Affinage

NOTCH2

Neurogenic locus notch homolog protein 2 · UniProt Q04721

Length
2471 aa
Mass
265.4 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOTCH2 is a type I transmembrane receptor that converts ligand engagement into transcriptional output to control cell-fate decisions across developmental, immune, skeletal, and oncogenic contexts (PMID:1295745, PMID:26062937). Productive signaling requires sequential proteolysis: upon Delta-like/Jagged ligand binding, ADAM10 (not ADAM17) and presenilin-dependent gamma-secretase cleave the receptor to release the intracellular domain (N2ICD), which enters the nucleus and assembles with RBPJκ and MAML1 to drive HES/HEY target gene transcription (PMID:24842903, PMID:34725461). Ligand selectivity and signal strength are tuned at the cell surface by Fringe-mediated O-fucosylation, where Lunatic fringe enhances DLL1/DLL4-driven activation and Manic fringe restrains Jagged-driven activation (PMID:32820046), and human NOTCH2 is distinguished from NOTCH1 and murine Notch2 by resistance to ligand-independent ADAM17 cleavage (PMID:25918160); ICD-swap experiments establish that the NOTCH1 and NOTCH2 ICDs are intrinsically equivalent, so paralog-specific outcomes reflect differences in signal strength and N2ICD duration set by tissue-specific gamma-secretase (PMID:26062937). N2ICD abundance is further governed post-translationally by E3 ligases KLHL6 and DTX3, the deubiquitinase OTUD1 (acting at K1770), and arginine methylation by CARM1 that strengthens N2ICD–MAML1 binding (PMID:37235754, PMID:31854042, PMID:36574342, PMID:34725461). Through this machinery NOTCH2 directs nephron progenitor and lens differentiation (PMID:20299358, PMID:22173065), drives CD11b+ dendritic cell and marginal-zone vs. germinal-center B cell fate decisions (PMID:22018469, PMID:33597542, PMID:38438375), imposes quiescence on neural stem cells via an Id4 axis (PMID:29386140, PMID:31390563), promotes osteoclastogenesis through NF-κB/NFATc1 (PMID:18710934, PMID:38159855), and regulates muscle mass via an endothelial Dll4–Notch2 axis (PMID:35228746). In cancer it is context-dependent, acting as a differentiation-promoting tumor suppressor in lung and breast models while being stabilized by oncogenic mutation in lymphoma (PMID:24509876, PMID:17675579, PMID:37235754). Loss-of-function NOTCH2 mutations that reduce signaling cause Alagille syndrome (PMID:22209762).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1992 Medium

    Establishing NOTCH2 as a distinct mammalian Notch paralog defined the receptor as a candidate fate-determining molecule with its own expression domains rather than a redundant copy of Notch1.

    Evidence cDNA cloning with Northern blot and in situ hybridization expression profiling

    PMID:1295745

    Open questions at the time
    • No functional or signaling mechanism defined
    • Ligand and downstream targets unknown at this stage
  2. 1999 High

    Genetic disruption of the cytoplasmic ankyrin repeats showed they are indispensable and that Notch2 has non-redundant functions distinct from Notch1, framing the ICD as the functional effector.

    Evidence Knock-in gene targeting replacing ankyrin repeats in mice, with TUNEL and in situ readouts

    PMID:10393120

    Open questions at the time
    • Did not resolve which downstream complex the ankyrin repeats engage
    • Embryonic lethality limited tissue-specific analysis
  3. 2002 Medium

    Comparing ICD transcriptional activities revealed paralog-specific, RBPJκ-dependent effects on HES promoters, raising the question of how paralog identity translates into distinct outputs.

    Evidence Luciferase reporter assays on HES1/HES5 promoters with truncated ICD constructs

    PMID:11866432

    Open questions at the time
    • In vitro overexpression may not reflect physiological stoichiometry
    • Cross-suppression mechanism not defined
  4. 2008 High

    Defining the Notch2 ICD–p65 interaction at the NFATc1 promoter established a concrete molecular mechanism coupling Notch2 to NF-κB during osteoclastogenesis.

    Evidence Co-IP, ChIP, reporter assays, knockdown and ICD overexpression in bone marrow macrophages

    PMID:18710934

    Open questions at the time
    • Whether NF-κB cooperation generalizes beyond osteoclasts unclear at the time
    • Direct contact surface between N2ICD and p65 not mapped
  5. 2011 High

    Tissue-specific knockouts established non-redundant Notch2 roles in dendritic cell differentiation and lens morphogenesis, moving the receptor from candidate to validated fate determinant in defined cell types.

    Evidence DC-specific and lens-specific conditional knockout mice with flow cytometry, T cell priming assays, histology and gene expression

    PMID:22018469 PMID:22173065

    Open questions at the time
    • Direct transcriptional targets in these tissues not fully defined
    • Ligand source driving activation in vivo not always identified
  6. 2011 Medium

    Demonstrating that Alagille-associated NOTCH2 variants reduce signaling established loss-of-function as the disease mechanism, linking quantitative signaling output to human pathology.

    Evidence Cell-based Notch reporter assays on six patient-derived NOTCH2 mutations

    PMID:22209762

    Open questions at the time
    • Tissue-level consequences of partial signaling loss not modeled
    • Single assay system for diverse mutation types
  7. 2014 High

    Dissecting the proteolytic cascade established that NOTCH2 activation depends on ADAM10 and presenilin gamma-secretase but not ADAM17, defining the canonical activation route shared with other Notch paralogs.

    Evidence Notch signaling and cleavage assays under ADAM10/ADAM17/presenilin knockout or inhibitor conditions

    PMID:24842903

    Open questions at the time
    • Did not address ligand-independent activation differences between species
    • Spatial site of cleavage not resolved
  8. 2014 High

    Knockouts in cancer and kidney models revealed that Notch2 can act as a tumor suppressor promoting differentiation and can signal to Akt for podocyte survival, expanding its functions beyond canonical HES transcription.

    Evidence Conditional Notch2 deletion in KrasG12D NSCLC model; Notch2 agonist antibody plus Akt inhibitor rescue in nephrosis model

    PMID:24509876 PMID:24526233

    Open questions at the time
    • Mechanism linking N2ICD to Akt not biochemically defined
    • Cell-type basis of tumor suppressor vs. oncogenic switch unresolved
  9. 2015 High

    ICD-swap and NRR comparison experiments resolved why paralogs differ: the ICDs are intrinsically equivalent and outcomes depend on signal strength, ICD duration, and species/paralog-specific regulatory regions.

    Evidence Knock-in ICD-swap mice across multiple tissues; biochemical NRR comparison of human vs. murine Notch1/Notch2

    PMID:25918160 PMID:26062937

    Open questions at the time
    • Molecular determinants setting tissue-specific gamma-secretase activity not identified
    • Quantitative ICD thresholds for fate decisions not measured
  10. 2018 High

    Multiple in vivo studies established Notch2 as a controller of stem cell quiescence and lineage selection, with a defined Notch2→Id4 axis and direct profibrotic targeting of Tfam, showing how the receptor reprograms differentiation and metabolism.

    Evidence Conditional knockouts in V-SVZ NSCs and renal tubular epithelium; ChIP on Tfam promoter; Tfam rescue; later Id4 epistasis with rescue

    PMID:29386140 PMID:30226866 PMID:31390563

    Open questions at the time
    • How Notch2 selects quiescence vs. proliferation programs not fully defined
    • Direct vs. indirect target relationships vary by tissue
  11. 2020 High

    Identifying Fringe-mediated O-fucosylation and E3 ligase DTX3 control established two layers—glycosylation and ubiquitin-dependent degradation—that tune NOTCH2 ligand selectivity and abundance.

    Evidence Mass spectrometry O-fucose site mapping with mutagenesis and signaling assays; Y2H, Co-IP and ubiquitination assays for DTX3

    PMID:31854042 PMID:32820046

    Open questions at the time
    • In vivo relevance of individual O-fucose sites for NOTCH2 incompletely defined
    • DTX3 regulation primarily shown in cancer cell systems
  12. 2021 High

    Discovery of CARM1 methylation of N2ICD and OTUD1 deubiquitination at K1770 established post-translational control of N2ICD stability and of its binding to MAML1, directly linking modification state to transcriptional output.

    Evidence ChIP-seq, site-directed mutagenesis of methylation sites, Co-IP of N2ICD-MAML1; site-specific K1770 deubiquitination assays with conditional knockouts and GVHD model

    PMID:34725461 PMID:36574342

    Open questions at the time
    • Interplay between methylation, ubiquitination, and degradation not integrated
    • Generality across tissues beyond gastric cancer and T cells untested
  13. 2021 High

    Inducible B-cell experiments established that a single Notch2 signaling event reprograms follicular B cells to marginal-zone identity, demonstrating Notch2 as a binary fate switch in mature cells.

    Evidence Inducible Notch2IC expression in mature FoB cells with transcriptome and functional characterization

    PMID:33597542

    Open questions at the time
    • Physiological trigger of the switch in vivo not defined here
    • Stability/reversibility of reprogrammed state untested
  14. 2022 High

    Identifying an endothelial Dll4–Notch2 axis acting on multinucleated myofibers without cell-cell contact extended Notch2 signaling to muscle mass regulation and a non-classical ligand presentation mode.

    Evidence Myofiber conditional knockout and Dll4/Notch2 blocking antibodies across disuse, diabetic atrophy and overload-hypertrophy models

    PMID:35228746

    Open questions at the time
    • Mechanism of contact-independent ligand delivery not resolved
    • Downstream transcriptional program in myofibers not detailed
  15. 2023 High

    Defining KLHL6 as an E3 ligase whose evasion by DLBCL mutations stabilizes NOTCH2 established a mutation-driven oncogenic mechanism and connected NOTCH2 stability to RAS signaling.

    Evidence CRISPR cullin-RING ligase screen, proteomics, ubiquitination assays, pharmacological rescue with gamma-secretase and AKT inhibitors

    PMID:37235754

    Open questions at the time
    • Mechanism linking stabilized NOTCH2 to RAS activation not fully mapped
    • Whether KLHL6 control operates in non-lymphoid tissues unknown
  16. 2023 Medium

    Mechanistic studies revealed that NOTCH2 output can occur through non-canonical routes, including TNFα-driven RBPJκ displacement in chondrocytes and Hes1-dependent metabolic reprogramming in osteoclasts, refining how context redirects signaling.

    Evidence Notch2 gain-of-function mouse cells with EMSA for RBPJκ binding, RNA-seq, scRNA-seq and Hes1 epistasis

    PMID:37865314 PMID:38159855

    Open questions at the time
    • Generality of RBPJκ displacement mechanism beyond chondrocytes untested
    • Single-lab models for the gain-of-function allele
  17. 2024 High

    Complementary B-cell and cancer studies refined Notch2 as a quantitative binary fate determinant (GC vs. MZB) and showed Wnt-pathway crosstalk via N2ICD activation of TCF7L2 transcription without direct protein interaction.

    Evidence Conditional ablation and constitutive activation in B cells with mathematical modeling; organoid screening, ADAM10 modulation, and negative N2ICD-TCF7L2 Co-IP with transcriptional assays

    PMID:38438375 PMID:39601111

    Open questions at the time
    • Indirect mechanism of TCF7L2 transcriptional activation not fully resolved
    • Thresholds setting the GC vs. MZB decision in physiological immunization incompletely quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the layered control of N2ICD dose and duration—glycosylation, methylation, ubiquitination/deubiquitination, and tissue-specific gamma-secretase—integrates to produce opposite (tumor-suppressive vs. oncogenic) outcomes in different cell types remains unresolved.
  • No unified quantitative model linking modification state to fate output
  • Determinants of cell-type-specific tumor suppressor vs. oncogene behavior undefined
  • Crosstalk hierarchy among the post-translational regulators not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060089 molecular transducer activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ADAM10CARM1DTX3KLHL6MAML1OTUD1RBPJTRAF6
Complex memberships
N2ICD-RBPJk-MAML1 transcriptional activation complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 NOTCH2 encodes a second mammalian Notch receptor containing all structural motifs characteristic of Notch proteins (EGF-like repeats, transmembrane domain, ankyrin repeats), establishing it as a paralog of Drosophila Notch with distinct spatial and temporal expression patterns from Notch1. cDNA cloning, Northern blot, in situ hybridization Development Medium 1295745
1999 The ankyrin repeats in the cytoplasmic domain of Notch2 are indispensable for its function; mice homozygous for a Notch2 mutation replacing ankyrin repeats die before E11.5 with increased apoptosis in neural tissues, while somitogenesis and neurogenic gene regulation (Hes-5, Mash1) are unaffected, distinguishing Notch2 from Notch1 functionally. Gene targeting (knock-in of beta-galactosidase replacing ankyrin repeats), X-gal staining, in situ hybridization, TUNEL assay Development High 10393120
2002 The intracellular domains of Notch1, Notch2, and Notch3 have distinct and non-equivalent transcriptional activities on HES1 and HES5 promoters; Notch2 ICD can suppress the transcriptional activities of Notch1 and Notch3 ICDs in a dose-dependent and promoter-dependent manner, and activity depends on RBP-Jκ expression levels. Luciferase reporter assay using HES1-Luc and HES5-Luc constructs, transfection of truncated ICD forms, co-expression experiments Biochemical and biophysical research communications Medium 11866432
2006 Constitutively activated Notch2 in pre-gonadotrope and pre-thyrotrope cells delays gonadotrope differentiation, with Hey1 as a candidate mediator; gonadotrope differentiation eventually completes but is mutually exclusive with Notch2 transgene expression, demonstrating that activated Notch2 is sufficient to delay pituitary progenitor differentiation. Transgenic mice expressing activated NOTCH2 ICD under alphaGSU promoter, histology, immunostaining for LH/FSH/Hey1 Molecular endocrinology Medium 16840533
2007 Notch2 ICD expression induces apoptosis in MDA-MB-231 breast adenocarcinoma cells and potently suppresses tumor xenograft growth in vivo, demonstrating a tumor-suppressive role distinct from the oncogenic Notch4 ICD in this context. Stable ICD expression, in vitro apoptosis assays, nude mouse xenograft tumor growth assay The American journal of pathology Medium 17675579
2008 RANKL induces expression of Jagged1 and Notch2 in bone marrow macrophages during osteoclastogenesis; Notch2 ICD and p65 (NF-κB) physically interact in the nucleus of RANKL-stimulated cells and are co-recruited to the NFATc1 promoter, driving NFATc1 expression and osteoclast differentiation. shRNA knockdown, gamma-secretase inhibitor, ectopic Notch2 ICD expression, luciferase reporter assay, Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) Molecular and cellular biology High 18710934
2010 SCF (stem cell factor) signaling induces upregulation of Notch2 in primary human erythroblasts; functional inhibition of Notch or Jagged1 blocks SCF-mediated erythroid expansion, and dominant-negative Notch2 inhibits both basal and SCF-mediated erythroblast expansion while counteracting SCF-mediated delay of differentiation. SCF also induces Hes-1 and GATA-2 downstream of Notch2. Primary human erythroblast culture, dominant-negative Notch2 retroviral transduction, Notch/Jagged1 inhibitory antibodies, gene expression analysis Cell death and differentiation Medium 20829885
2010 Constitutive activation of Notch2 in Six2-positive nephron progenitor cells of the metanephric mesenchyme depletes the progenitor pool through ectopic Wnt4 expression and premature tubule formation, and suppresses Pax2 possibly through Hesr genes, revealing a positive feedback loop between Notch2 and Wnt4 in which Notch2 stabilizes nephron fate by shutting down progenitor maintenance. Conditional Notch2 gain-of-function mouse (Six2-Cre), histology, in situ hybridization, gene expression analysis Journal of the American Society of Nephrology Medium 20299358
2011 DC-specific deletion of Notch2 ablates the Esam(hi) CD11b+ DC subset in the spleen (which requires lymphotoxin beta receptor signaling and facilitates CD4+ T cell priming) and eliminates CD11b+CD103+ DCs in the intestinal lamina propria, demonstrating that Notch2 is a common differentiation signal for T cell-priming CD11b+ DC subsets. DC-specific Notch2 conditional knockout mice, flow cytometry, T cell priming assays, in vivo lymphotoxin beta receptor signaling analysis Immunity High 22018469
2011 Conditional deletion of Notch2 in the ocular lens causes microphthalmia, persistent lens stalks, disrupted fiber cell morphology, aberrant DNA synthesis in fiber cells, denucleation defects, and cataracts; loss of Notch2 elevates Cdkn1a (p21), CyclinD2, and p63 while downregulating E-Cadherin, demonstrating roles for Notch2 in lens morphogenesis, apoptosis suppression, cell cycle withdrawal, and secondary fiber cell differentiation. Conditional Notch2 knockout (lens-specific Cre), histology, immunostaining, gene expression analysis, BrdU labeling Developmental biology High 22173065
2011 Functional analysis of NOTCH2 missense, nonsense, and splicing mutations found in Alagille syndrome patients demonstrated decreased Notch signaling activity for these variants, establishing loss-of-function as the molecular mechanism underlying NOTCH2-associated Alagille syndrome. Cell-based Notch signaling reporter assays for six patient-derived NOTCH2 mutations Journal of medical genetics Medium 22209762
2014 Proteolytic activation of NOTCH2 requires sequential cleavage by ADAM10 metalloprotease and presenilin-1 or -2 (gamma-secretase) upon canonical Delta/Jagged ligand binding; ADAM17/TACE is not required for ligand-induced NOTCH2 signaling, establishing that NOTCH1, -2, and -3 share a common ADAM10-dependent activation mechanism. Notch signaling assays with ADAM10/ADAM17/presenilin knockout or inhibitor conditions, NOTCH2 cleavage assays Molecular and cellular biology High 24842903
2014 Notch2 ICD-specific activation of Akt signaling protects podocytes from apoptosis; a Notch2 agonistic antibody ameliorates proteinuria and glomerulosclerosis in a nephrosis mouse model, and this protective effect is abolished by the Akt inhibitor triciribine, placing Notch2 upstream of Akt in podocyte survival. Notch2 agonistic monoclonal antibody in vivo, Notch2 siRNA knockdown in vitro, Akt inhibitor rescue experiment, mouse nephrosis model Nature communications High 24526233
2014 Notch2 deletion in a KrasG12D-driven NSCLC mouse model dramatically increases carcinogenesis and accelerates death; Notch2-deficient tumors show increased beta-catenin expression, undifferentiated phenotype, and aggressive growth, while Notch1 regulates MAPK via HES1-DUSP1. Notch2 and Notch1 have opposing roles: Notch2 mediates differentiation and tumor suppression, Notch1 promotes tumor initiation. Conditional Notch1 and Notch2 receptor deletion in KrasG12D endogenous NSCLC mouse model, tumor morphometry, IHC, gene expression Oncogene High 24509876
2015 Swapping the intracellular domains of Notch1 and Notch2 in mice shows their ICDs are functionally equivalent; differences in developmental outcomes between Notch1 and Notch2 are explained by differences in signal strength (number of ICD molecules reaching the nucleus) and duration (half-life of NICD-RBPjk-MAML-DNA complexes), with tissue-specific gamma-secretase complexes contributing to differential NICD stability. Knock-in ICD swap mice, T-cell development assays, skin differentiation, inner ear, lung, retina phenotyping; epistasis analysis Development High 26062937
2015 Human NOTCH2 is resistant to ligand-independent activation by ADAM17 (TACE), unlike human NOTCH1 and murine Notch2, which both require ADAM17 for ligand-independent signaling; this reveals subtle but functionally important differences in the negative regulatory region (NRR) between NOTCH paralogs and between human and murine NOTCH2. Biochemical cleavage assays, cell-based Notch signaling assays, comparison of human vs. murine Notch1/Notch2 NRR The Journal of biological chemistry High 25918160
2015 Simultaneous loss of Notch2 and Notch3 in vascular smooth muscle cells causes patent ductus arteriosus (PDA), aortic dilation, and subcutaneous hemorrhage, associated with decreased expression of smooth muscle contractile markers; these receptors have overlapping roles in vascular smooth muscle differentiation. Smooth muscle-specific Notch2 conditional knockout combined with global Notch3 deletion, vascular morphology analysis, IHC for contractile markers Genesis Medium 26453897
2017 Notch2 blockade (but not Notch1 blockade) sensitizes hematopoietic stem/progenitor cells (HSPCs) to mobilization stimuli and promotes their egress from marrow; Notch2 loss decreases CXCR4 expression on HSCs through direct regulation of CXCR4 transcription by the Notch transcriptional protein RBPJ. Notch receptor-blocking antibodies in vivo, conditional Notch2 knockout mice, flow cytometry, CXCR4 expression analysis, ChIP for RBPJ on CXCR4 promoter Haematologica High 28729299
2018 Notch2, but not Notch1, conveys quiescence to ventricular-subventricular zone (V-SVZ) neural stem cells (NSCs) by repressing cell-cycle-related genes and neurogenesis; loss of Notch2 activates quiescent NSCs leading to accelerated exhaustion and an aging-like phenotype. Conditional Notch2 knockout mice (V-SVZ NSC-specific), BrdU/EdU labeling, gene expression analysis, comparison with Notch1 and Rbpj knockouts Cell reports High 29386140
2018 Notch2 is the primary determinant of hepatocyte-derived intrahepatic cholangiocarcinoma (ICC) formation; deletion of Notch2 (but not Notch1) in AKT/Yap-induced tumors switches phenotype from ICC to hepatocellular adenoma-like lesions, and Notch2 silencing in ICC cell lines downregulates the biliary markers Sox9 and EpCAM. Notch1/Notch2 conditional knockout mice, AKT/Yap hydrodynamic injection model, lineage tracing, siRNA knockdown in human ICC/HCC lines, Western blot Oncogene High 29545603
2018 Jagged1/Notch2 signaling in renal tubular epithelial cells drives kidney fibrosis by directly targeting the mitochondrial transcription factor Tfam; re-expression of Tfam prevents Notch-induced metabolic and profibrotic reprogramming; tubule-specific deletion of Jag1 or Notch2 (but not Notch1 or Notch3) protects from folic acid-induced nephropathy. Tubule-specific Jag1 and Notch2 conditional knockout mice, folic acid nephropathy model, ChIP for Notch target on Tfam promoter, genome-wide expression studies, Tfam re-expression rescue PLoS biology High 30226866
2018 MINAR1 (KIAA1024/UPF0258) physically interacts with Notch2, increases its stability and signaling function, and negatively regulates angiogenesis; MINAR1 is a large intrinsically disordered protein with a single transmembrane domain expressed in breast epithelial and endothelial cells. Co-immunoprecipitation, pulldown, angiogenesis assays (cell culture, matrigel plug, zebrafish model), breast cancer xenograft model Journal of molecular cell biology Medium 29329397
2019 Id4 is a direct downstream target of Notch2 signaling in hippocampal dentate gyrus NSCs and maintains quiescence by blocking cell-cycle entry; Id4 expression is sufficient to promote NSC quiescence, Id4 knockdown rescues Notch2-induced inhibition of NSC proliferation, establishing a Notch2-Id4 axis that uncouples NSC activation from neuronal differentiation. Conditional Notch2 knockout, Id4 knockout and overexpression mice, lentiviral Id4 knockdown, BrdU labeling, gene expression analysis Cell reports High 31390563
2019 NOTCH2 intracellular domain (N2ICD) interacts with TRAF6 via immunoprecipitation, attenuating the TRAF6-AKT signaling axis to inhibit epithelial-mesenchymal transition (EMT) and suppress metastasis in nasopharyngeal carcinoma. Immunoprecipitation, Western blot, cell migration/invasion assays, mouse tumor metastasis models, GSEA Journal of experimental & clinical cancer research Medium 31699119
2020 Fringe enzymes differentially modulate NOTCH2 vs. NOTCH1: Lunatic fringe (LFNG) enhances NOTCH2 activation by DLL1/DLL4 through O-fucosylation on EGF8 and EGF12, while Manic fringe (MFNG) inhibits NOTCH2 activation by JAG1/JAG2; a single O-fucose site mutant blocking MFNG inhibition of NOTCH2-JAG1 signaling was not identifiable (unlike NOTCH1). O-fucosylation on EGF9 is important for trafficking of both NOTCH1 and NOTCH2. Cell-based Notch signaling assays, ligand-binding assays, mass spectrometry (O-fucose site mapping), site-directed mutagenesis of O-fucose sites The Journal of biological chemistry High 32820046
2020 DTX3 (Deltex E3 ubiquitin ligase 3) is a novel E3 ligase for NOTCH2; DTX3 promotes ubiquitination and proteasome-dependent degradation of NOTCH2, and DTX3 overexpression suppresses esophageal carcinoma cell proliferation and tumorigenicity. Yeast two-hybrid screening, Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, overexpression/knockdown functional assays Cancer science Medium 31854042
2020 CAFs-derived MFAP5 promotes bladder cancer by directly interacting with the NOTCH2 receptor to stimulate N2ICD release, activating the NOTCH2/HEY1 signaling pathway; DLL4/NOTCH2 pathway activation also mediates MFAP5 effects via PI3K-AKT signaling. Luciferase reporter assay, EMSA, Co-immunoprecipitation, shRNA knockdown, anti-NOTCH2 antibody (NRR2Mab), RNA-sequencing, in vivo xenograft FASEB journal Medium 32293074
2020 The DLL1-NOTCH2 ligand-receptor pair is required for satellite cell self-renewal during muscle regeneration; differentiating satellite cells expressing Dll1 signal via NOTCH2 to neighboring cells to maintain the progenitor pool in a proportional feedback mechanism. Single-cell RNA-sequencing (identifying Notch2-enriched satellite cell subpopulation), antagonistic antibodies against DLL1 and NOTCH2, in vivo muscle regeneration assay Cell reports High 32023464
2021 Induced Notch2 ICD expression in mature follicular B (FoB) cells reprograms them into bona fide marginal zone B (MZB) cells (surface phenotype, localization, immunological function, transcriptome), demonstrating plasticity between mature B cell populations driven by a singular Notch2 signaling event. Inducible Notch2IC expression in FoB cells in immunocompetent mice, flow cytometry, transcriptome analysis, localization and functional assays Nature communications High 33597542
2021 CARM1 (coactivator-associated arginine methyltransferase 1) is recruited to the nucleus by Nup54, where it cooperates with TFEB to activate Notch2 transcription by inducing H3R17me2 (but not H3R26me2) at the Notch2 promoter; CARM1 also methylates the Notch2 ICD (N2ICD) at R1786, R1838, and R2047, which enhances N2ICD binding to MAML1 and promotes gastric cancer cell proliferation. ChIP-seq, RNA-seq, Co-IP (Nup54-CARM1 and N2ICD-MAML1 interactions), site-directed mutagenesis of N2ICD methylation sites, in vitro and in vivo proliferation assays Oncogene High 34725461
2021 The deubiquitinase OTUD1 interacts with Notch2-ICD (NICD) and cleaves ubiquitin from NICD at the K1770 site, thereby stabilizing NICD protein in activated CD4+ T cells and promoting Th1/Th17 differentiation and graft-versus-host disease. Co-immunoprecipitation, ubiquitination assay, site-specific K1770 deubiquitination, conditional knockout mice, GVHD model, FDA-approved drug screen Blood High 36574342
2021 FCER2 pulls down N2ICD (NOTCH2 intracellular domain) and N2ICD binds FCER2 in human spermatogonial stem cells (SSCs); the RNF144B-FCER2-NOTCH2/HES1 pathway regulates SSC proliferation and survival. Co-immunoprecipitation (RNF144B-FCER2; FCER2-N2ICD), RNA sequencing, siRNA/overexpression functional assays Journal of cellular physiology Medium 35699595
2021 Notch2 signaling directly promotes FOXP3 transcription and Treg cell differentiation in human CD4+ T cells in vitro; in an allergic rhinitis mouse model, Notch2 overexpression increased Treg cell differentiation and reduced allergic inflammation. In vitro human CD4+ T cell differentiation assay, luciferase reporter for FOXP3 transcription, lentiviral Notch2 overexpression in AR mouse model, flow cytometry for Treg cells Life sciences Medium 34480930
2022 In skeletal muscle, multinucleated myofibers express Notch2, which is activated by endothelium-derived Dll4 released without direct cell-cell contact under atrophic conditions (disuse or diabetes); inhibition of the Dll4-Notch2 axis prevents muscle atrophy and promotes hypertrophy in mice. Conditional Notch2 knockout in myofibers, Dll4/Notch2 inhibitory antibodies, mouse models of disuse and diabetic atrophy and mechanical overload-induced hypertrophy, molecular analysis Nature metabolism High 35228746
2023 KLHL6 is a novel E3 ubiquitin ligase that targets plasma membrane-associated NOTCH2 for proteasome-dependent degradation; DLBCL-associated NOTCH2 mutations cause protein escape from this KLHL6-mediated ubiquitin-dependent proteolysis, leading to NOTCH2 stabilization and activation of oncogenic RAS signaling in chemoresistant tumors. CRISPR-Cas9 cullin-RING ligase library screen, proteomic approaches identifying KLHL6-NOTCH2 interaction, ubiquitination assays, pharmacological rescue with gamma-secretase inhibitor and AKT inhibitor Blood High 37235754
2023 DLL1-induced NOTCH2 signaling efficiently induces the transition of Ly6Chi TREML4- monocytes into Ly6Clo TREML4+ nonclassical monocytes in vitro; this transition requires IRF2 but can occur without NUR77 or BCL6, establishing a transcriptional hierarchy downstream of Notch2 in monocyte development. In vitro DLL1-driven Notch2 activation, myeloid-specific BCL6/IRF2 knockout mice, flow cytometry for monocyte subset phenotype PNAS Medium 37607223
2023 A pan-cancer tRNA-derived fragment CAT1 binds RBPMS and displaces NOTCH2 mRNA from RBPMS, thereby inhibiting CCR4-NOT deadenylation complex-mediated NOTCH2 mRNA decay and stabilizing NOTCH2 mRNA to promote lung cancer proliferation and metastasis. RNA pulldown, RIP assay, NOTCH2 mRNA stability assay, CAT1 overexpression/knockdown in vitro and in vivo Cell reports Medium 37943661
2023 NOTCH2 gain-of-function enhances osteoclastogenesis by upregulating cell metabolism, aerobic respiration, and mitochondrial function in osteoclast progenitors; these pathways are not enhanced in the context of Hes1 inactivation, placing Hes1 as an obligate mediator of NOTCH2-driven osteoclast metabolic enhancement. Bulk RNA-seq, single-cell RNA-seq, pseudotime trajectory analysis of Notch2 gain-of-function (Notch2tm1.1Ecan) and Hes1-conditional knockout bone marrow macrophages The Journal of biological chemistry Medium 38159855
2023 NOTCH2 gain-of-function enhances TNFα-induced Il6 and Il1b expression in chondrocytes; TNFα displaces RBPJκ from DNA binding sites (demonstrated by EMSA), explaining both increased Il6 expression and concomitant decrease in canonical Notch target genes Hes1/Hey1/Hey2/Heyl. NOTCH2 also enhances TNFα-activated NF-κB signaling. Notch2 gain-of-function mouse chondrocytes (Notch2tm1.1Ecan), NOTCH2-ICD overexpression, EMSA for RBPJκ DNA binding, RNA-seq, NF-κB signaling assays The Journal of biological chemistry High 37865314
2024 NOTCH2 mediates immune escape in hepatocellular carcinoma by NETs-activated NF-κB pathway upregulating CD73, which promotes regulatory T cell infiltration; DNase I inhibition of NETs reduces this NOTCH2-mediated CD73 upregulation. In vitro NETs stimulation, NOTCH2 pathway analysis, CD73 expression assays, mouse HCC model by hydrodynamic plasmid transfection, anti-PD-1 combination experiments Cancer letters Medium 38969159
2024 Notch2 signaling controls the fate decision between germinal center (GC) B cells and marginal zone B (MZB) cells upon immunization: antigen-activated FoB cells that turn off Notch2 signaling enter GCs, while high Notch2 signaling drives MZB cell generation or plasmablast differentiation; mathematical modeling supports a binary Notch2-dependent fate decision. Conditional Notch2 ablation and constitutive activation in B cells during T-cell-dependent immunization, flow cytometry for B cell subsets, mathematical modeling Nature communications High 38438375
2024 ADAM10 regulates NOTCH2 protein expression in colorectal cancer; the NOTCH2 ICD directly activates TCF7L2 transcription and Wnt target genes (MYC, JUN, CCND1/2) without directly interacting with TCF7L2 protein, establishing a NOTCH2-mediated transcriptional regulation of the Wnt pathway axis. High-throughput organoid drug screening, ADAM10 knockdown/inhibition, NOTCH2 and TCF7L2 Co-IP (negative for direct interaction), ChIP or transcriptional reporter assays for TCF7L2 regulation Advanced science Medium 39601111

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 434 22018469
1992 Notch2: a second mammalian Notch gene. Development (Cambridge, England) 321 1295745
1999 Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development (Cambridge, England) 238 10393120
2014 Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell reports 201 25558064
2011 NOTCH2 mutations in Alagille syndrome. Journal of medical genetics 162 22209762
2008 The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Molecular and cellular biology 151 18710934
2019 Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Human mutation 113 31343788
2007 Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. The American journal of pathology 100 17675579
2018 Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 98 29545603
2017 Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells. Stem cells (Dayton, Ohio) 93 29139178
2018 Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone. Cell reports 92 29386140
2007 Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner. Developmental dynamics : an official publication of the American Association of Anatomists 92 17080428
2002 Functional diversity among Notch1, Notch2, and Notch3 receptors. Biochemical and biophysical research communications 90 11866432
2019 Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus. Cell reports 81 31390563
2015 The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis. Development (Cambridge, England) 76 26062937
2018 Notch2-dependent DC2s mediate splenic germinal center responses. Proceedings of the National Academy of Sciences of the United States of America 74 30279176
2014 Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model. Oncogene 69 24509876
2014 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins. Molecular and cellular biology 69 24842903
2018 miR-181b/Notch2 overcome chemoresistance by regulating cancer stem cell-like properties in NSCLC. Stem cell research & therapy 68 30470250
2019 Notch2 pathway mediates breast cancer cellular dormancy and mobilisation in bone and contributes to haematopoietic stem cell mimicry. British journal of cancer 66 31239543
2018 Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS biology 65 30226866
2010 Notch2 activation in the embryonic kidney depletes nephron progenitors. Journal of the American Society of Nephrology : JASN 60 20299358
2020 Canonical Notch ligands and Fringes have distinct effects on NOTCH1 and NOTCH2. The Journal of biological chemistry 59 32820046
2017 MiR-18a-5p inhibits endothelial-mesenchymal transition and cardiac fibrosis through the Notch2 pathway. Biochemical and biophysical research communications 57 28733035
2016 Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut 56 26933171
1995 Differential expression of Notch1 and Notch2 in developing and adult mouse brain. Brain research. Molecular brain research 55 7609614
2013 MicroRNA-107 inhibits glioma cell migration and invasion by modulating Notch2 expression. Journal of neuro-oncology 54 23299462
2020 Aberrant expression of miR-29b-3p influences heart development and cardiomyocyte proliferation by targeting NOTCH2. Cell proliferation 53 32077168
2006 Persistent expression of Notch2 delays gonadotrope differentiation. Molecular endocrinology (Baltimore, Md.) 53 16840533
2020 Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal. Cell reports 52 32023464
2011 Differential Notch1 and Notch2 expression and frequent activation of Notch signaling in gastric cancers. Archives of pathology & laboratory medicine 52 21466361
2019 The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. American journal of cancer research 51 31218097
2019 JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix. Arthritis research & therapy 47 31619270
2014 NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML. Blood 47 24574459
2020 CAFs-derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 32293074
2003 Notch2 protein distribution in human teeth under normal and pathological conditions. Experimental cell research 46 12531696
2013 Increased LEF1 expression and decreased Notch2 expression are strong predictors of poor outcomes in colorectal cancer patients. Disease markers 45 24223455
2016 NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus. American journal of physiology. Gastrointestinal and liver physiology 44 27932500
2015 The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis. Oncotarget 44 26041881
2011 Conditional ablation of the Notch2 receptor in the ocular lens. Developmental biology 42 22173065
2022 The endothelial Dll4-muscular Notch2 axis regulates skeletal muscle mass. Nature metabolism 40 35228746
2019 NOTCH2 negatively regulates metastasis and epithelial-Mesenchymal transition via TRAF6/AKT in nasopharyngeal carcinoma. Journal of experimental & clinical cancer research : CR 40 31699119
2024 Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2. Cancer letters 37 38969159
2021 Notch2-mediated plasticity between marginal zone and follicular B cells. Nature communications 37 33597542
2014 Notch1 and Notch2 expression in osteoblast precursors regulates femoral microarchitecture. Bone 37 24508387
2016 Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations. Current osteoporosis reports 35 27241678
2014 Notch2 activation ameliorates nephrosis. Nature communications 35 24526233
2009 Notch2 expression is decreased in colorectal cancer and related to tumor differentiation status. Annals of surgical oncology 35 19653042
2018 lncAKHE enhances cell growth and migration in hepatocellular carcinoma via activation of NOTCH2 signaling. Cell death & disease 34 29706630
2020 Ubiquitination of NOTCH2 by DTX3 suppresses the proliferation and migration of human esophageal carcinoma. Cancer science 27 31854042
2018 Mesenchymal stem cell-mediated Notch2 activation overcomes radiation-induced injury of the hematopoietic system. Scientific reports 27 29915190
2015 Expression pattern and function of Notch2 in different subtypes of first trimester cytotrophoblast. Placenta 27 25659500
2015 Loss of Notch2 and Notch3 in vascular smooth muscle causes patent ductus arteriosus. Genesis (New York, N.Y. : 2000) 27 26453897
2019 NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer. Oncology letters 26 31186700
2020 Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis. Neuroscience research 25 33309869
2024 LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer. Cancer letters 24 38462037
2024 Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade. Nature communications 24 39505846
2021 MiR-485-3p promotes proliferation of osteoarthritis chondrocytes and inhibits apoptosis via Notch2 and the NF-κB pathway. Immunopharmacology and immunotoxicology 24 33961511
2021 Notch2 suppression mimicking changes in human pulmonary hypertension modulates Notch1 and promotes endothelial cell proliferation. American journal of physiology. Heart and circulatory physiology 24 34296965
2021 Notch2 suppresses the development of allergic rhinitis by promoting FOXP3 expression and Treg cell differentiation. Life sciences 24 34480930
2014 MicroRNA expression profiling and Notch1 and Notch2 expression in minimal deviation adenocarcinoma of uterine cervix. World journal of surgical oncology 24 25381598
2012 The expression of NOTCH2, HES1 and SOX9 during mouse retinal development. Gene expression patterns : GEP 24 23277114
2021 Nup54-induced CARM1 nuclear importation promotes gastric cancer cell proliferation and tumorigenesis through transcriptional activation and methylation of Notch2. Oncogene 23 34725461
2017 Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica 23 28729299
2023 DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood 22 37235754
2020 NOTCH2 participates in Jagged1-induced osteogenic differentiation in human periodontal ligament cells. Scientific reports 22 32770090
2015 Human NOTCH2 Is Resistant to Ligand-independent Activation by Metalloprotease Adam17. The Journal of biological chemistry 22 25918160
2013 The different role of Notch1 and Notch2 in astrocytic gliomas. PloS one 22 23349727
2019 miR-758-3p suppresses human bladder cancer cell proliferation, migration and invasion by targeting NOTCH2. Experimental and therapeutic medicine 21 30988799
2018 Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients. JCI insight 21 29875313
2010 The Notch2-Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell death and differentiation 21 20829885
2023 Pan-cancer tRNA-derived fragment CAT1 coordinates RBPMS to stabilize NOTCH2 mRNA to promote tumorigenesis. Cell reports 20 37943661
2018 Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology. Human mutation 20 30304577
2019 MicroRNA-16 is involved in the pathogenesis of pre-eclampsia via regulation of Notch2. Journal of cellular physiology 19 31643078
2017 Mechanism of MicroRNA-146a/Notch2 Signaling Regulating IL-6 in Graves Ophthalmopathy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 28278511
2000 Correlation of asymmetric Notch2 expression and mouse incisor rotation. Mechanisms of development 19 10704869
2021 LncRNA LINC01410 Induced by MYC Accelerates Glioma Progression via Sponging miR-506-3p and Modulating NOTCH2 Expression to Motivate Notch Signaling Pathway. Cellular and molecular neurobiology 18 33712887
2018 MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth. Journal of molecular cell biology 18 29329397
2020 TAO-kinase 3 governs the terminal differentiation of NOTCH2-dependent splenic conventional dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 17 33214146
2017 Pathobiology of Notch2 in lung cancer. Pathology 17 28666642
2015 Notch2 signaling contributes to cell growth, invasion, and migration in salivary adenoid cystic carcinoma. Molecular and cellular biochemistry 17 26427670
2022 RNF144B stimulates the proliferation and inhibits the apoptosis of human spermatogonial stem cells via the FCER2/NOTCH2/HES1 pathway and its abnormality is associated with azoospermia. Journal of cellular physiology 16 35699595
2021 CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract. Genes, chromosomes & cancer 16 34245196
2021 MicroRNA-181a restricts human γδ T cell differentiation by targeting Map3k2 and Notch2. EMBO reports 16 34821000
2020 Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome. The Journal of biological chemistry 16 31992595
2015 Effects of Notch2 and Notch3 on Cell Proliferation and Apoptosis of Trophoblast Cell Lines. International journal of medical sciences 16 26640406
2024 Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization. Nature communications 15 38438375
2024 Targeting the NOTCH2/ADAM10/TCF7L2 Axis-Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 39601111
2021 Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation. Cell death and differentiation 14 34635817
2019 ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling. Oncogene 14 31659254
2017 Notch2 and Notch3 suppress the proliferation and mediate invasion of trophoblast cell lines. Biology open 14 28606936
2023 The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease. Blood 13 36574342
2023 Bcl6, Irf2, and Notch2 promote nonclassical monocyte development. Proceedings of the National Academy of Sciences of the United States of America 12 37607223
2023 NOTCH2 promotes osteoclast maturation and metabolism and modulates the transcriptome profile during osteoclastogenesis. The Journal of biological chemistry 11 38159855
2022 Expression profiling of inflammation-related genes including IFI-16, NOTCH2, CXCL8, THBS1 in COVID-19 patients. Biologicals : journal of the International Association of Biological Standardization 11 36153188
2020 High expression of Notch2 drives tongue squamous cell carcinoma carcinogenesis. Experimental cell research 11 33382997
2019 Post-treatment curcumin reduced ischemia-reperfusion-induced pulmonary injury via the Notch2/Hes-1 pathway. The Journal of international medical research 11 31891282
2018 Notch2 and Proteomic Signatures in Mouse Neointimal Lesion Formation. Arteriosclerosis, thrombosis, and vascular biology 11 29853569
2012 Notch2 and immune function. Current topics in microbiology and immunology 11 22695918
2023 NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α. The Journal of biological chemistry 10 37865314

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