Affinage

GALNT14

Polypeptide N-acetylgalactosaminyltransferase 14 · UniProt Q96FL9

Length
552 aa
Mass
64.3 kDa
Annotated
2026-06-10
37 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    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

    PMID:12507512

    Open questions at the time
    • No in vivo substrate identified at this stage
    • Acceptor-site preference and protein substrates in cells not defined
  2. 2009 Low

    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

    PMID:19805900

    Open questions at the time
    • Direct binding inferred from functional modulation, not demonstrated
    • No glycosylation substrate shown
    • Single lab
  3. 2014 Medium

    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

    PMID:24962947

    Open questions at the time
    • Glycosylation substrate driving the EMT phenotype not identified
    • Mechanism linking enzyme to AP-1/MMP-2 promoter not resolved
  4. 2015 Medium

    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

    PMID:26544896

    Open questions at the time
    • Direct glycosylation target controlling β-catenin stability not identified
    • Single lab
  5. 2016 High

    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

    PMID:27133078 PMID:27982029

    Open questions at the time
    • Glycosylation substrates mediating BMP/FGF effects not identified
    • Direct enzymatic mechanism in the metastatic niche unresolved
  6. 2018 Medium

    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

    PMID:29428518 PMID:29702465

    Open questions at the time
    • EFEMP2 O-glycosylation site not mapped
    • Direct glycosylation of P-gp not demonstrated (Low-confidence finding)
  7. 2019 Medium

    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

    PMID:31292201 PMID:31336136 PMID:31713889

    Open questions at the time
    • DR5 glycosylation site not mapped
    • IGFBP-3 antagonism lacks direct biochemical mechanism (Low-confidence finding)
  8. 2020 Medium

    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

    PMID:32388539

    Open questions at the time
    • Glycosylation substrate linking GALNT14 to TGFβ output not identified
    • Single lab
  9. 2022 High

    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

    PMID:36376274

    Open questions at the time
    • Generality of PHB2 axis across tumor types not established
    • Structural basis of acceptor recognition unresolved
  10. 2023 Medium

    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

    PMID:37180502

    Open questions at the time
    • Direct IgA1 hinge glycosite modification not mapped
    • Relationship of cell-line glycan data to in vivo disease unclear
  11. 2024 Medium

    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

    PMID:39426495

    Open questions at the time
    • hnRNPUL1 glycosite not specified
    • Mechanism connecting hnRNPUL1 glycosylation to AKR1C2 transcription unresolved
  12. 2025 High

    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

    PMID:40153534 PMID:40931477

    Open questions at the time
    • Glycosylation substrate controlling B cell homing not identified
    • Substrate mediating ferroptosis protection unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
EFEMP2EGFRHNRNPUL1IGFBP3PHB2

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Recombinant enzyme activity assay using mucin-derived peptide substrates; phylogenetic analysis showing subfamily with pp-GalNAc-T2 Biochemical and biophysical research communications High 12507512
2014 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. RNAi knockdown and overexpression in MCF-7 cells; gelatin zymography; RT-qPCR; Western blot; promoter analysis Molecular carcinogenesis Medium 24962947
2015 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. Microarray; biochemical analyses; pharmacological β-catenin inhibition; invasion assays; overexpression/knockdown Oncotarget Medium 26544896
2016 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. In vitro and in vivo metastasis assays; signaling pathway analysis; macrophage co-culture; BMP pathway manipulation; genetic epistasis Nature communications High 27982029
2016 miR-125a directly targets GALNT14 (confirmed by luciferase reporter assay), reducing GALNT14 expression and thereby suppressing MMP2 and MMP9 activity in ovarian cancer cells. Luciferase reporter assay; gelatin zymography; miR-125a overexpression; siRNA knockdown of GALNT14 Biomedicine & pharmacotherapy Medium 27133078
2018 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. Yeast two-hybrid; Co-IP/pulldown (in vitro and in vivo binding assays); invasion assays with GALNT14 knockdown; Western blot for protein stability Translational oncology Medium 29428518
2018 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. GALNT14 knockdown and overexpression; Western blot for P-gp; MTT drug sensitivity assay Translational oncology Low 29702465
2019 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. siRNA knockdown; Endo H glycosylation inhibitor treatment; DISC formation assay; Western blot; co-treatment with benzyl-α-GalNAc glycosylation inhibitor Biochimie Medium 31336136
2019 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. ChIP-seq; GALNT14 knockdown; motility/invasion assays; RNA-seq; BORIS overexpression Molecular cancer research : MCR Medium 31292201
2020 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. GALNT14 knockdown; bortezomib treatment; in vitro and in vivo metastasis assays; gene expression analysis Oncogene Medium 32388539
2021 GALNT14 modifies O-glycosylation of EGFR; GALNT14 downregulation suppresses EGFR-mediated mTOR pathway activity, thereby reducing apoptosis and ferroptosis in ovarian cancer cells. Western blotting; GALNT14 knockdown; mTOR pathway activity assay; cell death assays (apoptosis and ferroptosis) Future oncology Low 34643088
2022 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. Lectin-capture glycoproteomic approach (LC-MS); site-directed mutagenesis (PHB2-S161); Co-IP for PHB2–IGFBP6 interaction; IGF1R signaling assays; cell functional assays Cell death & disease High 36376274
2023 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. GALNT14 overexpression and siRNA knockdown in Dakiki cells; IgA1 O-glycan analysis; subcellular localization by immunofluorescence Kidney international reports Medium 37180502
2024 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. LC-MS/MS glycoproteomic substrate identification; RNA-seq; RIP-seq; ROS measurement; in vitro and in vivo functional assays; siRNA knockdown Cellular signalling Medium 39426495
2025 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. 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 The Journal of clinical investigation High 40153534
2009 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. siRNA knockdown; flow cytometry; caspase-3 assay; RT-PCR; Western blot Journal of biosciences Low 19805900
2017 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. High-throughput Illumina sequencing to identify target genes; siRNA knockdown; overexpression; MTT drug sensitivity assay; Hoechst staining; Western blot Cellular physiology and biochemistry Medium 29227978
2019 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. Transfection/overexpression; MTT assay; colony formation assay; flow cytometry (cell cycle); Western blot The Journal of pharmacy and pharmacology Low 31713889
2025 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. GALNT14 overexpression and siRNA knockdown in HK-2 cells; in vivo cisplatin-AKI mouse model with GALNT14 overexpression; Western blot for ferroptosis markers; histopathology Kidney & blood pressure research Medium 40931477

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 GALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment. Nature communications 81 27982029
2003 Cloning and characterization of a novel UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase, pp-GalNAc-T14. Biochemical and biophysical research communications 78 12507512
2014 GALNT14 mediates tumor invasion and migration in breast cancer cell MCF-7. Molecular carcinogenesis 64 24962947
2021 GALNT14 regulates ferroptosis and apoptosis of ovarian cancer through the EGFR/mTOR pathway. Future oncology (London, England) 50 34643088
2015 Identification of GALNT14 as a novel neuroblastoma predisposition gene. Oncotarget 38 26309160
2016 MiR-125a regulates ovarian cancer proliferation and invasion by repressing GALNT14 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 37 27133078
2020 GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers. International journal of molecular sciences 36 32098271
2022 GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells. Cell death & disease 35 36376274
2020 Connectivity map-based drug repositioning of bortezomib to reverse the metastatic effect of GALNT14 in lung cancer. Oncogene 32 32388539
2010 Development of immunohistochemistry assays to assess GALNT14 and FUT3/6 in clinical trials of dulanermin and drozitumab. Clinical cancer research : an official journal of the American Association for Cancer Research 32 20179215
2015 GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma. Oncotarget 29 26544896
2011 GALNT14 SNP as a potential predictor of response to combination chemotherapy using 5-FU, mitoxantrone and cisplatin in advanced HCC. Pharmacogenomics 29 21635146
2013 A single nucleotide polymorphism on the GALNT14 gene as an effective predictor of response to chemotherapy in advanced hepatocellular carcinoma. International journal of cancer 27 23959947
2016 GALNT14 genotype effectively predicts the therapeutic response in unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Pharmacogenomics 22 26871639
2019 BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14. Molecular cancer research : MCR 19 31292201
2018 GALNT14 Involves the Regulation of Multidrug Resistance in Breast Cancer Cells. Translational oncology 18 29702465
2018 EFEMP2 Mediates GALNT14-Dependent Breast Cancer Cell Invasion. Translational oncology 16 29428518
2019 Oridonin enhances TRAIL-induced apoptosis through GALNT14-mediated DR5 glycosylation. Biochimie 15 31336136
2017 GALNT14 genotype as a response predictor for concurrent chemoradiotherapy in advanced esophageal squamous cell carcinoma. Oncotarget 14 28418863
2025 Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy. The Journal of clinical investigation 12 40153534
2014 Genotyping the GALNT14 gene by joint analysis of two linked single nucleotide polymorphisms using liver tissues for clinical and geographical comparisons. Oncology letters 11 25295111
2019 Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14. Current molecular medicine 9 31362688
2009 GalNAc-T14 may be involved in regulating the apoptotic action of IGFBP-3. Journal of biosciences 9 19805900
2023 Potentially functional genetic variants in ferroptosis-related CREB3 and GALNT14 genes predict survival of hepatitis B virus-related hepatocellular carcinoma. Cancer medicine 8 38151984
2023 GalNAc-T14 may Contribute to Production of Galactose-Deficient Immunoglobulin A1, the Main Autoantigen in IgA Nephropathy. Kidney international reports 7 37180502
2024 GALNT14-mediated O-glycosylation drives lung adenocarcinoma progression by reducing endogenous reactive oxygen species generation. Cellular signalling 5 39426495
2019 Effects of IGFBP-3 and GalNAc-T14 on proliferation and cell cycle of glioblastoma cells and its mechanism. The Journal of pharmacy and pharmacology 5 31713889
2017 Role of GALNT14 in lung metastasis of breast cancer. BMB reports 5 28347399
2017 Osterix Decreases the Chemosensitivity of Breast Cancer Cells by Upregulating GALNT14. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 29227978
2022 Association of rs9679162 Genetic Polymorphism and Aberrant Expression of Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) in Head and Neck Cancer. Cancers 4 36077753
2024 GALNT14 in association with GDF-15 promotes stemness and drug resistance through β-catenin signalling pathway in breast cancer. Molecular biology reports 3 38796671
2023 Stromal-epithelial interaction induces GALNT14 in prostate carcinoma cells. Frontiers in oncology 3 37671061
2023 Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) as a Chemosensitivity-Related Biomarker for Osteosarcoma. Journal of oncology 3 38024474
2025 GALNT14 deficiency: connecting multiple links in the IgA nephropathy pathogenetic chain. The Journal of clinical investigation 1 40371648
2024 GALNT6, GALNT14, and Gal-3 in association with GDF-15 promotes drug resistance and stemness of breast cancer via β-catenin axis. Growth factors (Chur, Switzerland) 1 38889447
2026 Integrative Systems Biology and Experimental Validation Unveil GALNT14 as a Novel Diagnostic Biomarker and Therapeutic Target for Sepsis. Human mutation 0 42147809
2025 Identification of GALNT14 as a Key Regulator of Ferroptosis in Cisplatin-Induced Acute Kidney Injury: A Potential Target for Kidney Injury Treatment. Kidney & blood pressure research 0 40931477

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