Affinage

NOTCH2

Neurogenic locus notch homolog protein 2 · UniProt Q04721

Length
2471 aa
Mass
265.4 kDa
Annotated
2026-04-29
100 papers in source corpus 38 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOTCH2 is a transmembrane receptor that transduces extracellular signals into transcriptional programs governing cell fate decisions across diverse tissues, including biliary specification, marginal zone B cell commitment, dendritic cell subset differentiation, neural stem cell quiescence, satellite cell self-renewal, and osteoclastogenesis. Upon binding Delta or Jagged family ligands, NOTCH2 undergoes sequential proteolytic cleavage by ADAM10 and γ-secretase (presenilin-1/2) to release its intracellular domain (N2ICD), which enters the nucleus, converts the transcriptional repressor RBPJ/CBF1 into an activator, and induces context-dependent targets including HES1, NFATc1, Id4, and CXCR4 (PMID:9032325, PMID:24842903, PMID:18710934, PMID:31390563, PMID:28729299). Signal strength is tuned by O-fucosylation (Fringe enzymes modulate ligand selectivity), O-glucose elongation (GXYLT1/GXYLT2 control surface trafficking), extracellular domain properties that govern cleavage efficiency, and protein turnover via the E3 ubiquitin ligases KLHL6 and DTX3 (PMID:32820046, PMID:32423029, PMID:23806616, PMID:37235754, PMID:31854042). DLBCL-associated gain-of-function NOTCH2 mutations escape KLHL6-mediated degradation to constitutively activate oncogenic signaling, while activated NOTCH2 is sufficient to reprogram follicular B cells into marginal zone B cells and hepatocytes into biliary epithelial cells (PMID:37235754, PMID:33597542, PMID:23315998).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1992 High

    Identification of NOTCH2 as a second mammalian Notch receptor with distinct expression patterns from NOTCH1 established that multiple non-redundant Notch paralogs exist in mammals.

    Evidence cDNA cloning and Northern blot/in situ hybridization in rat tissues

    PMID:1295745

    Open questions at the time
    • Functional distinctions from NOTCH1 not yet demonstrated
    • Ligands and downstream targets unknown
  2. 1997 High

    Demonstration that NOTCH2 ICD binds RBPJ/CBF1, translocates to the nucleus, and activates HES1 transcription established the core canonical signaling mechanism shared with NOTCH1.

    Evidence Co-immunoprecipitation, nuclear localization assay, luciferase reporters, and myoblast differentiation blockade

    PMID:9032325

    Open questions at the time
    • Upstream proteolytic activation events not defined
    • Whether NOTCH2 has unique transcriptional targets beyond HES1 unknown
  3. 1999 High

    Showing that loss of NOTCH2 ankyrin repeats causes embryonic lethality with neural apoptosis — distinct from NOTCH1 somitogenesis defects — proved non-redundant in vivo requirements.

    Evidence Knock-in deletion of ankyrin repeats in mice with TUNEL and histological analysis

    PMID:10393120

    Open questions at the time
    • Specific cell types requiring NOTCH2 not resolved
    • Downstream effectors of NOTCH2 in neural survival unknown
  4. 2004 High

    Constitutively active NOTCH2 promoted brain tumor cell proliferation while NOTCH1 inhibited it, revealing that Notch paralogs can have opposing oncogenic versus tumor-suppressive roles in the same cellular context.

    Evidence Truncated ICD expression in embryonal brain tumor lines with soft agar and xenograft assays

    PMID:15520184

    Open questions at the time
    • Molecular basis for opposite effects of NOTCH1 vs NOTCH2 ICD not identified
    • Relevance to spontaneous human tumors not established
  5. 2008 High

    Discovery that NOTCH2 ICD physically interacts with NF-κB p65 and is co-recruited to the NFATc1 promoter during osteoclastogenesis revealed a non-canonical co-activator mechanism linking NOTCH2 to bone resorption.

    Evidence ChIP, Co-IP, γ-secretase inhibition, and shRNA knockdown in RANKL-stimulated bone marrow macrophages

    PMID:18710934

    Open questions at the time
    • Whether NOTCH2-NF-κB interaction occurs in other cell types unknown
    • Structural basis of the interaction not defined
  6. 2009 High

    Conditional NOTCH2 ICD expression converted hepatoblasts into biliary epithelial cells and induced ectopic bile ducts, establishing NOTCH2 as a direct fate switch for intrahepatic biliary specification.

    Evidence Conditional transgenic mouse with liver-specific Notch2ICD, bile duct morphometry

    PMID:19551907

    Open questions at the time
    • Downstream transcriptional program executing biliary fate not fully mapped
    • Relationship to RBPJ dependence not tested in this study
  7. 2011 High

    DC-specific NOTCH2 deletion ablated Esam-hi CD11b+ splenic DCs and intestinal CD103+ DCs, identifying NOTCH2 as the receptor required for T cell-priming DC subset differentiation.

    Evidence DC-specific conditional Notch2 knockout with flow cytometry and T cell priming assays

    PMID:22018469

    Open questions at the time
    • Ligand source and identity for DC differentiation not identified
    • NOTCH2 target genes in DC progenitors unknown
  8. 2013 High

    ICD-swap knock-in mice revealed that NOTCH2 specificity in proximal nephron development arises from differences in extracellular domain properties (surface abundance, cleavage efficiency, Fringe modulation) rather than ICD identity, fundamentally reframing paralog specificity as a signal-strength problem.

    Evidence ICD-swap knock-in mice, cell surface quantification, ligand cleavage assays with Fringe co-expression

    PMID:23806616

    Open questions at the time
    • Structural basis for differential ECD cleavage efficiency not resolved
    • Whether this principle generalizes to all tissues not tested
  9. 2013 High

    NOTCH2-driven biliary reprogramming was shown to require RBPJ but not HES1, proving that HES1-independent RBPJ targets mediate biliary fate.

    Evidence Epistasis analysis using N2IC transgene with RBPJ and HES1 conditional knockouts in mouse liver

    PMID:23315998

    Open questions at the time
    • Identity of the critical RBPJ-dependent, HES1-independent targets unknown
  10. 2014 High

    Enzymatic dissection showed that ligand-induced NOTCH2 activation requires ADAM10 (not ADAM17) followed by presenilin-dependent γ-secretase cleavage, defining the obligate protease cascade.

    Evidence Cell-based signaling assays with ADAM10/ADAM17 knockdown and presenilin inhibition

    PMID:24842903

    Open questions at the time
    • Whether tissue-specific γ-secretase complexes differentially process NOTCH2 in vivo not resolved
  11. 2015 High

    In vivo ICD-swap across multiple tissues confirmed that NOTCH1 and NOTCH2 ICDs are functionally equivalent; paralog-specific outcomes arise from differences in NICD nuclear concentration and half-life, influenced by tissue-specific γ-secretase composition.

    Evidence Multi-tissue analysis of ICD-swap knock-in mice with biochemical half-life measurements

    PMID:26062937

    Open questions at the time
    • Molecular identity of tissue-specific γ-secretase modulators unknown
    • How NICD half-life is set at the structural level not defined
  12. 2019 High

    Identification of Id4 as a direct NOTCH2 target in hippocampal neural stem cells, with epistatic rescue, established a NOTCH2→Id4 axis maintaining adult NSC quiescence.

    Evidence Conditional Notch2 knockout, Id4 knockdown rescue, BrdU labeling in mouse hippocampus

    PMID:31390563

    Open questions at the time
    • Whether Id4 is the sole mediator of NOTCH2-dependent quiescence not excluded
    • Chromatin-level mechanism of Id4 activation not shown
  13. 2020 High

    DLL1 on differentiating satellite cells was shown to signal through NOTCH2 on quiescent neighbors to maintain self-renewal during muscle regeneration, defining the ligand-receptor pair governing proportional stem cell maintenance.

    Evidence Single-cell RNA-seq and in vivo antagonistic antibody treatment against DLL1 and NOTCH2

    PMID:32023464

    Open questions at the time
    • Downstream transcriptional targets of NOTCH2 in satellite cells not identified
    • Whether other ligands contribute remains untested
  14. 2020 High

    Comprehensive glycosylation analysis revealed that Fringe enzymes modulate NOTCH2 ligand selectivity (LFNG enhances DLL1 response; MFNG inhibits JAG1/JAG2) through O-fucose modifications on specific EGF repeats, and O-glucose elongation by GXYLT1/GXYLT2 controls NOTCH2 surface trafficking.

    Evidence Mass spectrometry of O-fucose/O-glucose sites, site-directed mutagenesis, cell-based signaling assays, GXYLT1/GXYLT2 knockout

    PMID:32423029 PMID:32820046

    Open questions at the time
    • In vivo relevance of individual glycosylation sites not tested
    • How glycosylation affects NOTCH2 folding/quality control at atomic resolution unknown
  15. 2021 High

    Activated NOTCH2 was shown to be both necessary and sufficient for marginal zone B cell fate: induced N2ICD reprogrammed follicular B cells into functional MZB cells, and NOTCH2 signaling maintained MZB identity by sustaining mTORC1/Myc programs enabling division-independent plasmablast differentiation.

    Evidence Inducible N2ICD transgene in FoB cells, in vivo NOTCH2 antibody blockade, Myc conditional deletion, flow cytometry, transcriptomics

    PMID:33597542 PMID:34473651

    Open questions at the time
    • How NOTCH2 integrates with BCR signaling to make the binary GCB vs MZB decision not fully resolved
    • Direct transcriptional targets mediating mTORC1 activation unknown
  16. 2022 High

    Endothelium-derived DLL4 was shown to activate NOTCH2 on mature myofibers in a non-contact-dependent manner to drive muscle atrophy in disuse and diabetes, establishing a paracrine NOTCH2 role in post-developmental muscle homeostasis.

    Evidence Conditional Notch2 knockout in muscle fibers, DLL4 antibody blockade, disuse and diabetes mouse models

    PMID:35228746

    Open questions at the time
    • Mechanism of non-contact DLL4 delivery (e.g. exosomes vs soluble cleavage) not defined
    • NOTCH2 transcriptional targets driving atrophy gene program unknown
  17. 2023 High

    An unbiased CRISPR screen identified KLHL6 as the E3 ubiquitin ligase targeting membrane-associated NOTCH2 for proteasomal degradation; DLBCL-associated NOTCH2 mutations escape this degradation, directly linking NOTCH2 protein stability control to lymphomagenesis.

    Evidence CRISPR cullin-RING ligase library screen, proteomics, proteasome inhibition, DLBCL mutation analysis

    PMID:37235754

    Open questions at the time
    • Structural basis for how DLBCL mutations evade KLHL6 recognition unknown
    • Whether KLHL6 regulation operates in non-B cell contexts not tested
  18. 2024 High

    Quantitative in vivo analysis showed that NOTCH2 signal level governs a binary fate decision in antigen-activated B cells: high NOTCH2 drives MZB/plasmablast fate while signal extinction permits germinal center entry.

    Evidence Conditional ablation and constitutive activation upon immunization, mathematical modeling, B cell fate tracking

    PMID:38438375

    Open questions at the time
    • What tunes NOTCH2 signal level in individual B cells is not defined
    • Whether this binary switch model applies in chronic infection or autoimmunity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for differential ECD-mediated signal strength between NOTCH paralogs; the identity of NOTCH2-specific transcriptional targets (beyond HES1/Id4/NFATc1) in most tissue contexts; how tissue-specific γ-secretase complexes tune NICD stability; and the full spectrum of E3 ligases controlling NOTCH2 turnover across cell types.
  • No structural model of NOTCH2 ECD-ligand complexes exists
  • Comprehensive ChIP-seq for N2ICD/RBPJ across tissues is lacking
  • Relative contributions of proteasomal vs lysosomal degradation pathways in vivo not systematically compared

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:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4
Partners
ADAM10DLL1DTX3JAG1KLHL6MINAR1RBPJRELA
Complex memberships
NOTCH2-RBPJ/CBF1-MAML transcription complexγ-secretase (presenilin-containing) complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 NOTCH2 encodes a second mammalian Notch receptor protein containing all structural motifs characteristic of Notch proteins (EGF repeats, ankyrin repeats, transmembrane domain), with distinct spatial and temporal expression patterns from NOTCH1 in rat, indicating non-redundant functions. cDNA cloning, Northern blot, in situ hybridization Development High 1295745
1997 The intracellular domain of NOTCH2 (Notch2IC) interacts with the repression domain of CBF1 (RBPJ), translocates to the nucleus, transactivates CBF1-responsive target genes by masking CBF1-mediated repression, activates endogenous HES-1, and blocks muscle cell differentiation — the same mechanism used by NOTCH1 and mimicked by EBV EBNA2. Co-immunoprecipitation, nuclear localization assay, luciferase reporter assay, CBF1 mutagenesis, cell differentiation assay Journal of Virology High 9032325
1999 Ankyrin repeats in the NOTCH2 cytoplasmic domain are indispensable for NOTCH2 function; mice homozygous for ankyrin repeat deletion show early embryonic lethality with increased apoptosis in neural tissues, without the somitogenesis defects seen in Notch1 knockouts, demonstrating non-redundant roles. Gene targeting (knock-in of beta-galactosidase replacing ankyrin repeats), X-gal staining, histology, TUNEL, in situ hybridization Development High 10393120
2002 The intracellular domains of NOTCH1, NOTCH2, and NOTCH3 have markedly different transcriptional activities on HES1 and HES5 promoters; NOTCH2 ICD reduces activities of NOTCH1 and NOTCH3 ICDs when co-expressed, and relative activities depend on RBP-Jκ expression levels. Luciferase reporter assays with truncated intracellular domain constructs, RBP-Jκ co-expression Biochemical and biophysical research communications Medium 11866432
2004 Constitutively active NOTCH2 (truncated intracellular domain) promotes cell proliferation, soft agar colony formation, and xenograft growth of embryonal brain tumor cell lines, while constitutively active NOTCH1 inhibits growth — demonstrating opposite oncogenic/tumor-suppressive roles for the two paralogs in the same cellular context. Truncated constitutively active receptor expression, cell proliferation assay, soft agar colony formation, xenograft mouse model, FISH for gene amplification Cancer Research High 15520184
2008 RANKL induces Jagged1 and NOTCH2 expression in bone marrow macrophages during osteoclast differentiation; NOTCH2 intracellular domain and NF-κB p65 interact in the nucleus and are co-recruited to the NFATc1 promoter, driving NFATc1 expression and osteoclastogenesis. shRNA knockdown, gamma-secretase inhibitor, ectopic Notch2 ICD expression, NFATc1 luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation Molecular and Cellular Biology High 18710934
2009 Conditional expression of activated NOTCH2 ICD in the liver differentiates hepatoblasts into biliary epithelial cells (BECs), induces formation of additional and ectopic bile ducts, and promotes BEC survival, establishing NOTCH2 as a direct regulator of BEC fate specification and tubulogenesis during intrahepatic bile duct development. Conditional transgenic mouse (Notch2ICD expression), histology, immunofluorescence, bile duct morphometry Hepatology High 19551907
2011 DC-specific deletion of NOTCH2 ablates the splenic Esam-hi CD11b+ DC subset (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 DC subsets. DC-specific conditional Notch2 knockout, flow cytometry, T cell priming assays, intestinal DC phenotyping Immunity High 22018469
2011 Conditional ablation of Notch2 in the lens causes microphthalmia, disrupted fiber cell morphology, loss of anterior epithelium, denucleation defects, and cataracts; loss of Notch2 elevates Cdkn1a (p21), Ccnd2 (CyclinD2), and Trp63 while downregulating Cdh1 (E-Cadherin), and blocks lens progenitor cell survival. Conditional Notch2 knockout in lens, histology, gene expression analysis, BrdU incorporation Developmental Biology High 22173065
2012 Numb and Numblike co-deletion in the developing heart leads to increased Notch2 activity, hypertrabeculation, reduced compaction, and ventricular septum defects that phenocopy constitutively active Notch2 overexpression, identifying Numb/Numblike as upstream suppressors of Notch2 in myocardial compaction. Conditional Numb/Numblike double knockout, constitutively active Notch2 transgene, histology, expression profiling Cardiovascular Research High 22865640
2013 The NOTCH2 extracellular domain (NECD) increases NOTCH2 cell-surface abundance during kidney development and is cleaved more efficiently upon ligand binding compared to NOTCH1 ECD; this context-specific asymmetry in NICD release efficiency is further enhanced by Fringe and explains why NOTCH2 but not NOTCH1 is required for proximal nephron specification. ICD-swap knock-in mice, cell surface quantification, ligand cleavage assays, Fringe co-expression Developmental Cell High 23806616
2013 NOTCH2-driven biliary cell fate determination and tubule formation in embryonic hepatoblasts and adult hepatocytes depends on canonical signaling through RBP-Jκ but does not require HES1, and activated NOTCH2 can reprogram adult hepatocytes into biliary cells with tubular-cystic structures. Genetic mouse models with N2IC transgene, RBP-Jκ and HES1 conditional knockouts, liver histology, lineage tracing Hepatology High 23315998
2014 NOTCH2 and NOTCH3 signaling is activated by both Delta- and Jagged-type ligands and requires sequential cleavage by ADAM10 metalloprotease and then presenilin-1 or -2 (γ-secretase); ADAM17/TACE plays no role in ligand-induced NOTCH2 signaling. Cell-based signaling assays with ADAM10 and ADAM17 knockdown/inhibition, presenilin knockdown, ligand stimulation assays Molecular and Cellular Biology High 24842903
2014 In a Kras(G12D)-driven NSCLC mouse model, Notch2 deletion dramatically increases carcinogenesis and decreases differentiation associated with upregulation of β-catenin, whereas Notch1 deletion reduces tumor formation; Notch2-deficient tumors show increased MAPK activity and undifferentiated morphology, demonstrating a tumor-suppressive differentiation function for Notch2 in vivo. Conditional Notch1 and Notch2 knockout in Kras(G12D) NSCLC model, tumor burden analysis, immunohistochemistry, MAPK activity assays Oncogene High 24509876
2015 NOTCH2 ICD physically interacts with TRAF6, and this interaction suppresses the TRAF6-AKT signaling axis, thereby inhibiting EMT and metastasis in nasopharyngeal carcinoma. Co-immunoprecipitation, Western blot, immunofluorescence, mouse metastasis model, NOTCH2 overexpression/knockdown Journal of Experimental & Clinical Cancer Research Medium 31699119
2015 The intracellular domains of NOTCH1 and NOTCH2 are functionally equivalent when swapped in vivo; differences in outcomes attributed to each receptor reflect differences in signal strength (number of NICD molecules reaching the nucleus) and duration (NICD-RBPjk-MAML-DNA complex half-life), not ICD amino acid composition. Tissue-specific γ-secretase complexes influence NICD stability. In vivo ICD-swap knock-in mice analyzed across multiple tissue contexts (T cells, skin, inner ear, lung, retina), biochemical half-life measurements Development High 26062937
2015 NOTCH2 inhibits PDGF-B-dependent vascular smooth muscle cell (VSMC) proliferation, and NOTCH2 expression is decreased by PDGF-B, while NOTCH3 promotes proliferation; NOTCH2 does not protect VSMCs from apoptosis or activate MAP kinase signaling (unlike NOTCH3), demonstrating distinct receptor-specific functions in VSMCs. NOTCH2 and NOTCH3 knockdown/overexpression in cultured VSMCs, proliferation assay, apoptosis assay, MAP kinase signaling analysis Journal of Biological Chemistry Medium 25957400
2015 Notch2 signaling in the ocular lens blocks lens progenitor cell death (apoptosis), regulates cell cycle withdrawal, and is required for secondary fiber cell differentiation; loss of Notch2 but not another receptor accounts for this function, establishing a specific requirement for Notch2 in lens morphogenesis. Conditional Notch2 knockout in lens, histology, TUNEL, BrdU, gene expression (Cdkn1a, Ccnd2, Cdh1) Developmental Biology High 22173065
2019 Id4 is a direct downstream target of NOTCH2 signaling in adult hippocampal neural stem cells (NSCs); Id4 promotes NSC quiescence by blocking cell-cycle entry, and Id4 knockdown rescues NOTCH2-induced inhibition of NSC proliferation, establishing a NOTCH2-Id4 axis that maintains NSC quiescence. Conditional Notch2 knockout, Id4 knockdown, Id4 overexpression, BrdU labeling, flow cytometry, gene expression analysis in mouse hippocampus Cell Reports High 31390563
2019 Midkine binds Notch2 (identified as a candidate midkine receptor) and activates NOTCH2-HES1 signaling in neuroblastoma; midkine deficiency in MYCN-transgenic mice reduces Notch2 activation and delays tumor formation, and midkine RNA aptamer suppresses NOTCH2-HES1 signaling and tumor growth. Midkine genetic knockout in MYCN-transgenic mice, RNA aptamer treatment, xenograft, immunostaining for Notch2/HES1 Cancer Research Medium 23243020
2020 DLL1 expressed on differentiating satellite cells signals through NOTCH2 on neighboring satellite cells to maintain satellite cell self-renewal during muscle regeneration; antagonistic antibodies against DLL1 and NOTCH2 block self-renewal, establishing this ligand-receptor pair as required for proportional muscle regeneration. Single-cell RNA sequencing, in vivo antagonistic antibody treatment, satellite cell fate tracking Cell Reports High 32023464
2020 Lunatic fringe (LFNG) modification of O-fucose on EGF8 and EGF12 of NOTCH2 enhances DLL1-NOTCH2 activation; Manic fringe (MFNG) inhibits NOTCH2 activation by JAG1 and JAG2; elimination of O-fucose on EGF12 allows LFNG to inhibit JAG1-NOTCH2, and O-fucosylation on EGF9 is important for NOTCH2 trafficking to the cell surface. Cell-based Notch signaling and ligand-binding assays, site-directed mutagenesis, mass spectrometry of O-fucose sites, GXYLT1/GXYLT2 double knockout cells Journal of Biological Chemistry High 32820046
2020 Xylosyl elongation of O-glucose glycans on NOTCH2 EGF repeats by GXYLT1 and GXYLT2 promotes cell surface trafficking of overexpressed NOTCH2; GXYLT1/GXYLT2 double knockout reduces secretion of NOTCH2 ECD, indicating a role for O-Glc elongation in quality control of NOTCH2. Mass spectrometry of O-Glc glycans on all 17 EGF repeats, GXYLT1/GXYLT2 double knockout cells, cell surface expression assay, in vitro secretion assay Cells High 32423029
2021 Induced Notch2IC expression in mature follicular B (FoB) cells re-programs them into bona fide marginal zone B (MZB) cells (confirmed by surface phenotype, localization, immunological function, and transcriptome), demonstrating Notch2 activation as a singular event sufficient to drive FoB-to-MZB trans-differentiation. Inducible Notch2IC transgene expression in FoB cells in immunocompetent wildtype mice, flow cytometry, transcriptomics, functional immunological assays Nature Communications High 33597542
2021 In vivo Notch2 blockade in marginal zone (MZ) B cells reverses division-independent plasma cell differentiation and decreases mTORC1- and Myc-regulated gene transcription; Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state enabling rapid mitosis-independent plasma cell generation. Short-term in vivo Notch2 blockade with antibodies, Myc conditional deletion, ectopic mTORC1 activation in follicular B cells, plasma cell differentiation assays Journal of Clinical Investigation High 34473651
2022 Multinucleated myofibers express Notch2; in disuse and diabetes-induced muscle atrophy, microvascular endothelium upregulates and releases the Notch ligand Dll4, which activates muscular Notch2 without direct cell-cell contact. Inhibition of Dll4-Notch2 axis prevents muscle atrophy and promotes hypertrophy in mice. Conditional Notch2 knockout in muscle fibers, Dll4 antibody blockade, mouse models of disuse and diabetes-induced atrophy, muscle mass and fiber-type analysis Nature Metabolism High 35228746
2023 KLHL6 is an E3 ubiquitin ligase that targets plasma membrane-associated NOTCH2 for proteasome-dependent degradation; DLBCL-associated NOTCH2 mutations result in a protein that escapes KLHL6-mediated ubiquitin-dependent proteolysis, leading to protein stabilization and activation of oncogenic RAS signaling. CRISPR-Cas9 cullin-RING ligase library screen, proteomic identification of KLHL6-NOTCH2 interaction, proteasome inhibition, mutation analysis in CHOP-resistant DLBCL Blood High 37235754
2020 DTX3 (Deltex E3 ubiquitin ligase 3) was identified by yeast two-hybrid screening as a novel E3 ligase for NOTCH2 and promotes NOTCH2 ubiquitination and degradation in esophageal carcinoma cells. Yeast two-hybrid screening, Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression functional studies Cancer Science Medium 31854042
2019 N-acetylcysteine (NAC) promotes NOTCH2 degradation through an Itch-dependent lysosomal pathway in glioblastoma cells, independent of its antioxidant function, thereby reducing downstream HES1 and HEY1 expression. Western blot, lysosome inhibitors, Itch E3 ligase co-expression, cell-based assays in glioblastoma Journal of Experimental & Clinical Cancer Research Medium 30606241
2018 MINAR1 (major intrinsically disordered Notch2-associated receptor 1) physically interacts with NOTCH2, increases NOTCH2 stability and function, and inhibits angiogenesis and breast cancer growth; MINAR1 is an intrinsically disordered protein with a single transmembrane domain expressed in breast epithelium and endothelium. Co-immunoprecipitation, overexpression/knockdown, in vitro angiogenesis assay, zebrafish angiogenesis model, mouse matrigel plug, xenograft Journal of Molecular Cell Biology Medium 29329397
2010 SCF induces Notch2 expression in human erythroblasts; functional inhibition of Notch2 or its ligand Jagged1 blocks SCF-driven erythroblast expansion and delays differentiation; dominant-negative Notch2 inhibits basal and SCF-mediated erythroblast proliferation, placing Notch2-Jagged1 signaling downstream of c-kit in SCF-mediated erythropoiesis. Dominant-negative Notch2 transduction in primary erythroblasts, Notch/Jagged1 functional inhibition, erythroblast expansion and differentiation assays Cell Death and Differentiation Medium 20829885
2017 BCL6 directly binds and represses NOTCH2 and Notch pathway gene promoters in follicular lymphoma (FL) cells; inducible Notch2 expression abrogates GC formation in mice and kills FL cells; BCL6 inhibition leads to NOTCH2 induction and FL cell death, rescued by NOTCH2 depletion — establishing BCL6 repression of NOTCH2 as essential for FL survival. ChIP-seq of BCL6 binding in primary FL cells, inducible Notch2 expression in mice, BCL6 inhibitors in xenografts and primary FL, NOTCH2 depletion rescue experiments Cancer Discovery High 28232365
2021 NOTCH2 blockade reduces CXCR4 expression on hematopoietic stem cells (HSCs), and NOTCH2 (via its transcriptional partner RBPJ) directly regulates CXCR4 transcription; Notch2 blockade or deficiency leads to decreased HSC quiescence, enhanced egress from marrow, and transient myeloid progenitor expansion. NOTCH2 blocking antibodies, Notch2 conditional knockout mice, RBPJ ChIP at CXCR4 promoter, flow cytometry of HSCs and progenitors Haematologica High 28729299
2014 Notch2 signaling is specifically required for cytokine-induced goblet cell metaplasia in airway epithelial cells; inhibition of Notch2 (but not other Notch receptors) prevents goblet cell metaplasia induced by inflammatory cytokines both in vitro (3D culture system) and in vivo. 3D airway epithelial culture screen, Notch2-specific antibody inhibition, in vivo mouse model of goblet cell metaplasia Cell Reports High 25558064
2024 In antigen-activated follicular B cells, high NOTCH2 signaling drives MZB cell fate or plasmablast differentiation, while cells that turn off NOTCH2 signaling enter germinal centers; NOTCH2 signaling governs expansion of IgG1+ germinal center B cells and controls a binary fate decision between GCB and MZB cell fates. Notch2 conditional ablation and constitutive activation upon immunization, mathematical modeling, flow cytometry, B cell fate tracking Nature Communications High 38438375
2023 The lncRNA LINC01977 physically binds RBM39 to prevent ubiquitination and degradation of NOTCH2, promoting its nuclear entry and HCC progression; IGF2BP2 (an m6A reader) stabilizes LINC01977 mRNA to maintain high levels in HCC. RNA immunoprecipitation, Co-IP, ubiquitination assay, nuclear fractionation, loss/gain-of-function in vitro and in vivo Cell Death Discovery Medium 37198207
2023 The pan-cancer 3'-tRF CAT1 binds RBPMS and displaces NOTCH2 mRNA from RBPMS, thereby inhibiting CCR4-NOT deadenylation complex-mediated NOTCH2 mRNA decay and increasing NOTCH2 expression to promote lung cancer cell proliferation and metastasis. RNA immunoprecipitation, RNA decay assay, CAT1 overexpression/knockdown, RBPMS knockdown, in vitro and in vivo tumor models Cell Reports Medium 37943661
2021 Gm364 (a multi-pass transmembrane protein) directly binds and anchors the ubiquitin ligase MIB2 on the membrane; membrane MIB2 ubiquitinates and activates DLL3; activated DLL3 binds and activates Notch2, generating NICD2 that activates AKT within the cytoplasm to regulate oocyte meiosis and quality. Global Gm364 knockout in mice, Co-immunoprecipitation, ubiquitination assay, NICD2 detection, AKT activation assay, follicle and oocyte phenotyping Cell Death and Differentiation Medium 34635817
2022 Jagged-1 (JAG1)/Notch2 signaling in the liver is antagonized by Delta-like 4 (Dll4)/Notch1 signaling; Jag1 deletion in desmin-positive mesenchymal cells during chemical hepatocarcinogenesis induces ectopic Dll4 expression in hepatocytes with loss of Notch2 signaling, leading to tumor progression. Hepatocyte-specific Dll4 knockout, Jag1 deletion, diethylnitrosamine-induced hepatocarcinogenesis model, immunostaining, Notch pathway target analysis Communications Biology Medium 35064244

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 431 22018469
2004 Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer research 321 15520184
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
2015 Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clinical cancer research : an official journal of the American Association for Cancer Research 204 25934888
2014 Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell reports 200 25558064
2019 miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization. Journal of hematology & oncology 180 30808369
2008 The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Molecular and cellular biology 149 18710934
2001 Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development. The Journal of comparative neurology 126 11438922
2017 LncRNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging miR-195-5p. Biochemical and biophysical research communications 113 29229388
2019 Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Human mutation 112 31343788
2007 Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. The American journal of pathology 100 17675579
1997 Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation. Journal of virology 99 9032325
1996 Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. Journal of virology 98 8892932
2009 Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice. Hepatology (Baltimore, Md.) 95 19551907
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
2013 The extracellular domain of Notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. Developmental cell 84 23806616
2019 Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus. Cell reports 80 31390563
2013 Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology (Baltimore, Md.) 77 23315998
2015 The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis. Development (Cambridge, England) 76 26062937
2015 Differential Regulation of NOTCH2 and NOTCH3 Contribute to Their Unique Functions in Vascular Smooth Muscle Cells. The Journal of biological chemistry 74 25957400
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
2017 miR-598 inhibits metastasis in colorectal cancer by suppressing JAG1/Notch2 pathway stimulating EMT. Experimental cell research 67 28161537
2011 Upregulation of notch2 and six1 is associated with progression of early-stage lung adenocarcinoma and a more aggressive phenotype at advanced stages. Clinical cancer research : an official journal of the American Association for Cancer Research 60 22190591
2020 Canonical Notch ligands and Fringes have distinct effects on NOTCH1 and NOTCH2. The Journal of biological chemistry 59 32820046
2012 P53-induced microRNA-107 inhibits proliferation of glioma cells and down-regulates the expression of CDK6 and Notch-2. Neuroscience letters 59 23220650
2017 MiR-18a-5p inhibits endothelial-mesenchymal transition and cardiac fibrosis through the Notch2 pathway. Biochemical and biophysical research communications 57 28733035
2012 Inhibition of Notch2 by Numb/Numblike controls myocardial compaction in the heart. Cardiovascular research 57 22865640
2015 Notch1 and Notch2 in Podocytes Play Differential Roles During Diabetic Nephropathy Development. Diabetes 55 26293507
2012 Midkine promotes neuroblastoma through Notch2 signaling. Cancer research 54 23243020
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 51 32023464
2019 The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. American journal of cancer research 51 31218097
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
2019 JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix. Arthritis research & therapy 46 31619270
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 45 32293074
2019 N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling. Journal of experimental & clinical cancer research : CR 45 30606241
2003 Notch2 protein distribution in human teeth under normal and pathological conditions. Experimental cell research 45 12531696
2015 The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis. Oncotarget 44 26041881
2019 Long Noncoding RNA (lncRNA) MIR22HG Suppresses Gastric Cancer Progression through Attenuating NOTCH2 Signaling. Medical science monitor : international medical journal of experimental and clinical research 43 30670679
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
2017 BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells. Cancer discovery 39 28232365
2017 An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. Blood 37 28851699
2021 Notch2-mediated plasticity between marginal zone and follicular B cells. Nature communications 36 33597542
2014 Notch1 and Notch2 expression in osteoblast precursors regulates femoral microarchitecture. Bone 36 24508387
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
2016 Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations. Current osteoporosis reports 34 27241678
2021 Silencing long non-coding RNA MEG8 inhibits the proliferation and induces the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis. Biochemical and biophysical research communications 33 33839417
2021 Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation. The Journal of clinical investigation 33 34473651
2020 Circular RNA circKIF4A Sponges miR-375/1231 to Promote Bladder Cancer Progression by Upregulating NOTCH2 Expression. Frontiers in pharmacology 32 32457613
2010 Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine. Blood 31 20971948
2016 Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. Oncology reports 30 27221981
2024 Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2. Cancer letters 29 38969159
2021 Extracellular vesicle-derived microRNA-18b ameliorates preeclampsia by enhancing trophoblast proliferation and migration via Notch2/TIM3/mTORC1 axis. Journal of cellular and molecular medicine 29 33835684
2009 Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus-infected B cells. Blood 28 19339697
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 Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus. Cell death & disease 27 26018735
2015 Loss of Notch2 and Notch3 in vascular smooth muscle causes patent ductus arteriosus. Genesis (New York, N.Y. : 2000) 27 26453897
2018 MicroRNA-1 suppresses proliferation, migration and invasion by targeting Notch2 in esophageal squamous cell carcinoma. Scientific reports 26 29581534
2015 Expression pattern and function of Notch2 in different subtypes of first trimester cytotrophoblast. Placenta 26 25659500
2020 Notch1 and Notch2 collaboratively maintain radial glial cells in mouse neurogenesis. Neuroscience research 25 33309869
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
2020 Xylosyl Extension of O-Glucose Glycans on the Extracellular Domain of NOTCH1 and NOTCH2 Regulates Notch Cell Surface Trafficking. Cells 24 32423029
2012 The expression of NOTCH2, HES1 and SOX9 during mouse retinal development. Gene expression patterns : GEP 24 23277114
2017 Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica 23 28729299
2015 Clinical Significance of NOTCH1 and NOTCH2 Expression in Gastric Carcinomas: An Immunohistochemical Study. Frontiers in oncology 23 25954607
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 22 38462037
2024 Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade. Nature communications 22 39505846
2023 DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance. Blood 22 37235754
2017 High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 22 28856714
2013 The different role of Notch1 and Notch2 in astrocytic gliomas. PloS one 22 23349727
2022 The effect of mitochondrial fusion on chondrogenic differentiation of cartilage progenitor/stem cells via Notch2 signal pathway. Stem cell research & therapy 21 35337368
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 The cancer-testis lncRNA LINC01977 promotes HCC progression by interacting with RBM39 to prevent Notch2 ubiquitination. Cell death discovery 19 37198207
2019 MicroRNA-16 is involved in the pathogenesis of pre-eclampsia via regulation of Notch2. Journal of cellular physiology 19 31643078
2018 Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology. Human mutation 19 30304577
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
2018 MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth. Journal of molecular cell biology 18 29329397
2023 Pan-cancer tRNA-derived fragment CAT1 coordinates RBPMS to stabilize NOTCH2 mRNA to promote tumorigenesis. Cell reports 17 37943661
2020 MiR-485-5p Promotes Neuron Survival through Mediating Rac1/Notch2 Signaling Pathway after Cerebral Ischemia/Reperfusion. Current neurovascular research 17 32294039
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
2020 Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome. The Journal of biological chemistry 16 31992595
2021 CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract. Genes, chromosomes & cancer 15 34245196
2021 MicroRNA-181a restricts human γδ T cell differentiation by targeting Map3k2 and Notch2. EMBO reports 15 34821000
2024 Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization. Nature communications 14 38438375
2022 Two distinct Notch signals, Delta-like 4/Notch1 and Jagged-1/Notch2, antagonistically regulate chemical hepatocarcinogenesis in mice. Communications biology 14 35064244
2021 Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation. Cell death and differentiation 14 34635817