Affinage

NOTCH4

Neurogenic locus notch homolog protein 4 · UniProt Q99466

Length
2003 aa
Mass
209.6 kDa
Annotated
2026-06-10
100 papers in source corpus 50 papers cited in narrative 50 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOTCH4 is an endothelial-enriched transmembrane Notch receptor whose intracellular domain (N4ICD) couples cell-surface ligand sensing to transcriptional and signaling programs that govern vascular remodeling, cell survival, and inflammation (PMID:8681805, PMID:9693032). Structurally it comprises 29 EGF-like repeats, LIN-12/Notch repeats, a transmembrane region, cdc10/ankyrin repeats, and a PEST domain; the int-3 oncogene encodes only the intracellular domain, and loss of the extracellular and LIN-12 regulatory regions renders the receptor constitutively active (PMID:8681805, PMID:9150355, PMID:9693032). Activated NOTCH4 signals partly through RBP-Jkappa (CBF-1) via its ankyrin repeats and partly through RBP-Jkappa-independent routes: the ankyrin repeats alone drive RBP-Jkappa-dependent transcription and partial inhibition of endothelial sprouting, while a constitutively active RBP-Jkappa recapitulates this only weakly, defining parallel dependent and independent outputs (PMID:14701863, PMID:15187023, PMID:18836481). In the vasculature, constitutively active NOTCH4 inhibits VEGF-induced endothelial sprouting and angiogenesis—in part by switching beta1-integrin to a high-affinity conformation that increases collagen adhesion—and promotes endothelial survival via RBP-Jkappa-dependent JNK suppression and RBP-Jkappa-independent Bcl-2 upregulation (PMID:11909975, PMID:14701863, PMID:18802018). In vivo, endothelial expression of activated NOTCH4 produces arteriovenous malformations through enlargement of capillary-caliber microvessels driven by increased individual endothelial-cell area, with arterialization marked by ephrinB2 induction; these lesions reverse upon transgene repression and require restoration of venous EphB4 expression, and the receptor acts downstream of VEGF/DLL4 to direct arterial differentiation (PMID:15994223, PMID:16951162, PMID:22261032, PMID:25468970). NOTCH4 nuclear signaling is negatively gated by AKT, which phosphorylates N4ICD at four sites to generate 14-3-3 binding sites that retain it in the cytoplasm (PMID:25740432). Beyond canonical activation, NOTCH4 cis-inhibits NOTCH1 signaling, and its own transcription is controlled by AP-1, glucocorticoid receptor, PEA3/c-Jun, YB-1/RSK, and RUNX1 inputs in a cell-type-specific manner (PMID:15684396, PMID:17220278, PMID:24667410, PMID:23593654, PMID:21679465, PMID:29101237). In cancer, NOTCH4 maintains breast cancer stem-cell activity and anti-estrogen resistance and directly transactivates SLUG, GAS1, HEY1, and Nodal to control EMT, quiescence, and tumorigenesis (PMID:20068161, PMID:26387946, PMID:32104513, PMID:21159651, PMID:26801977). In immune cells, NOTCH4 on regulatory T cells suppresses amphiregulin-dependent tissue repair and subverts Tregs toward TH2/TH17 effector fates via Wnt/Hippo and GDF15 mechanisms, while in macrophages it acts anti-inflammatory by favoring STAT3 over STAT1 and suppressing NF-kappaB, and it dampens TLR/TAK1 signaling by binding TAK1 and blocking TRAF6 ubiquitination (PMID:32929274, PMID:33915108, PMID:34925319, PMID:29228365).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1996 High

    Established NOTCH4 as an endothelial-restricted transmembrane Notch receptor and identified the int-3 oncogene as its constitutively active, extracellular-domain-less intracellular fragment, framing the receptor's activation logic.

    Evidence cDNA cloning, sequence analysis, and in situ hybridization; sequence analysis of nine MMTV-induced tumors

    PMID:8681805 PMID:9150355

    Open questions at the time
    • Did not define the physiological ligand or the proteolytic activation steps for full-length receptor
    • Endothelial restriction left the breast-tumor context mechanistically unexplained
  2. 1998 High

    Resolved the full domain architecture and promoter features of human NOTCH4 and showed that the CBF-1/RBP-Jkappa interaction domain plus the ankyrin repeats constitute the minimal effector module for biological output.

    Evidence Genomic sequencing and isoform characterization; deletion-mutant branching morphogenesis assays in mammary epithelial cells

    PMID:9576833 PMID:9693032

    Open questions at the time
    • Did not separate RBP-Jkappa-dependent from -independent contributions
    • Ligand-driven activation not addressed
  3. 2001 High

    Demonstrated in vivo that activated NOTCH4 in embryonic endothelium disrupts vessel patterning and remodeling, establishing a developmental vascular role beyond cell culture.

    Evidence Flk1-driven activated Notch4 transgenic mouse with vascular phenotyping

    PMID:11344305

    Open questions at the time
    • Embryonic lethality precluded adult analysis
    • Downstream effectors of vessel dilation undefined
  4. 2003 High

    Dissected NOTCH4 survival signaling into RBP-Jkappa-dependent JNK suppression and RBP-Jkappa-independent Bcl-2 upregulation, defining parallel anti-apoptotic outputs.

    Evidence Apoptosis assays, RBP-Jkappa reporters, RAM-domain deletion, and Bcl-2 western blot in endothelial cells

    PMID:14701863

    Open questions at the time
    • Molecular route to Bcl-2 induction not mapped
    • Relevance to in vivo vascular phenotypes not tested here
  5. 2002 High

    Identified beta1-integrin conformational activation as a non-transcriptional mechanism by which NOTCH4 inhibits endothelial sprouting, mechanistically linking the receptor to angiogenesis control.

    Evidence In vitro sprouting and chick CAM assays, integrin-conformation flow cytometry, function-activating antibodies

    PMID:11909975

    Open questions at the time
    • How N4ICD activates integrin conformation biochemically is unresolved
    • Did not connect integrin activation to the in vivo AVM phenotype
  6. 2004 High

    Mapped the ankyrin repeats as necessary and sufficient for RBP-Jkappa-dependent gene activation and partial sprouting inhibition, while showing a constitutively active RBP-Jkappa underperforms full N4ICD—formally establishing RBP-Jkappa-independent signaling.

    Evidence Endothelial sprouting assays with N4IC deletion mutants and RBP-Jkappa reporters; hematopoietic progenitor transduction assays

    PMID:14961038 PMID:15187023 PMID:15231576

    Open questions at the time
    • Identity of RBP-Jkappa-independent partners not determined
    • VEGFR-2/VE-cadherin downregulation insufficient to explain phenotype
  7. 2005 High

    Showed NOTCH4 cross-talks with TGF-beta by binding Smad2/3/4 to attenuate TGF-beta signaling, and that endothelial AP-1 complexes occupy NOTCH4 chromatin to drive its tissue-specific transcription.

    Evidence Co-IP/binding and deletion analysis with reporters and gamma-secretase inhibition; ChIP, RNA FISH, and transgenic reporters

    PMID:15684396 PMID:16007227

    Open questions at the time
    • Physiological setting of Smad antagonism within endothelium not established
    • Upstream signals controlling AP-1 occupancy only partially defined
  8. 2005 High

    Established that adult endothelial activation of NOTCH4 causes reversible AV malformations with arterialization, providing a tractable disease model and linking the receptor to ephrinB2-driven arterial identity.

    Evidence Tetracycline-repressible endothelial transgenic mice with ephrinB2 immunostaining and doxycycline rescue

    PMID:15994223

    Open questions at the time
    • Did not yet resolve whether vessel enlargement reflects cell-size versus cell-number changes
    • Downstream effector required for reversal unidentified
  9. 2006 Medium

    Placed NOTCH4 downstream of VEGF/DLL4 in a cascade that upregulates ephrinB2 and downregulates EphB4 to specify arterial endothelial fate.

    Evidence HUVEC treatment with pharmacological inhibition (presenilin, soluble DLL4) and in vivo hepatocarcinoma model

    PMID:16951162

    Open questions at the time
    • Pharmacological inhibitors are not NOTCH4-specific
    • Direct transcriptional control of ephrinB2 by N4ICD not shown
  10. 2007 High

    Defined a composite AP-1/glucocorticoid-receptor response element through which FGF-2 and cortisol cooperatively reprogram the NOTCH4 locus, extending transcriptional control to hormonal and growth-factor inputs.

    Evidence ChIP, luciferase reporters, and histone-modification analysis in endothelial and 10T1/2 cells

    PMID:17220278

    Open questions at the time
    • Physiological contexts where GR and AP-1 converge on NOTCH4 not delineated
    • In vivo requirement of the composite element untested
  11. 2008 High

    Showed brain AVMs from activated NOTCH4 arise from enlarged microvasculature with reduced capillary density, mechanistically tying the disease to NOTCH4's inhibition of sprouting, and that basal NOTCH4 maintains EC quiescence and survival.

    Evidence Inducible/reversible endothelial transgenic mice with disease reversal; endothelial siRNA knockdown with VCAM-1, apoptosis, and injury-repair assays

    PMID:18667694 PMID:18802018

    Open questions at the time
    • Cellular basis of vessel enlargement not yet imaged at single-cell resolution
    • TNFalpha-PI3K suppression of NOTCH4 mechanism only outlined
  12. 2008 High

    Genetically separated NOTCH4 oncogenic functions, demonstrating RBP-Jkappa-dependent developmental arrest but RBP-Jkappa-independent mammary tumorigenesis.

    Evidence Conditional Rbpj knockout in Wap-Int3 transgenic mice with histology and tumor frequency

    PMID:18836481

    Open questions at the time
    • The RBP-Jkappa-independent oncogenic effector remained unidentified
    • Did not address whether vascular phenotypes share this independence
  13. 2009 High

    Extended the reversible AVM model to adult lung, confirming organ-intrinsic NOTCH4-driven AV shunting.

    Evidence Tetracycline-repressible endothelial transgenic mice, vascular casting, and whole-lung organ culture

    PMID:19933399

    Open questions at the time
    • Tissue-specific modifiers of lung versus brain AVM not defined
    • Downstream signaling not dissected in this study
  14. 2010 Medium

    Identified NOTCH4 as a dominant driver of cancer stem-cell activity and, in melanoma, an RBP-Jkappa-dependent activator of the embryonic morphogen Nodal, linking the receptor to tumor initiation and plasticity.

    Evidence Stem-cell enrichment and tumor-formation assays with gamma-secretase inhibition and siRNA; RBPJ-dependent Nodal enhancer reporter and vasculogenic-mimicry assays

    PMID:20068161 PMID:21159651

    Open questions at the time
    • Direct NOTCH4 promoter occupancy on stemness targets not shown here
    • Single-lab observations awaiting orthogonal confirmation
  15. 2011 Medium

    Showed PEA3 directly activates NOTCH4 transcription in a c-Jun/AP-1-dependent manner distinct from its NOTCH1 regulation, refining the transcriptional logic that distinguishes the two receptors.

    Evidence ChIP, siRNA, NOTCH4 luciferase reporter with TAM-67 and c-Jun knockdown in breast cancer cells

    PMID:21679465

    Open questions at the time
    • Functional consequence of PEA3-driven NOTCH4 not tested in vivo
    • Single-lab finding
  16. 2012 High

    Demonstrated by live imaging that AV-shunt regression upon NOTCH4 normalization proceeds via vessel narrowing without EC loss and requires restored venous EphB4 expression, identifying EphB4 as the key downstream mediator of reversal.

    Evidence 4D two-photon cranial-window imaging with doxycycline-mediated transgene repression and EphB4 analysis

    PMID:22261032

    Open questions at the time
    • How NOTCH4 represses EphB4 mechanistically not resolved
    • Translatability of reversal to human AVM untested
  17. 2013 Medium

    Expanded NOTCH4 transcriptional regulation to PKCalpha/AP-1 and a YB-1/RSK axis, connecting kinase signaling to NOTCH4 expression and estrogen-independent growth.

    Evidence ChIP, siRNA/overexpression, in vitro RSK kinase assays, and luteolin treatment in breast cancer cells; N4IC adipocyte differentiation assays

    PMID:23237809 PMID:23593654 PMID:23917222

    Open questions at the time
    • In vivo relevance of YB-1/RSK and PKCalpha control not established
    • Adipocyte role rests on a single gain-of-function dataset
  18. 2014 High

    Revealed that NOTCH4 fails to signal in response to ligand in culture and instead cis-inhibits NOTCH1, while germline Notch4-null mice show only mild retinal vascular delay—reframing NOTCH4 as an atypical, partly inhibitory Notch receptor.

    Evidence Cell-based signaling assays, extracellular-domain constructs, and complete-coding-region Notch4-null mice with retinal analysis

    PMID:24667410

    Open questions at the time
    • Mild null phenotype contrasts with strong gain-of-function effects, leaving physiological role uncertain
    • Structural basis of cis-inhibition undefined
  19. 2015 High

    Identified AKT-mediated phosphorylation of N4ICD at four sites generating 14-3-3 binding sites that retain it in the cytoplasm, defining a growth-factor/PI3K-controlled brake on NOTCH4 nuclear signaling, and connected JAG1-NOTCH4 to anti-estrogen-induced breast cancer stem-cell resistance.

    Evidence In vitro/in vivo kinase and phosphorylation assays, 14-3-3 binding, localization analysis; PDX and patient-sample BCSC assays with NOTCH4 inhibition

    PMID:25740432 PMID:26387946

    Open questions at the time
    • Whether AKT-14-3-3 gating operates in endothelial AVM remains untested
    • Phosphosite mutants not validated in vivo
  20. 2016 High

    Showed N4ICD induces Hey1/Hey2 that directly repress Snail2 and Twist1 promoters to drive a mesenchymal-to-epithelial switch in melanoma, demonstrating context-dependent, anti-invasive transcriptional output.

    Evidence N4ICD expression, EMSA, Hey1/Hey2 ChIP and promoter reporters, and xenografts

    PMID:26801977

    Open questions at the time
    • Apparent opposite EMT effects across cancer types not reconciled
    • Determinants of Hey1/2 target selection unknown
  21. 2017 High

    Established the NOTCH4-HEY1 axis as a driver of EMT and cisplatin resistance in head and neck cancer and identified RUNX1 as a negative transcriptional regulator of NOTCH4 whose loss enhances megakaryopoiesis.

    Evidence siRNA and TCGA analysis with functional assays; integrative genomics and CRISPR-Cas9 NOTCH4 knockout in iPSCs with MK differentiation

    PMID:29101237 PMID:29146722

    Open questions at the time
    • Direct NOTCH4 binding to HEY1 promoter not demonstrated in the HNSCC study
    • RUNX1 regulatory element function not tested in vivo
  22. 2018 High

    Defined a non-canonical anti-inflammatory mechanism whereby N4ICD binds TAK1 and blocks TRAF6 autoubiquitination to suppress proinflammatory cytokine production, with Notch4-deficient mice resisting M. tuberculosis.

    Evidence Co-IP, ubiquitination assays, and Notch4-deficient mouse infection model

    PMID:29228365

    Open questions at the time
    • Whether this requires nuclear N4ICD or cytoplasmic pools is unclear
    • Generalizability beyond mycobacterial infection not shown
  23. 2019 Medium

    Implicated NOTCH4 as a downstream effector in profibrotic and renal-injury contexts, with N4ICD deletion improving HIV-associated nephropathy and reducing NF-kappaB/IL-6/CCL2.

    Evidence siRNA/pathway inhibition in endometrial stromal fibrosis; Notch4 ICD global knockout in Tg26 HIVAN mice with cytokine and histology analysis

    PMID:31515487 PMID:31727625

    Open questions at the time
    • Direct molecular targets of NOTCH4 in these tissues undefined
    • Single-lab in vivo observations
  24. 2020 High

    Identified SLUG and GAS1 as direct NOTCH4 transcriptional targets controlling EMT and stem-cell quiescence in TNBC, and established a Treg-intrinsic NOTCH4 program that subverts regulatory T cells into TH2/TH17 effectors via Wnt/Hippo and GDF15.

    Evidence ChIP and dual-luciferase reporters with stable OE/KD and in vivo serial dilution; conditional Treg Notch4 deletion, anti-Notch4 antibody, and Wnt/Hippo inhibitors with human Treg analysis

    PMID:32104513 PMID:32929274

    Open questions at the time
    • Upstream ligand and activation step driving Treg NOTCH4 signaling not fully defined here
    • Whether SLUG/GAS1 control generalizes beyond TNBC untested
  25. 2021 High

    Showed NOTCH4 on Tregs suppresses IL-18-induced amphiregulin to impair tissue repair in viral injury, and that NOTCH4 has distinct, non-canonical roles in lymphangiogenesis and macrophage inflammation, broadening its immune and vascular repertoire.

    Evidence Treg-specific Notch4 deletion and antibody therapy with amphiregulin rescue and a COVID-19 cohort; Notch4-null lymphatic analysis with DNMAML epistasis; macrophage STAT1/STAT3 and NF-kappaB assays; MAPK Co-IP in lung adenocarcinoma

    PMID:33915108 PMID:34665379 PMID:34925319 PMID:34988077

    Open questions at the time
    • How NOTCH4 mechanistically biases STAT3 over STAT1 beyond HES1 is incomplete
    • Reconciliation of pro- and anti-inflammatory roles across cell types unresolved
  26. 2022 High

    Connected JAG1-NOTCH4 to flow-mechanosensing in atherosclerosis and to MAPK-dependent pulmonary vascular remodeling, and tied an IL-4Ralpha variant to GRB2/IL-6-driven NOTCH4 induction on Tregs that exacerbates lung inflammation.

    Evidence Disturbed-flow models with EC-specific Jag1 knockout and scRNA-seq; Notch4-MAPK Co-IP with AAV1 silencing in hypoxic rats; Il4raR576 knock-in with Treg Notch4 deletion and human PBMC analysis

    PMID:35016680 PMID:35841382 PMID:36044575

    Open questions at the time
    • Direct transcriptional targets downstream of flow-activated NOTCH4 not defined
    • MAPK interaction studies remain single-lab Co-IP-based

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NOTCH4's atypical, largely ligand-unresponsive and cis-inhibitory behavior reconciles with the strong, RBP-Jkappa-dependent and -independent outputs of its constitutively active intracellular domain across endothelium, immune cells, and cancer.
  • No structure of NOTCH4 or its cis-inhibitory interface with NOTCH1
  • The physiological ligand-dependent signaling state versus gain-of-function biology is not unified
  • The full set of RBP-Jkappa-independent effectors mediating tumorigenesis and inflammation is incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4
Partners
AKT1DLL4JAG1NOTCH1RBPJSMAD3TAK1TRAF6

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Notch4 is a transmembrane receptor with EGF-like repeats and intracellular domain; the int-3 oncogene encodes only the intracellular domain of Notch4, and loss of the extracellular domain leads to constitutive activation. Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. cDNA cloning, deduced amino acid sequence analysis, in situ hybridization Development High 8681805
1997 NOTCH4 (INT3) protein contains 29 EGF-like repeats (instead of 36 in other Notch homologs); all MMTV-induced tumorigenic INT3 mutations result from proviral insertions that cause expression of only the intracellular domain, demonstrating that constitutive activation occurs in the absence of the extracellular domain and LIN12 repeat regulatory sequences. Nucleotide sequence analysis, characterization of host-viral junction fragments from nine independent mammary tumors Oncogene High 9150355
1998 The human NOTCH4 protein contains 29 EGF-like repeats, 3 Notch/lin-12 repeats, a transmembrane region, 6 cdc10/ankyrin repeats, and a PEST domain; two alternatively spliced isoforms (NOTCH4(L) and NOTCH4(S)) were identified; the promoter is TATA-less and contains RBP-Jkappa and GATA recognition sites. Genomic sequencing, Northern blot, cDNA isoform characterization Genomics High 9693032
1998 The activated Notch4(int-3) oncoprotein inhibits HGF- and TGF-beta2-induced branching morphogenesis of mammary epithelial cells. The minimal domain required for this inhibition consists of the CBF-1 (RBP-Jkappa) interaction domain and the cdc10/ankyrin repeat domain. Wnt-1 can overcome Notch4-mediated inhibition of branching morphogenesis. 3D collagen gel branching morphogenesis assay, deletion mutant analysis in TAC-2 mammary epithelial cells Developmental biology High 9576833
2000 Activated Notch4/int-3 (lacking most of the extracellular domain) disrupts normal alveolar epithelial morphogenesis and induces invasion of the extracellular matrix by mammary epithelial cells, and disrupts contact inhibition of proliferation. 3D collagen gel morphogenesis assay, invasion assay in TAC-2 cells expressing Notch4(int-3) International journal of cancer Medium 10797286
2000 Both activated Notch4/int-3 and Jagged-1 induce microvessel-like structures in rat brain endothelial cells. Activation of Notch signaling was confirmed by induction of endogenous Notch4 and Jagged-1 genes and proteins. Full-length Notch4 (without activation) did not affect these cells. Ectopic expression in RBE4 rat brain endothelial cells, morphological and biochemical characterization Microvascular research Medium 10964583
2001 Expression of activated Notch4 in embryonic endothelium (under Flk1/VEGFR regulation) causes embryonic lethality, restricted vascular development, disorganized vascular networks, large dilated vessels with compromised wall integrity, and abnormal yolk-sac vasculature, implicating Notch4 in vessel patterning and remodeling. Transgenic mouse model with Flk1-driven activated Notch4, in vivo vascular phenotyping PNAS High 11344305
2002 Constitutively active Notch4 inhibits endothelial sprouting and VEGF-induced angiogenesis. The mechanism involves activation of beta1-integrin into a high-affinity conformation (not increased surface expression), leading to increased adhesion to collagen and inhibition of migration through collagen. Activation of beta1-integrins alone is sufficient to inhibit VEGF-induced sprouting. In vitro endothelial sprouting assay (HMEC-1 cells), chick chorioallantoic membrane in vivo assay, flow cytometry for integrin conformation, function-activating beta1-integrin antibodies Molecular and cellular biology High 11909975
2003 Constitutively active Notch4 intracellular domain inhibits endothelial apoptosis triggered by LPS via two mechanisms: (1) RBP-Jkappa-dependent inhibition of the JNK proapoptotic pathway, and (2) RBP-Jkappa-independent upregulation of Bcl-2. A Notch4 mutant lacking the RAM domain showed only partial anti-apoptotic activity but equivalent RBP-Jkappa transcriptional activation. Apoptosis assays in endothelial cells, RBP-Jkappa reporter assays, RAM-domain deletion mutants, Bcl-2 western blot The Journal of biological chemistry High 14701863
2004 Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats but not the RAM domain or C-terminal region. The ankyrin repeats alone are sufficient for RBP-Jkappa-dependent gene upregulation and partial inhibition of sprouting. N4IC reduced VEGFR-2 and VE-cadherin expression, but neither event alone is necessary and sufficient to explain inhibition. A constitutively active RBP-Jkappa mutant inhibits sprouting less strongly than full N4IC, suggesting RBP-Jkappa-dependent and -independent mechanisms. Quantitative endothelial sprouting assay with N4IC deletion mutants, RBP-Jkappa reporter assays, VEGFR-2/VE-cadherin expression analysis Blood High 15187023
2004 Constitutively active Notch4 (Notch4-IC) in human hematopoietic progenitors reduces colony-forming and short-term proliferative ability while increasing primitive progenitor content in long-term cultures. In vivo, Notch4-IC-transduced cells engraft more efficiently and generate an immature CD4+CD8+ T-cell population while blocking B-cell development. Retroviral transduction of human marrow/cord cells, long-term culture assay, transplantation into beta2-microglobulin-/- NOD/SCID mice Blood Medium 15231576
2004 The ANK domain and C-terminal domain of Int-3 (constitutively active Notch4) are important for inhibition of differentiation and growth arrest in myeloid leukemia cells. Expression of Int-3 in mouse bone marrow stem cells inhibits differentiation and expands colony-forming progenitors 3-5 fold. Retroviral transduction with Int-3 deletion mutants in HL-60 cells and mouse bone marrow, colony-forming assays, cell cycle analysis Leukemia Medium 14961038
2005 Notch4 intracellular domain (ICD4) binds to Smad2, Smad3, and Smad4 (with highest affinity to Smad3 via its MH2 domain, independent of the RAM23 region). ICD4 attenuates TGF-beta signaling: cells expressing ICD4 resist TGF-beta growth inhibition, and ICD4 inhibits Smad-binding element and 3TP luciferase reporter activity and PAI-1 expression. Blocking Notch4 processing by gamma-secretase inhibitor restores TGF-beta sensitivity in MCF-7 cells. Co-immunoprecipitation/binding assay, deletion analysis, luciferase reporter assays, RT-PCR, western blot, gamma-secretase inhibitor treatment Oncogene High 16007227
2005 NOTCH4 transcription in endothelial cells is regulated by cell-type-specific AP-1 complexes that occupy NOTCH4 chromatin. Intron 1 or upstream sequences are required for expression in the vasculature of transgenic mouse embryos. Vascular angiogenic factors activate AP-1 and can reprogram the endogenous NOTCH4 gene from a repressed to a transcriptionally active state in non-endothelial cells (HeLa). ChIP, RNA FISH, transfection assays, transgenic mice, endothelial cell-specific histone modification mapping Molecular and cellular biology High 15684396
2005 Endothelial expression of constitutively active Notch4 (int3) in adult mice causes profound blood vessel enlargement, AV shunting (hallmarks of AVM), and lethality. This is accompanied by arterialization including ectopic venous expression of ephrinB2, increased smooth muscle cells, and upregulation of endogenous Notch signaling. Repression of int3 expression reverses the vascular defects. Constitutively active Notch1 induces similar hepatic vascular lesions. Tetracycline-repressible transgenic system with endothelial-specific expression, vascular phenotyping, ephrinB2 immunostaining, doxycycline rescue PNAS High 15994223
2006 VEGF upregulates DLL4 and presenilin, leading to activation of Notch4, which in turn upregulates ephrin B2 and downregulates EphB4, directing the differentiation of venous endothelial cells toward an arterial phenotype. Disruption of Notch4 signaling by presenilin inhibition or soluble DLL4 inhibits VEGF-induced venous endothelial cell migration and differentiation. In vitro HUVEC treatment, western blot, pharmacological inhibition (presenilin inhibitor, soluble DLL4), in vivo transgenic hepatocarcinoma mouse model with immunostaining Cancer research Medium 16951162
2007 AP-1 and the glucocorticoid receptor (GR) synergistically activate Notch4 transcription in endothelial cells through a composite response element (imperfect half-glucocorticoid response element + AP-1 motif) in the Notch4 promoter. FGF-2 induces AP-1 occupancy and cortisol induces GR occupancy at this element; AP-1 stabilizes GR occupancy. In multipotent 10T1/2 cells, FGF-2 and cortisol reprogram the Notch4 locus from repressed to active state. ChIP, luciferase reporter assays, histone modification analysis, transfection in endothelial and 10T1/2 cells Molecular and cellular biology High 17220278
2008 Constitutively active Notch4 in endothelial cells from birth causes brain AVMs (cerebral AV shunting, vessel enlargement, hemorrhage, neuronal death) in mice by 3 weeks. Repression of Notch4* (int3) resolves ataxia and reverses disease progression. int3 expression results in enlarged microvasculature coinciding with reduced capillary density, linking vessel enlargement to Notch's inhibition of vessel sprouting. Tetracycline-regulatable transgenic system (endothelial-specific, from birth), vascular phenotyping, doxycycline-mediated repression and disease reversal PNAS High 18667694
2008 Notch4 and Hes1 knockdown in endothelial cells enhances VCAM-1 expression, promotes apoptosis, and inhibits repair of endothelial injury, demonstrating that basal Notch4 activity is required to maintain EC quiescence and survival. TNFα decreases Notch4 expression predominantly via PI3-kinase signaling pathways, reducing CBF1 activity and Hes1 expression. siRNA knockdown, VCAM-1 expression assay, apoptosis assay, endothelial injury/repair assay, CBF1 reporter assay in arterial endothelial cells Arteriosclerosis, thrombosis, and vascular biology Medium 18802018
2008 Rbpj conditional knockout in Notch4/Int3-expressing mammary glands normalizes mammary gland development (demonstrating developmental arrest requires RBP-Jkappa-dependent signaling), but mammary tumor development still occurs in Rbpj-null/Int3 mice, demonstrating that Notch4-induced mammary tumorigenesis is independent of RBP-Jkappa interaction. Conditional Rbpj knockout (Wap-Cre) in Wap-Int3 transgenic mice, mammary gland histology, tumor frequency analysis Oncogene High 18836481
2009 Constitutively active Notch4 in adult mouse endothelium causes lung AV shunts and lung hemorrhages. Cessation of Notch4* expression reverses these effects. Whole lung organ culture confirmed the lung vascular effects are a primary lung phenomenon. Tetracycline-repressible transgenic system (endothelial-specific), vascular casting, fluorescent microsphere analysis, organ culture American journal of physiology. Lung cellular and molecular physiology High 19933399
2010 Notch4 signaling activity is 8-fold higher in breast cancer stem cell-enriched populations compared with differentiated cells. Pharmacologic or genetic inhibition of Notch4 reduces stem cell activity in vitro and reduces/abolishes tumor formation in vivo. Notch4 inhibition produces more robust suppression of tumor initiation than Notch1 inhibition. Stem cell enrichment by anoikis resistance or ESA+/CD44+/CD24low selection, in vitro stem cell activity assays, in vivo tumor formation assays, gamma-secretase inhibitor and siRNA knockdown Cancer research Medium 20068161
2010 Notch4 is specifically required for expression of the embryonic morphogen Nodal in aggressive melanoma cells via an RBPJ-dependent Nodal enhancer element. Notch4 regulates vasculogenic mimicry and anchorage-independent growth, effects mediated in part through Notch4 regulation of Nodal, placing Notch4 upstream of Nodal in this pathway. RBPJ-dependent Nodal enhancer luciferase reporter assay, siRNA knockdown of Notch4, vasculogenic mimicry and soft agar assays in aggressive melanoma cells Cancer research Medium 21159651
2012 Normalization of Notch signaling by repressing Notch4* expression converts large-caliber high-flow AV shunts to capillary-like vessels. This regression is initiated by vessel narrowing without loss of endothelial cells and requires restoration of EphB4 receptor expression by venous endothelial cells. 4D two-photon imaging through cranial window, doxycycline-mediated Notch4* repression, EphB4 expression analysis Science translational medicine High 22261032
2013 PKCα selectively increases Notch-4 (but not Notch-1) expression through activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCα-overexpressing cells, while Notch-4IC expression stimulates it. ChIP for AP-1 at Notch-4 promoter, siRNA knockdown, Notch-4IC overexpression, estrogen-independent growth assays Oncogenesis Medium 23917222
2013 YB-1 binding to the Notch4 promoter (12-fold enrichment by ChIP-on-ChIP) regulates Notch4 transcription. Silencing YB-1 decreases Notch4 mRNA; constitutively active YB-1 increases it. The RSK kinase phosphorylates YB-1 to activate this axis. Luteolin inhibits RSK, suppresses YB-1 phosphorylation, and thereby reduces Notch4 expression and N4ICD levels. ChIP-on-ChIP, siRNA knockdown of YB-1, YB-1 overexpression, in vitro kinase assay for RSK, luteolin treatment with RSK/YB-1/Notch4 correlation Oncotarget Medium 23593654
2014 NOTCH4 did not signal in response to ligand in cultured cells. Moreover, NOTCH4 inhibited signaling from NOTCH1 receptor in cis (first report of cis-inhibition by another Notch receptor). The NOTCH4 extracellular domain alone, expressed in cis, also inhibits NOTCH1 signaling. Notch4 null mice (entire coding region deleted) exhibit slightly delayed vessel growth in the retina. Cell-based signaling assays in cultured cells, NOTCH4 extracellular domain expression constructs, Notch4 null mouse generation (complete coding region deletion), retinal vascular analysis Biochimica et biophysica acta High 24667410
2014 Brain AVMs arise from enlargement of preexisting microvessels with capillary diameter driven by increased individual endothelial cell area (not increased EC number/proliferation). AV shunting begins promptly after Notch4* expression. Altering Notch signaling in ECs of all vessels (but not arteries alone) affects AVM formation, suggesting Notch4 functions in the microvasculature/veins. A positive feedback loop of increasing blood flow and vessel diameter drives focal AVM growth. Time-lapse two-photon imaging through cranial windows, conditional endothelial Notch4* expression, hemodynamic measurements PNAS High 25468970
2015 AKT binds to Notch4-ICD and phosphorylates it at four distinct sites in vitro and in vivo. This phosphorylation is regulated by growth factors and is sensitive to PI3K inhibitors. Phosphorylation generates binding sites for 14-3-3 proteins, which restrict phosphorylated Notch4-ICD to the cytoplasm, providing a negative regulatory mechanism for Notch4 nuclear signaling. In vitro kinase assay, co-immunoprecipitation, in vivo phosphorylation assays, PI3K inhibitor treatment, 14-3-3 binding assay, subcellular localization analysis Scientific reports High 25740432
2015 JAG1-NOTCH4 receptor activation in breast cancer cells is induced by anti-estrogens (tamoxifen, fulvestrant) and drives breast cancer stem cell (BCSC) activity and anti-estrogen resistance. Targeting NOTCH4 reverses the increase in BCSC activity induced by anti-estrogens in patient-derived and PDX tumor samples. Primary patient samples and PDX models, BCSC activity assays (ALDH1, mammosphere), NOTCH4 inhibition by antibody/siRNA, in vivo tumor assays Cell reports Medium 26387946
2016 Expression of constitutively active Notch4 intracellular domain (N4ICD) in melanoma cells induces Hey1 and Hey2, which bind directly to promoter regions of Snail2 and Twist1 and repress their transcription (demonstrated by EMSA and luciferase assays), causing a mesenchymal-to-epithelial-like switch, reduced invasion and migration, and reduced tumor growth in vivo. N4ICD expression, EMSA, luciferase reporter assays for Snail2 and Twist1 promoters, Hey1/Hey2 ChIP, in vivo xenograft Cancer research High 26801977
2017 NOTCH4 transcriptionally activates HEY1 in head and neck squamous cell carcinoma, and the NOTCH4-HEY1 axis drives EMT (decreased E-cadherin, increased Vimentin, Fibronectin, TWIST1, SOX2), proliferation, cisplatin resistance, and increased invasion/migration. siRNA knockdown, TCGA data analysis, in vitro proliferation/apoptosis/cell-cycle/invasion/migration assays Clinical cancer research Medium 29146722
2017 RUNX1 negatively controls NOTCH4 expression via a novel regulatory DNA element within the NOTCH4 locus. Specific CRISPR-Cas9-mediated inactivation of NOTCH4 in human iPSCs enhances megakaryopoiesis. Small-molecule Notch signaling inhibitors promote megakaryocyte generation from human iPSCs and postnatal CD34+ hematopoietic stem/progenitor cells. Integrative genomic analysis of FPD-iPSCs, improved CRISPR-Cas9 NOTCH4 knockout in human iPSCs, MK differentiation assays, Notch inhibitor treatment of CD34+ cells Blood High 29101237
2018 Notch4 intracellular domain interacts with TAK1 and inhibits its activation; Notch4 also prevents TRAF6 autoubiquitination and suppresses TRAF6-mediated TAK1 polyubiquitination, thereby inhibiting M. tuberculosis-induced proinflammatory cytokine production. Notch4-deficient mice show lower bacterial burden and reduced lung pathology after M. tuberculosis infection. Co-immunoprecipitation (Notch4-TAK1 interaction), ubiquitination assays (TRAF6 autoubiquitination, TAK1 polyubiquitination), Notch4-deficient mice, in vivo infection model The Journal of infectious diseases High 29228365
2020 NOTCH4 transcriptionally upregulates SLUG and GAS1 in TNBC cells; dual-luciferase reporter and ChIP assays identified genuine NOTCH4 binding sites on SLUG and GAS1 promoters. NOTCH4-SLUG upregulation promotes EMT, and NOTCH4-GAS1 upregulation promotes quiescence in mesenchymal-like breast cancer stem cells. SLUG also harnesses GAS1 via its anti-apoptotic function. Dual-luciferase reporter assay, ChIP, RNA-seq, stable OE/KD cell lines, mammosphere formation, chemoresistance assays, in vivo serial dilution Theranostics High 32104513
2020 IL-6/STAT3-dependent upregulation of Notch4 on lung tissue regulatory T cells is necessary for allergen/pollutant-induced airway inflammation. Notch4 subverts Treg cells into TH2 and TH17 effector T cells via Wnt and Hippo pathway-dependent mechanisms. Wnt activation in Tregs induces GDF15 expression, which activates group 2 innate lymphoid cells to amplify inflammation. Conditional Notch4 deletion in Treg cells (mouse models), anti-Notch4 antibody therapy, Wnt/Hippo pathway inhibitors, human circulating Treg cell analysis Nature immunology High 32929274
2021 Notch4 on regulatory T cells suppresses induction of amphiregulin (a tissue repair cytokine) by IL-18. Deletion of Notch4 in Treg cells or anti-Notch4 antibody therapy rescues disease morbidity and mortality in influenza and synthetic viral RNA models. Protection by Notch4 inhibition is recapitulated by amphiregulin therapy and abrogated by its antagonism. Treg-specific Notch4 deletion (conventional and humanized mice), anti-Notch4 antibody therapy, amphiregulin administration/antagonism, prospective COVID-19 patient cohort Immunity High 33915108
2021 Notch4 null mice have increased closure of lymphangiogenic fronts, reduced lymphatic vessel caliber at E14.5, and reduced branching at E16.5. Notch4 activation suppresses lymphatic endothelial cell migration more strongly than Notch1 activation. Loss of Notch4 does not affect canonical LEC Notch signaling, indicating Notch4 and canonical Notch signaling have distinct functions in lymphangiogenesis. Notch4 null mice, embryonic dermal lymphatic analysis, LEC migration wounding assay, comparison with DNMAML (canonical Notch blockade) Prox1-Cre mice Angiogenesis High 34665379
2022 Disturbed blood flow activates the JAG1-NOTCH4 signaling pathway in endothelial cells. EC-specific deletion of Jag1 (Jag1) in mice demonstrates JAG1 promotes atherosclerosis at sites of disturbed flow. Single-cell RNA sequencing showed Jag1 suppresses subsets of ECs that proliferate and migrate. Porcine and murine artery exposure to disturbed flow, cultured human coronary artery ECs, light-sheet imaging, EC-specific Jag1 conditional KO mice, single-cell RNA sequencing Science advances High 36044575
2022 Notch4 interacts with ERK, JNK, and P38 MAPK (confirmed by co-immunoprecipitation) and promotes HPASMC proliferation and migration while inhibiting apoptosis via these signaling pathways. AAV1-mediated Notch4 silencing in vivo reduces right ventricular systolic pressure and pulmonary vascular remodeling in hypoxic rats. Co-immunoprecipitation (Notch4-ERK/JNK/P38), siRNA knockdown and overexpression in HPASMCs, cell viability/proliferation/apoptosis/migration assays, AAV1-si-Notch4 in vivo Respiratory research Medium 35016680
2022 IL-4Rα R576 variant upregulates Notch4 expression on lung Treg cells in an IL-6- and GRB2-dependent manner. Signaling via IL-4RαR576 upregulates Notch4 and its downstream mediators Yap1 and beta-catenin in lung Tregs, leading to exacerbated lung inflammation. Treg-specific Notch4 deletion or anti-Notch4 antibody inhibits this augmented inflammation. Il4raR576 knock-in mouse model, Treg-specific Notch4 deletion, GRB2 and IL-6R inhibition, Yap1/beta-catenin expression analysis, human PBMC analysis Allergy High 35841382
2021 Constitutively active Notch4 intracellular domain promotes proliferation of 3T3-L1 preadipocytes through the ERK pathway and cell cycle modulation, and facilitates differentiation by upregulating adipogenic genes (C/EBPα, PPARγ, aP2, LPL, HSL) and repressing the inhibitor Pref-1. HES1, Hey1, C/EBPδ, and PPARγ are upregulated downstream of N4IC. Transient and stable transfection of N4IC in 3T3-L1 cells, qRT-PCR, western blot, proliferation and differentiation assays Biochemical and biophysical research communications Medium 23237809
2011 PEA3 (ETS transcription factor) directly activates Notch-4 transcription in MDA-MB-231 breast cancer cells; ChIP confirmed enrichment of PEA3 on the Notch-4 promoter. PEA3 recruitment to the Notch-4 promoter is c-JUN (AP-1)-dependent, while its recruitment to Notch-1 is AP-1-independent. A Notch-4 luciferase reporter confirmed PEA3/AP-1 activation. ChIP, siRNA knockdown, Notch-4 luciferase reporter assay, TAM-67 and c-Jun siRNA, real-time PCR Breast cancer research Medium 21679465
2019 VEGF165 inhibits pro-fibrotic differentiation of endometrial stromal cells via the DLL4/Notch4/Smad7 pathway; inhibition of Smad7 or Notch4 expression, or blockade of Notch signaling, abrogates this beneficial VEGF165 effect, indicating Smad7 and Notch4 are essential downstream effectors. siRNA knockdown of Notch4/Smad7, Notch signaling inhibitor, TGFβ1-induced fibrotic model in primary human endometrial stromal cells, conditional VEGF knockout mice Cell death & disease Medium 31515487
2021 Hypoxia activates Delta-like 4 and Notch4 in lung adenocarcinoma (LUAD) cells; Notch4 physically interacts with ERK, JNK, and P38 (confirmed by Co-IP) and their activation is required for Notch4's pro-proliferative, anti-apoptotic, and pro-migratory effects, which are reversed by pathway inhibitors. Co-immunoprecipitation (Notch4-ERK/JNK/P38), siRNA/OE, MAPK inhibitors, in vitro proliferation/apoptosis/migration, in vivo xenograft models Frontiers in cell and developmental biology Medium 34988077
2021 NOTCH4 exhibits anti-inflammatory activity in macrophages by (1) interfering with STAT1-dependent transcription downstream of IFN-γ, favoring STAT3 over STAT1 phosphorylation without affecting their expression; (2) inhibiting NF-κB transcriptional activity via diminished STAT1 activation downstream of TLR/LPS. HES1 mediates, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 overexpression/knockdown in macrophages, STAT1/STAT3 phosphorylation western blot, NF-κB luciferase reporter, IRF1/SOCS1/CXCL10 expression analysis, Hes1 reporter Frontiers in immunology Medium 34925319
2019 Notch4 activation promotes HIV-associated nephropathy (HIVAN) disease progression; global deletion of the Notch4 intracellular domain in Tg26 mice (Notch4 ICD KO) significantly improved renal function, decreased mortality, reduced glomerular and tubulointerstitial injury, decreased interstitial inflammation, and reduced expression of IL-6, CCL2, and NF-κB (Nfkb1/p65). Notch4 ICD global deletion in Tg26 HIVAN mice, renal function assays, histology, cytokine qRT-PCR, NF-κB protein analysis Disease models & mechanisms Medium 31727625
1999 Retroviral splicing events between an intracisternal type A particle (IAP) and Notch4/int3 sequences generate two fusion transcripts encoding different portions of the intracellular domain (one with RAM domain, one without). These two proteins show different subcellular localizations in mammary epithelial cells (HC-11): both cytoplasm+nucleus vs. nucleus only. Sequence analysis of mammary tumor, immunofluorescence of transfected cells, subcellular localization analysis Journal of virology Medium 10233982
2004 A truncated Notch4/Int3 protein lacking the CBF1-binding region (RAM23) localizes to both cytoplasm and nucleus (vs. nucleus-only for full Int3-ICD), and mammary tumors arising from its expression show activation of the Notch target Hes-1, but with longer latency, suggesting a gradient of CBF1-dependent Notch4 signaling determines the extent of oncogenicity. Immunofluorescence of transfected COS-1 cells, transgenic mouse mammary tumor model, RT-PCR/western blot for Hes-1 Oncogene Medium 15531924
2008 HIV protease inhibitor Nelfinavir (but not Saquinavir, Indinavir, or Ritonavir) specifically increases Notch4 processing and Notch4 intracellular domain nuclear localization, leading to induction of NFκB and MMP2 expression in cerebral endothelial cells. Pre-treatment with Vitamin E partially prevents Nelfinavir-induced changes in Notch4 processing and localization. Western blot for Notch4 processing, nuclear localization analysis, NFκB/MMP2 expression assay, antioxidant rescue experiment in cerebral endothelial cells BMC neuroscience Low 18302767

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development (Cambridge, England) 428 8681805
2010 Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer research 420 20068161
2001 Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proceedings of the National Academy of Sciences of the United States of America 227 11344305
2005 Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proceedings of the National Academy of Sciences of the United States of America 167 15994223
1997 The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene 166 9150355
2015 Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity. Cell reports 160 26387946
2002 Activated Notch4 inhibits angiogenesis: role of beta 1-integrin activation. Molecular and cellular biology 140 11909975
2006 The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer research 138 16951162
2008 Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proceedings of the National Academy of Sciences of the United States of America 114 18667694
1998 Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Developmental biology 111 9576833
2021 Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity 110 33915108
2020 A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma. Nature immunology 106 32929274
2010 Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype. Cancer research 101 21159651
2003 Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. The Journal of biological chemistry 98 14701863
2011 Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood 97 21602525
2007 Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver international : official journal of the International Association for the Study of the Liver 95 17696940
2005 Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling. Oncogene 81 16007227
2000 Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. International journal of cancer 80 10797286
2010 Inflammation dysregulates Notch signaling in endothelial cells: implication of Notch2 and Notch4 to endothelial dysfunction. Biochemical pharmacology 78 20643108
2017 The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 76 29146722
2014 Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proceedings of the National Academy of Sciences of the United States of America 76 25468970
2011 Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer. International journal of surgical pathology 73 22084425
2012 Notch4 normalization reduces blood vessel size in arteriovenous malformations. Science translational medicine 72 22261032
2020 NOTCH4 maintains quiescent mesenchymal-like breast cancer stem cells via transcriptionally activating SLUG and GAS1 in triple-negative breast cancer. Theranostics 70 32104513
2017 Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer. Cancer letters 65 28108315
2005 Molecular determinants of NOTCH4 transcription in vascular endothelium. Molecular and cellular biology 63 15684396
2008 Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant arteriosclerosis. Arteriosclerosis, thrombosis, and vascular biology 61 18802018
2005 Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation. Gene expression patterns : GEP 60 15939383
2004 Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood 60 15231576
2014 Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells. Breast cancer research : BCR 59 24919951
2013 Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis 57 23917222
2000 Notch4 and Jagged-1 induce microvessel differentiation of rat brain endothelial cells. Microvascular research 57 10964583
2012 Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast cancer research and treatment 54 22965833
2011 NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications. Breast cancer research : BCR 54 21679465
2021 Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy. BMC medicine 52 34284787
2014 NOTCH4 is a potential therapeutic target for triple-negative breast cancer. Anticancer research 51 24403446
2019 FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC cancer 50 30975104
2017 Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway. Apoptosis : an international journal on programmed cell death 49 28374086
2014 Notch4 reveals a novel mechanism regulating Notch signal transduction. Biochimica et biophysica acta 48 24667410
2013 Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Oncotarget 48 23593654
2016 Notch4+ cancer stem-like cells promote the metastatic and invasive ability of melanoma. Cancer science 45 27234159
2016 Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors. Cancer research 44 26801977
2008 Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene 44 18836481
2001 Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland. Nature genetics 44 11381258
2004 Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh). Oncogene 41 15531924
2002 A family-based and case-control association study of the NOTCH4 gene and schizophrenia. Molecular psychiatry 40 11803454
2001 NOTCH4 gene polymorphism and susceptibility to schizophrenia and schizoaffective disorder. Neuroscience letters 40 11239712
2004 Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-Jkappa. Blood 38 15187023
2017 Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation. Blood 37 29101237
1998 Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene. Genomics 37 9693032
2022 Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension. Respiratory research 36 35016680
2018 The association between Notch4 expression, and clinicopathological characteristics and clinical outcomes in patients with breast cancer. Oncology letters 36 29805613
2015 Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma. International journal of oncology 34 26530164
2000 Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers. International journal of oncology 34 11078798
2010 Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity. Journal of neurochemistry 33 20722969
2021 NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling. Frontiers in immunology 32 34925319
2004 Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. Pharmacogenetics 32 15115916
2022 The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer. Cytokine & growth factor reviews 31 35941043
2014 NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer. Medicina (Kaunas, Lithuania) 31 25060200
2001 The (CTG)n polymorphism in the NOTCH4 gene is not associated with schizophrenia in Japanese individuals. BMC psychiatry 31 11407996
2021 Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4. Nature communications 30 34785669
2020 Androgen receptor suppresses vasculogenic mimicry in hepatocellular carcinoma via circRNA7/miRNA7-5p/VE-cadherin/Notch4 signalling. Journal of cellular and molecular medicine 30 33118329
2019 Quartz crystal microbalance biosensor for label-free MDA MB 231 cancer cell detection via notch-4 receptor. Talanta 30 31357373
2014 Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling. Molecular and cellular biochemistry 30 25511451
2012 A re-review of the association between the NOTCH4 locus and schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 30 22488909
2010 Notch-4 contributes to the metastasis of salivary adenoid cystic carcinoma. Oncology reports 30 20596622
2003 Notch4, a non-HLA gene in the MHC is strongly associated with the most severe form of alopecia areata. Human genetics 30 12589427
2022 JAG1-NOTCH4 mechanosensing drives atherosclerosis. Science advances 29 36044575
2018 Notch4 Negatively Regulates the Inflammatory Response to Mycobacterium tuberculosis Infection by Inhibiting TAK1 Activation. The Journal of infectious diseases 29 29228365
2016 NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation. Journal of neurosurgery 29 27231971
2003 NOTCH4 and the frontal lobe in schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 28 12627456
2003 NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia. Psychiatric genetics 27 12782960
2015 AKT and 14-3-3 regulate Notch4 nuclear localization. Scientific reports 26 25740432
2021 Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives. Cancer management and research 25 34526819
2012 Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes. Biochemical and biophysical research communications 25 23237809
2009 Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice. American journal of physiology. Lung cellular and molecular physiology 25 19933399
2004 NOTCH4 gene haplotype is associated with schizophrenia in African Americans. Biological psychiatry 24 14732589
2004 Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors. Leukemia 24 14961038
2015 The role of polycomb group protein Bmi-1 and Notch4 in breast cancer stem cell inhibition by benzyl isothiocyanate. Breast cancer research and treatment 23 25663545
1997 Gene organization of human NOTCH4 and (CTG)n polymorphism in this human counterpart gene of mouse proto-oncogene Int3. Gene 23 9168133
2022 A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit. Allergy 22 35841382
2021 Unique functions for Notch4 in murine embryonic lymphangiogenesis. Angiogenesis 22 34665379
2004 A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501. Tissue antigens 22 14651518
2022 Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer. Cellular oncology (Dordrecht, Netherlands) 21 35543859
2019 Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway. Cell death & disease 21 31515487
2015 The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 26472724
2008 Alterations in the Notch4 pathway in cerebral endothelial cells by the HIV aspartyl protease inhibitor, nelfinavir. BMC neuroscience 20 18302767
2007 Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Molecular and cellular biology 20 17220278
2006 A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20 16894623
2005 Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses. Schizophrenia research 20 15653273
2003 Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples. Biological psychiatry 20 12873802
2021 Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis. Frontiers in cell and developmental biology 18 34988077
2018 NOTCH4 regulates colorectal cancer proliferation, invasiveness, and determines clinical outcome of patients. Journal of cellular physiology 18 29693251
2016 Association of Notch4 with metastasis in human oral squamous cell carcinoma. Life sciences 18 27197026
1999 Intracisternal type A particle-mediated activation of the Notch4/int3 gene in a mouse mammary tumor: generation of truncated Notch4/int3 mRNAs by retroviral splicing events. Journal of virology 18 10233982
2019 Notch4 activation aggravates NF-κB-mediated inflammation in HIV-1-associated nephropathy. Disease models & mechanisms 17 31727625
2012 Investigation of NOTCH4 coding region polymorphisms in sporadic inclusion body myositis. Journal of neuroimmunology 16 22732452
2009 Peroxisome-proliferator-activated receptor-binding protein (PBP) is essential for the growth of active Notch4-immortalized mammary epithelial cells by activating SOX10 expression. The Biochemical journal 16 19852756
2023 Silencing Notch4 promotes tumorigenesis and inhibits metastasis of triple-negative breast cancer via Nanog and Cdc42. Cell death discovery 15 37149651
2020 Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene. Journal of medical genetics 15 32900838

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