing intracellular reactive oxygen species (ROS) accumulation to drive lung adenocarcinoma cell proliferation, migration, and invasion; miR-125a directly modulates GALNT14 expression.","method":"LC-MS/MS glycoproteomic substrate identification; RNA-seq; RIP-seq; ROS measurement; in vitro and in vivo functional assays; siRNA knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by LC-MS/MS, downstream mechanism supported by RNA-seq/RIP-seq and functional assays, single lab","pmids":["39426495"],"is_preprint":false},{"year":2025,"finding":"Loss-of-function of GALNT14 in Galnt14-null mice leads to elevated serum IgA, increased ex vivo B cell IgA production, glomerular IgA deposition, attenuated colonic mucin layer, redistribution of IgA-producing cells from mucosal to systemic sites, and impaired homing of B lymphocytes (shown by adoptive transfer); human LOF variant carriers did not show altered levels of poorly glycosylated IgA1, indicating B cell homing and mucosal immunity defects are the primary disease mechanism rather than IgA1 glycosylation status alone.","method":"Galnt14-null mouse model; adoptive transfer experiments; ex vivo B cell IgA production; glomerular IgA staining; colonic mucin layer analysis; whole-exome sequencing of human family","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and ex vivo methods including adoptive transfer, whole-exome sequencing, and null mouse model with multiple tissue readouts","pmids":["40153534"],"is_preprint":false},{"year":2009,"finding":"GalNAc-T14 is a binding partner of IGFBP-3 and modulates IGFBP-3-induced apoptosis; siRNA knockdown of GalNAc-T14 in IGFBP-3-overexpressing cells increased apoptosis (measured by flow cytometry and caspase-3 assay), suggesting GalNAc-T14 partially suppresses IGFBP-3 apoptotic signaling.","method":"siRNA knockdown; flow cytometry; caspase-3 assay; RT-PCR; Western blot","journal":"Journal of biosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction inferred from functional modulation rather than direct binding assay shown in abstract, limited mechanistic resolution","pmids":["19805900"],"is_preprint":false},{"year":2017,"finding":"Osterix (Osx) transcriptionally upregulates GALNT14 expression; GALNT14 is required for Osx-mediated decrease in chemosensitivity of breast cancer cells (silencing GALNT14 in Osx-overexpressing cells restores chemosensitivity; GALNT14 overexpression in Osx-knockdown cells abrogates increased chemosensitivity), placing GALNT14 downstream of Osx in an anti-apoptotic pathway.","method":"High-throughput Illumina sequencing to identify target genes; siRNA knockdown; overexpression; MTT drug sensitivity assay; Hoechst staining; Western blot","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis established by bidirectional rescue experiments, multiple orthogonal methods, single lab","pmids":["29227978"],"is_preprint":false},{"year":2019,"finding":"GalNAc-T14 co-overexpression with IGFBP-3 in glioblastoma cells inhibits IGFBP-3-driven proliferation, colony formation and G1/S phase progression, and downregulates CyclinE, CDK2, and p-ERK1/2, demonstrating that GalNAc-T14 antagonizes IGFBP-3-mediated ERK activation and cell cycle progression.","method":"Transfection/overexpression; MTT assay; colony formation assay; flow cytometry (cell cycle); Western blot","journal":"The Journal of pharmacy and pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional overexpression without direct biochemical mechanism of antagonism, no binding or glycosylation assay shown","pmids":["31713889"],"is_preprint":false},{"year":2025,"finding":"GALNT14 overexpression in HK-2 renal tubular cells reduces ferroptosis markers (FSP1) and kidney injury markers (KIM1, NGAL) while increasing GPX4 expression; in vivo, GALNT14 overexpression in cisplatin-AKI mice attenuates kidney injury and tubular ferroptosis, establishing GALNT14 as an inhibitor of ferroptosis in renal tubular cells.","method":"GALNT14 overexpression and siRNA knockdown in HK-2 cells; in vivo cisplatin-AKI mouse model with GALNT14 overexpression; Western blot for ferroptosis markers; histopathology","journal":"Kidney & blood pressure research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent in vitro and in vivo gain- and loss-of-function with defined molecular markers, single lab","pmids":["40931477"],"is_preprint":false}],"current_model":"GALNT14 is a Golgi-localized type II membrane enzyme that initiates mucin-type O-GalNAc glycosylation on serine/threonine residues of substrate proteins including mucins, PHB2 (at Ser161), hnRNPUL1, EGFR, EFEMP2, and the IgA1 hinge region; through these glycosylation events it modulates downstream signaling cascades (IGF1R, WNT/β-catenin/HOXB9, TGFβ, BMP, FGF, mTOR, ERK, ROS/AKR1C2) to promote cancer cell invasion, metastasis, stemness, and drug resistance, while in non-malignant contexts its loss impairs B lymphocyte homing and mucosal IgA production, contributing to IgA nephropathy pathogenesis."},"narrative":{"mechanistic_narrative":"GALNT14 is a Golgi/trans-Golgi-localized type II membrane UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase that initiates mucin-type O-GalNAc glycosylation on serine/threonine residues of substrate proteins, an activity demonstrated directly against mucin-derived peptides in vitro [PMID:12507512, PMID:37180502]. Through site-specific O-glycosylation of defined substrates it controls protein stability and downstream signaling: it glycosylates PHB2 at Ser161 to strengthen PHB2–IGFBP6 binding and activate IGF1R signaling [PMID:36376274], stabilizes EFEMP2 to promote invasion [PMID:29428518], and glycosylates hnRNPUL1 to upregulate AKR1C2 and suppress reactive oxygen species [PMID:39426495]. These glycosylation events feed into multiple cancer-relevant cascades, including WNT/β-catenin–HOXB9 [PMID:26544896], TGFβ [PMID:32388539], and EMT/MMP programs driving invasion and metastasis [PMID:24962947], with lung-specific breast cancer metastasis occurring through suppression of anti-metastatic BMP signaling and exploitation of macrophage-derived FGFs downstream of KRAS-PI3K-c-JUN [PMID:27982029]. GALNT14 expression is itself regulated transcriptionally by BORIS/CTCF and Osterix and post-transcriptionally by miR-125a [PMID:31292201, PMID:29227978, PMID:27133078, PMID:39426495]. In non-malignant immunity, Galnt14 loss in mice elevates serum IgA, causes glomerular IgA deposition, thins the colonic mucin layer, and impairs B lymphocyte homing, defining a B-cell homing and mucosal immunity defect that links GALNT14 to IgA nephropathy pathogenesis [PMID:40153534, PMID:37180502].","teleology":[{"year":2003,"claim":"Established that GALNT14 is a catalytically active enzyme rather than an uncharacterized family member, defining its core biochemical activity as initiation of mucin-type O-glycosylation.","evidence":"Recombinant enzyme activity assay on mucin-derived peptide substrates plus phylogenetic placement","pmids":["12507512"],"confidence":"High","gaps":["No in vivo substrate identified at this stage","Acceptor-site preference and protein substrates in cells not defined"]},{"year":2009,"claim":"First implicated GALNT14 in IGFBP-3 apoptotic signaling, hinting at a non-canonical signaling-modulatory role beyond bulk mucin glycosylation.","evidence":"siRNA knockdown in IGFBP-3-overexpressing cells with flow cytometry and caspase-3 readouts","pmids":["19805900"],"confidence":"Low","gaps":["Direct binding inferred from functional modulation, not demonstrated","No glycosylation substrate shown","Single lab"]},{"year":2014,"claim":"Connected GALNT14 to an EMT/invasion transcriptional program in breast cancer, establishing a pro-invasive cellular phenotype.","evidence":"RNAi/overexpression in MCF-7 with zymography, promoter analysis, and Western blot","pmids":["24962947"],"confidence":"Medium","gaps":["Glycosylation substrate driving the EMT phenotype not identified","Mechanism linking enzyme to AP-1/MMP-2 promoter not resolved"]},{"year":2015,"claim":"Placed GALNT14 upstream of WNT/β-catenin signaling and HOXB9 induction, defining a signaling axis for invasion and metastasis.","evidence":"Microarray, biochemical analysis and pharmacological β-catenin inhibition in lung adenocarcinoma cells","pmids":["26544896"],"confidence":"Medium","gaps":["Direct glycosylation target controlling β-catenin stability not identified","Single lab"]},{"year":2016,"claim":"Defined the upstream regulation (KRAS-PI3K-c-JUN, miR-125a) and tissue-specific output of GALNT14, showing it drives lung-specific metastasis via BMP suppression and macrophage-FGF exploitation.","evidence":"In vitro/in vivo metastasis assays with signaling epistasis and macrophage co-culture; luciferase reporter for miR-125a targeting","pmids":["27982029","27133078"],"confidence":"High","gaps":["Glycosylation substrates mediating BMP/FGF effects not identified","Direct enzymatic mechanism in the metastatic niche unresolved"]},{"year":2018,"claim":"Identified the first protein substrate-stabilization mechanism (EFEMP2) and extended GALNT14 to multidrug resistance via P-glycoprotein.","evidence":"Yeast two-hybrid plus binding assays and invasion readouts for EFEMP2; knockdown/overexpression and MTT for P-gp","pmids":["29428518","29702465"],"confidence":"Medium","gaps":["EFEMP2 O-glycosylation site not mapped","Direct glycosylation of P-gp not demonstrated (Low-confidence finding)"]},{"year":2019,"claim":"Showed GALNT14 transcription is induced by BORIS/CTCF and that GALNT14-mediated DR5 glycosylation modulates TRAIL-induced apoptosis, expanding its regulatory inputs and apoptotic outputs.","evidence":"ChIP-seq with functional rescue for BORIS/CTCF; siRNA, Endo H and benzyl-α-GalNAc inhibition for DR5/DISC; IGFBP-3 overexpression with cell-cycle assays","pmids":["31292201","31336136","31713889"],"confidence":"Medium","gaps":["DR5 glycosylation site not mapped","IGFBP-3 antagonism lacks direct biochemical mechanism (Low-confidence finding)"]},{"year":2020,"claim":"Positioned GALNT14 as a regulator of TGFβ-dependent metastatic gene expression in lung cancer.","evidence":"Genetic knockdown and bortezomib treatment with in vitro and in vivo metastasis assays","pmids":["32388539"],"confidence":"Medium","gaps":["Glycosylation substrate linking GALNT14 to TGFβ output not identified","Single lab"]},{"year":2022,"claim":"Provided the most direct substrate-level mechanism: GALNT14 glycosylates PHB2 at Ser161 to enhance PHB2–IGFBP6 interaction and IGF1R signaling, connecting a mapped glycosite to a defined downstream pathway and phenotype.","evidence":"Lectin-capture glycoproteomics with site-directed mutagenesis, Co-IP, and IGF1R signaling/functional assays in HCC cells","pmids":["36376274"],"confidence":"High","gaps":["Generality of PHB2 axis across tumor types not established","Structural basis of acceptor recognition unresolved"]},{"year":2023,"claim":"Linked GALNT14 to galactose-deficient IgA1 production and confirmed trans-Golgi localization, providing a biochemical entry point into IgA nephropathy.","evidence":"Overexpression/knockdown in IgA1-producing Dakiki cells with glycan analysis and immunofluorescence localization","pmids":["37180502"],"confidence":"Medium","gaps":["Direct IgA1 hinge glycosite modification not mapped","Relationship of cell-line glycan data to in vivo disease unclear"]},{"year":2024,"claim":"Identified hnRNPUL1 as a substrate and a ROS-suppressing AKR1C2 axis, broadening GALNT14 substrates to RNA-binding proteins and redox control.","evidence":"LC-MS/MS substrate identification, RNA-seq/RIP-seq, ROS measurement, and in vitro/in vivo functional assays","pmids":["39426495"],"confidence":"Medium","gaps":["hnRNPUL1 glycosite not specified","Mechanism connecting hnRNPUL1 glycosylation to AKR1C2 transcription unresolved"]},{"year":2025,"claim":"Resolved the primary in vivo disease mechanism, showing GALNT14 loss impairs B lymphocyte homing and mucosal immunity rather than acting solely through IgA1 glycosylation, redefining its role in IgA nephropathy; a parallel study established GALNT14 as a ferroptosis inhibitor in renal tubular injury.","evidence":"Galnt14-null mice with adoptive transfer, ex vivo B cell assays and tissue readouts plus human whole-exome sequencing; HK-2 cell and cisplatin-AKI mouse models with ferroptosis markers","pmids":["40153534","40931477"],"confidence":"High","gaps":["Glycosylation substrate controlling B cell homing not identified","Substrate mediating ferroptosis protection unknown"]},{"year":null,"claim":"It remains unknown how GALNT14's single enzymatic activity selects among its diverse substrates and how those individual glycosylation events mechanistically translate into the many divergent signaling and disease outcomes attributed to it.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Acceptor-site selectivity and structural basis of substrate choice undefined","Most reported downstream pathways lack a mapped glycosite linking enzyme to effect","No structural model of substrate engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,5,11,12,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,11,13]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,12]}],"complexes":[],"partners":["PHB2","EFEMP2","IGFBP3","HNRNPUL1","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FL9","full_name":"Polypeptide N-acetylgalactosaminyltransferase 14","aliases":["Polypeptide GalNAc transferase 14","GalNAc-T14","pp-GaNTase 14","Protein-UDP acetylgalactosaminyltransferase 14","UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 14"],"length_aa":552,"mass_kda":64.3,"function":"Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Displays activity toward mucin-derived peptide substrates such as Muc2, Muc5AC, Muc7, and Muc13 (-58). May be involved in O-glycosylation in kidney","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q96FL9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GALNT14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GALNT14","total_profiled":1310},"omim":[{"mim_id":"608225","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 14; GALNT14","url":"https://www.omim.org/entry/608225"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":38.6}],"url":"https://www.proteinatlas.org/search/GALNT14"},"hgnc":{"alias_symbol":["GalNac-T10","FLJ12691","GalNac-T14"],"prev_symbol":[]},"alphafold":{"accession":"Q96FL9","domains":[{"cath_id":"3.90.550.10","chopping":"49-335","consensus_level":"medium","plddt":95.8903,"start":49,"end":335},{"cath_id":"2.80.10.50","chopping":"421-552","consensus_level":"high","plddt":86.1055,"start":421,"end":552}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FL9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FL9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FL9-F1-predicted_aligned_error_v6.png","plddt_mean":89.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GALNT14","jax_strain_url":"https://www.jax.org/strain/search?query=GALNT14"},"sequence":{"accession":"Q96FL9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FL9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FL9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FL9"}},"corpus_meta":[{"pmid":"27982029","id":"PMC_27982029","title":"GALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27982029","citation_count":81,"is_preprint":false},{"pmid":"12507512","id":"PMC_12507512","title":"Cloning and characterization of a novel UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase, pp-GalNAc-T14.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12507512","citation_count":78,"is_preprint":false},{"pmid":"24962947","id":"PMC_24962947","title":"GALNT14 mediates tumor invasion and migration in breast cancer cell MCF-7.","date":"2014","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24962947","citation_count":64,"is_preprint":false},{"pmid":"34643088","id":"PMC_34643088","title":"GALNT14 regulates ferroptosis and apoptosis of ovarian cancer through the EGFR/mTOR pathway.","date":"2021","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34643088","citation_count":50,"is_preprint":false},{"pmid":"26309160","id":"PMC_26309160","title":"Identification of GALNT14 as a novel neuroblastoma predisposition gene.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26309160","citation_count":38,"is_preprint":false},{"pmid":"27133078","id":"PMC_27133078","title":"MiR-125a regulates ovarian cancer proliferation and invasion by repressing GALNT14 expression.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27133078","citation_count":37,"is_preprint":false},{"pmid":"32098271","id":"PMC_32098271","title":"GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers.","date":"2020","source":"International journal of molecular 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defects to alterations in B cell homing in IgA nephropathy.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40153534","citation_count":12,"is_preprint":false},{"pmid":"25295111","id":"PMC_25295111","title":"Genotyping the GALNT14 gene by joint analysis of two linked single nucleotide polymorphisms using liver tissues for clinical and geographical comparisons.","date":"2014","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25295111","citation_count":11,"is_preprint":false},{"pmid":"19805900","id":"PMC_19805900","title":"GalNAc-T14 may be involved in regulating the apoptotic action of IGFBP-3.","date":"2009","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19805900","citation_count":9,"is_preprint":false},{"pmid":"31362688","id":"PMC_31362688","title":"Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38889447","citation_count":1,"is_preprint":false},{"pmid":"40931477","id":"PMC_40931477","title":"Identification of GALNT14 as a Key Regulator of Ferroptosis in Cisplatin-Induced Acute Kidney Injury: A Potential Target for Kidney Injury Treatment.","date":"2025","source":"Kidney & blood pressure research","url":"https://pubmed.ncbi.nlm.nih.gov/40931477","citation_count":0,"is_preprint":false},{"pmid":"42147809","id":"PMC_42147809","title":"Integrative Systems Biology and Experimental Validation Unveil GALNT14 as a Novel Diagnostic Biomarker and Therapeutic Target for Sepsis.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/42147809","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20365,"output_tokens":4816,"usd":0.066668,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12938,"output_tokens":4014,"usd":0.08252,"stage2_stop_reason":"end_turn"},"total_usd":0.149188,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"GALNT14 (pp-GalNAc-T14) is a type II membrane protein that transfers GalNAc to mucin-derived peptide substrates (Muc2, Muc5AC, Muc7, Muc13) in vitro, establishing it as a functional UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase initiating mucin-type O-glycosylation.\",\n      \"method\": \"Recombinant enzyme activity assay using mucin-derived peptide substrates; phylogenetic analysis showing subfamily with pp-GalNAc-T2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrates, recombinant protein, foundational characterization paper\",\n      \"pmids\": [\"12507512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GALNT14 overexpression in MCF-7 breast cancer cells increases MMP-2 enzymatic activity (demonstrated by gelatin zymography) through the AP-1-binding site in the MMP-2 promoter, and upregulates N-cadherin, vimentin, VEGF, TGF-β while downregulating E-cadherin, promoting EMT-related invasion and migration. GALNT14 knockdown reduces MUC1 expression.\",\n      \"method\": \"RNAi knockdown and overexpression in MCF-7 cells; gelatin zymography; RT-qPCR; Western blot; promoter analysis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (zymography, promoter assay, Western blot), single lab\",\n      \"pmids\": [\"24962947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GalNAc-T14 increases β-catenin protein stability and enhances WNT signaling sensitivity, leading to upregulation of HOXB9 expression, which drives invasion and metastasis in lung adenocarcinoma cells; pharmacological inhibition of β-catenin in GalNAc-T14-expressing cells suppressed HOXB9 and invasion.\",\n      \"method\": \"Microarray; biochemical analyses; pharmacological β-catenin inhibition; invasion assays; overexpression/knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (microarray, biochemical, pharmacological inhibition), single lab\",\n      \"pmids\": [\"26544896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GALNT14 promotes lung-specific breast cancer metastasis by: (1) inhibiting the anti-metastatic BMP signaling from lung stroma to enhance metastasis initiation; (2) inducing macrophage infiltration and exploiting macrophage-derived FGFs for colony growth. Upstream, KRAS-PI3K-c-JUN signaling drives elevated GALNT14 expression in lung-metastatic breast cancer cells.\",\n      \"method\": \"In vitro and in vivo metastasis assays; signaling pathway analysis; macrophage co-culture; BMP pathway manipulation; genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods, defined signaling pathway placement, published in high-impact journal\",\n      \"pmids\": [\"27982029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-125a directly targets GALNT14 (confirmed by luciferase reporter assay), reducing GALNT14 expression and thereby suppressing MMP2 and MMP9 activity in ovarian cancer cells.\",\n      \"method\": \"Luciferase reporter assay; gelatin zymography; miR-125a overexpression; siRNA knockdown of GALNT14\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter (direct target validation) plus functional readouts, single lab\",\n      \"pmids\": [\"27133078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GALNT14 interacts with EFEMP2 (identified by yeast two-hybrid and confirmed by in vitro and in vivo binding assays), mediates O-glycosylation of EFEMP2, and this O-glycosylation stabilizes the EFEMP2 protein, thereby promoting breast cancer cell invasion.\",\n      \"method\": \"Yeast two-hybrid; Co-IP/pulldown (in vitro and in vivo binding assays); invasion assays with GALNT14 knockdown; Western blot for protein stability\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro/in vivo binding confirmation plus functional glycosylation readout, single lab\",\n      \"pmids\": [\"29428518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GALNT14 regulates the stability of P-glycoprotein (P-gp), and higher GALNT14 levels correlate with and contribute to P-gp-mediated multidrug resistance in breast cancer cells.\",\n      \"method\": \"GALNT14 knockdown and overexpression; Western blot for P-gp; MTT drug sensitivity assay\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlation and knockdown/OE with Western blot but no direct glycosylation of P-gp demonstrated\",\n      \"pmids\": [\"29702465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oridonin upregulates GALNT14 expression, which mediates glycosylation of death receptor 5 (DR5); GALNT14 knockdown by siRNA and Endo H treatment both reduced oridonin-induced DR5 glycosylation, demonstrating that GALNT14-mediated DR5 glycosylation enhances DISC formation and TRAIL-induced apoptosis.\",\n      \"method\": \"siRNA knockdown; Endo H glycosylation inhibitor treatment; DISC formation assay; Western blot; co-treatment with benzyl-α-GalNAc glycosylation inhibitor\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (siRNA, enzymatic inhibitor, pharmacological glycosylation inhibitor) converging on same mechanism, single lab\",\n      \"pmids\": [\"31336136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BORIS expression in fallopian tube secretory epithelial cells induces GALNT14 transcription via de novo CTCF binding at the GALNT14 locus (ChIP-seq), and GALNT14 knockdown abrogates BORIS-induced cell motility and invasion, placing GALNT14 downstream of BORIS/CTCF in an invasion pathway.\",\n      \"method\": \"ChIP-seq; GALNT14 knockdown; motility/invasion assays; RNA-seq; BORIS overexpression\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus functional rescue experiment, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31292201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GALNT14 knockdown and bortezomib treatment both attenuate TGFβ-mediated gene expression and suppress TGFβ-dependent metastatic genes in lung cancer, placing GALNT14 as a regulator of TGFβ signaling in metastasis.\",\n      \"method\": \"GALNT14 knockdown; bortezomib treatment; in vitro and in vivo metastasis assays; gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent in vitro and in vivo data with genetic and pharmacological approaches, single lab\",\n      \"pmids\": [\"32388539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GALNT14 modifies O-glycosylation of EGFR; GALNT14 downregulation suppresses EGFR-mediated mTOR pathway activity, thereby reducing apoptosis and ferroptosis in ovarian cancer cells.\",\n      \"method\": \"Western blotting; GALNT14 knockdown; mTOR pathway activity assay; cell death assays (apoptosis and ferroptosis)\",\n      \"journal\": \"Future oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, O-glycosylation of EGFR inferred from pathway activity rather than direct site mapping, single method set\",\n      \"pmids\": [\"34643088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GALNT14 mediates O-glycosylation of PHB2 at serine-161 (identified by comparative lectin-capture glycoproteomics and confirmed by site-directed mutagenesis); this O-glycosylation is required for increased PHB2–IGFBP6 interaction, which activates IGF1R-mediated signaling to promote HCC cell growth, migration, and drug resistance.\",\n      \"method\": \"Lectin-capture glycoproteomic approach (LC-MS); site-directed mutagenesis (PHB2-S161); Co-IP for PHB2–IGFBP6 interaction; IGF1R signaling assays; cell functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct substrate identification by glycoproteomics, site confirmed by mutagenesis, downstream pathway and functional consequences established, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36376274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GALNT14 overexpression in the IgA1-producing Dakiki cell line enhances galactose deficiency of IgA1, while siRNA-mediated knockdown reduces galactose-deficient IgA1 production; GalNAc-T14 localizes to the trans-Golgi network.\",\n      \"method\": \"GALNT14 overexpression and siRNA knockdown in Dakiki cells; IgA1 O-glycan analysis; subcellular localization by immunofluorescence\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with direct glycan readout, localization confirmed, single lab\",\n      \"pmids\": [\"37180502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GALNT14 O-glycosylates hnRNPUL1, which upregulates AKR1C2 expression, thereby reducing intracellular reactive oxygen species (ROS) accumulation to drive lung adenocarcinoma cell proliferation, migration, and invasion; miR-125a directly modulates GALNT14 expression.\",\n      \"method\": \"LC-MS/MS glycoproteomic substrate identification; RNA-seq; RIP-seq; ROS measurement; in vitro and in vivo functional assays; siRNA knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by LC-MS/MS, downstream mechanism supported by RNA-seq/RIP-seq and functional assays, single lab\",\n      \"pmids\": [\"39426495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss-of-function of GALNT14 in Galnt14-null mice leads to elevated serum IgA, increased ex vivo B cell IgA production, glomerular IgA deposition, attenuated colonic mucin layer, redistribution of IgA-producing cells from mucosal to systemic sites, and impaired homing of B lymphocytes (shown by adoptive transfer); human LOF variant carriers did not show altered levels of poorly glycosylated IgA1, indicating B cell homing and mucosal immunity defects are the primary disease mechanism rather than IgA1 glycosylation status alone.\",\n      \"method\": \"Galnt14-null mouse model; adoptive transfer experiments; ex vivo B cell IgA production; glomerular IgA staining; colonic mucin layer analysis; whole-exome sequencing of human family\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and ex vivo methods including adoptive transfer, whole-exome sequencing, and null mouse model with multiple tissue readouts\",\n      \"pmids\": [\"40153534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GalNAc-T14 is a binding partner of IGFBP-3 and modulates IGFBP-3-induced apoptosis; siRNA knockdown of GalNAc-T14 in IGFBP-3-overexpressing cells increased apoptosis (measured by flow cytometry and caspase-3 assay), suggesting GalNAc-T14 partially suppresses IGFBP-3 apoptotic signaling.\",\n      \"method\": \"siRNA knockdown; flow cytometry; caspase-3 assay; RT-PCR; Western blot\",\n      \"journal\": \"Journal of biosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction inferred from functional modulation rather than direct binding assay shown in abstract, limited mechanistic resolution\",\n      \"pmids\": [\"19805900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Osterix (Osx) transcriptionally upregulates GALNT14 expression; GALNT14 is required for Osx-mediated decrease in chemosensitivity of breast cancer cells (silencing GALNT14 in Osx-overexpressing cells restores chemosensitivity; GALNT14 overexpression in Osx-knockdown cells abrogates increased chemosensitivity), placing GALNT14 downstream of Osx in an anti-apoptotic pathway.\",\n      \"method\": \"High-throughput Illumina sequencing to identify target genes; siRNA knockdown; overexpression; MTT drug sensitivity assay; Hoechst staining; Western blot\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis established by bidirectional rescue experiments, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29227978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GalNAc-T14 co-overexpression with IGFBP-3 in glioblastoma cells inhibits IGFBP-3-driven proliferation, colony formation and G1/S phase progression, and downregulates CyclinE, CDK2, and p-ERK1/2, demonstrating that GalNAc-T14 antagonizes IGFBP-3-mediated ERK activation and cell cycle progression.\",\n      \"method\": \"Transfection/overexpression; MTT assay; colony formation assay; flow cytometry (cell cycle); Western blot\",\n      \"journal\": \"The Journal of pharmacy and pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional overexpression without direct biochemical mechanism of antagonism, no binding or glycosylation assay shown\",\n      \"pmids\": [\"31713889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GALNT14 overexpression in HK-2 renal tubular cells reduces ferroptosis markers (FSP1) and kidney injury markers (KIM1, NGAL) while increasing GPX4 expression; in vivo, GALNT14 overexpression in cisplatin-AKI mice attenuates kidney injury and tubular ferroptosis, establishing GALNT14 as an inhibitor of ferroptosis in renal tubular cells.\",\n      \"method\": \"GALNT14 overexpression and siRNA knockdown in HK-2 cells; in vivo cisplatin-AKI mouse model with GALNT14 overexpression; Western blot for ferroptosis markers; histopathology\",\n      \"journal\": \"Kidney & blood pressure research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent in vitro and in vivo gain- and loss-of-function with defined molecular markers, single lab\",\n      \"pmids\": [\"40931477\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GALNT14 is a Golgi-localized type II membrane enzyme that initiates mucin-type O-GalNAc glycosylation on serine/threonine residues of substrate proteins including mucins, PHB2 (at Ser161), hnRNPUL1, EGFR, EFEMP2, and the IgA1 hinge region; through these glycosylation events it modulates downstream signaling cascades (IGF1R, WNT/β-catenin/HOXB9, TGFβ, BMP, FGF, mTOR, ERK, ROS/AKR1C2) to promote cancer cell invasion, metastasis, stemness, and drug resistance, while in non-malignant contexts its loss impairs B lymphocyte homing and mucosal IgA production, contributing to IgA nephropathy pathogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GALNT14 is a Golgi/trans-Golgi-localized type II membrane UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase that initiates mucin-type O-GalNAc glycosylation on serine/threonine residues of substrate proteins, an activity demonstrated directly against mucin-derived peptides in vitro [#0, #12]. Through site-specific O-glycosylation of defined substrates it controls protein stability and downstream signaling: it glycosylates PHB2 at Ser161 to strengthen PHB2\\u2013IGFBP6 binding and activate IGF1R signaling [#11], stabilizes EFEMP2 to promote invasion [#5], and glycosylates hnRNPUL1 to upregulate AKR1C2 and suppress reactive oxygen species [#13]. These glycosylation events feed into multiple cancer-relevant cascades, including WNT/\\u03b2-catenin\\u2013HOXB9 [#2], TGF\\u03b2 [#9], and EMT/MMP programs driving invasion and metastasis [#1], with lung-specific breast cancer metastasis occurring through suppression of anti-metastatic BMP signaling and exploitation of macrophage-derived FGFs downstream of KRAS-PI3K-c-JUN [#3]. GALNT14 expression is itself regulated transcriptionally by BORIS/CTCF and Osterix and post-transcriptionally by miR-125a [#8, #16, #4, #13]. In non-malignant immunity, Galnt14 loss in mice elevates serum IgA, causes glomerular IgA deposition, thins the colonic mucin layer, and impairs B lymphocyte homing, defining a B-cell homing and mucosal immunity defect that links GALNT14 to IgA nephropathy pathogenesis [#14, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that GALNT14 is a catalytically active enzyme rather than an uncharacterized family member, defining its core biochemical activity as initiation of mucin-type O-glycosylation.\",\n      \"evidence\": \"Recombinant enzyme activity assay on mucin-derived peptide substrates plus phylogenetic placement\",\n      \"pmids\": [\"12507512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo substrate identified at this stage\", \"Acceptor-site preference and protein substrates in cells not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First implicated GALNT14 in IGFBP-3 apoptotic signaling, hinting at a non-canonical signaling-modulatory role beyond bulk mucin glycosylation.\",\n      \"evidence\": \"siRNA knockdown in IGFBP-3-overexpressing cells with flow cytometry and caspase-3 readouts\",\n      \"pmids\": [\"19805900\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct binding inferred from functional modulation, not demonstrated\", \"No glycosylation substrate shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected GALNT14 to an EMT/invasion transcriptional program in breast cancer, establishing a pro-invasive cellular phenotype.\",\n      \"evidence\": \"RNAi/overexpression in MCF-7 with zymography, promoter analysis, and Western blot\",\n      \"pmids\": [\"24962947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycosylation substrate driving the EMT phenotype not identified\", \"Mechanism linking enzyme to AP-1/MMP-2 promoter not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed GALNT14 upstream of WNT/\\u03b2-catenin signaling and HOXB9 induction, defining a signaling axis for invasion and metastasis.\",\n      \"evidence\": \"Microarray, biochemical analysis and pharmacological \\u03b2-catenin inhibition in lung adenocarcinoma cells\",\n      \"pmids\": [\"26544896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct glycosylation target controlling \\u03b2-catenin stability not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the upstream regulation (KRAS-PI3K-c-JUN, miR-125a) and tissue-specific output of GALNT14, showing it drives lung-specific metastasis via BMP suppression and macrophage-FGF exploitation.\",\n      \"evidence\": \"In vitro/in vivo metastasis assays with signaling epistasis and macrophage co-culture; luciferase reporter for miR-125a targeting\",\n      \"pmids\": [\"27982029\", \"27133078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosylation substrates mediating BMP/FGF effects not identified\", \"Direct enzymatic mechanism in the metastatic niche unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the first protein substrate-stabilization mechanism (EFEMP2) and extended GALNT14 to multidrug resistance via P-glycoprotein.\",\n      \"evidence\": \"Yeast two-hybrid plus binding assays and invasion readouts for EFEMP2; knockdown/overexpression and MTT for P-gp\",\n      \"pmids\": [\"29428518\", \"29702465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EFEMP2 O-glycosylation site not mapped\", \"Direct glycosylation of P-gp not demonstrated (Low-confidence finding)\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed GALNT14 transcription is induced by BORIS/CTCF and that GALNT14-mediated DR5 glycosylation modulates TRAIL-induced apoptosis, expanding its regulatory inputs and apoptotic outputs.\",\n      \"evidence\": \"ChIP-seq with functional rescue for BORIS/CTCF; siRNA, Endo H and benzyl-\\u03b1-GalNAc inhibition for DR5/DISC; IGFBP-3 overexpression with cell-cycle assays\",\n      \"pmids\": [\"31292201\", \"31336136\", \"31713889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DR5 glycosylation site not mapped\", \"IGFBP-3 antagonism lacks direct biochemical mechanism (Low-confidence finding)\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned GALNT14 as a regulator of TGF\\u03b2-dependent metastatic gene expression in lung cancer.\",\n      \"evidence\": \"Genetic knockdown and bortezomib treatment with in vitro and in vivo metastasis assays\",\n      \"pmids\": [\"32388539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycosylation substrate linking GALNT14 to TGF\\u03b2 output not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the most direct substrate-level mechanism: GALNT14 glycosylates PHB2 at Ser161 to enhance PHB2\\u2013IGFBP6 interaction and IGF1R signaling, connecting a mapped glycosite to a defined downstream pathway and phenotype.\",\n      \"evidence\": \"Lectin-capture glycoproteomics with site-directed mutagenesis, Co-IP, and IGF1R signaling/functional assays in HCC cells\",\n      \"pmids\": [\"36376274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of PHB2 axis across tumor types not established\", \"Structural basis of acceptor recognition unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked GALNT14 to galactose-deficient IgA1 production and confirmed trans-Golgi localization, providing a biochemical entry point into IgA nephropathy.\",\n      \"evidence\": \"Overexpression/knockdown in IgA1-producing Dakiki cells with glycan analysis and immunofluorescence localization\",\n      \"pmids\": [\"37180502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IgA1 hinge glycosite modification not mapped\", \"Relationship of cell-line glycan data to in vivo disease unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified hnRNPUL1 as a substrate and a ROS-suppressing AKR1C2 axis, broadening GALNT14 substrates to RNA-binding proteins and redox control.\",\n      \"evidence\": \"LC-MS/MS substrate identification, RNA-seq/RIP-seq, ROS measurement, and in vitro/in vivo functional assays\",\n      \"pmids\": [\"39426495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"hnRNPUL1 glycosite not specified\", \"Mechanism connecting hnRNPUL1 glycosylation to AKR1C2 transcription unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the primary in vivo disease mechanism, showing GALNT14 loss impairs B lymphocyte homing and mucosal immunity rather than acting solely through IgA1 glycosylation, redefining its role in IgA nephropathy; a parallel study established GALNT14 as a ferroptosis inhibitor in renal tubular injury.\",\n      \"evidence\": \"Galnt14-null mice with adoptive transfer, ex vivo B cell assays and tissue readouts plus human whole-exome sequencing; HK-2 cell and cisplatin-AKI mouse models with ferroptosis markers\",\n      \"pmids\": [\"40153534\", \"40931477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycosylation substrate controlling B cell homing not identified\", \"Substrate mediating ferroptosis protection unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how GALNT14's single enzymatic activity selects among its diverse substrates and how those individual glycosylation events mechanistically translate into the many divergent signaling and disease outcomes attributed to it.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acceptor-site selectivity and structural basis of substrate choice undefined\", \"Most reported downstream pathways lack a mapped glycosite linking enzyme to effect\", \"No structural model of substrate engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 5, 11, 12, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PHB2\", \"EFEMP2\", \"IGFBP3\", \"hnRNPUL1\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}