Affinage

NOTCH3

Neurogenic locus notch homolog protein 3 · UniProt Q9UM47

Length
2321 aa
Mass
243.6 kDa
Annotated
2026-04-29
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOTCH3 is a transmembrane receptor that functions as a central regulator of vascular smooth muscle cell and pericyte biology, controlling mural cell differentiation, arterial wall maintenance, and vessel stabilization through both canonical RBP-Jκ/CBF1-dependent transcription and non-canonical signaling. Ligand-induced activation requires sequential proteolysis by ADAM10 and presenilin/γ-secretase, releasing an intracellular domain (ICD) that is degraded by lysosomes rather than proteasomes, and an ectodomain whose clearance is critical for vascular homeostasis (PMID:24842903, PMID:19735738, PMID:10712431). In pericytes, NOTCH3 drives DLL4 expression to activate endothelial NOTCH1, stabilizing VE-cadherin junctions and inducing angiopoietin-2 for vessel maturation, while in the absence of ligand it can act as a dependence receptor triggering endothelial apoptosis independently of RBPJ (PMID:34878922, PMID:20689064, PMID:28719575). Mutations in NOTCH3 EGF-like repeats that alter cysteine residues cause CADASIL, a hereditary cerebral small vessel disease, through enhanced ectodomain multimerization and co-aggregation of wild-type with mutant NOTCH3 ECD, leading to sequestration of extracellular matrix proteins (TIMP3, vitronectin, LTBP-1), arterial smooth muscle cell loss, cerebral blood flow deficits, and white matter lesions (PMID:8878478, PMID:38386425, PMID:26648042, PMID:25190493).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Identifying NOTCH3 as the gene mutated in CADASIL established the first direct link between a Notch receptor and a human vascular disease, opening the field to mechanistic investigation of how NOTCH3 dysfunction causes cerebral small vessel pathology.

    Evidence Genetic mapping and mutation analysis in CADASIL families

    PMID:8878478

    Open questions at the time
    • Mechanism by which mutations cause disease was unknown
    • No functional characterization of NOTCH3 protein at this stage
  2. 1997 High

    Demonstrating that CADASIL mutations cluster in EGF-like repeats and invariably alter cysteine residues suggested that aberrant disulfide bonding, rather than simple loss of function, underlies the molecular pathogenesis.

    Evidence SSCP and sequence analysis of 50 CADASIL patients showing cysteine gain/loss pattern

    PMID:9388399

    Open questions at the time
    • Whether aberrant dimerization actually occurs was inferred, not demonstrated biochemically
    • Functional consequence on signaling not yet tested
  3. 2000 High

    Discovery that NOTCH3 is proteolytically processed into a 210-kDa ectodomain and 97-kDa transmembrane/intracellular fragment, with CADASIL mutations specifically impairing ectodomain clearance, shifted focus toward ectodomain accumulation as a disease driver.

    Evidence Immunoblotting of transfected cells and CADASIL brain tissue; immunohistochemistry

    PMID:10712431

    Open questions at the time
    • Identity of the protease(s) responsible for cleavage not yet defined
    • Mechanism of impaired clearance unknown
  4. 2005 Medium

    Two studies clarified that CADASIL mutations impair Fringe-mediated glycosylation and promote aberrant multimerization, while a common CADASIL mutation retains ligand binding and CBF1 activation, indicating that canonical signaling deficiency alone does not explain the disease.

    Evidence Biochemical glycosylation assays, co-immunoprecipitation for dimerization, flow cytometry ligand-binding and CBF1-reporter assays

    PMID:15857853 PMID:16107360

    Open questions at the time
    • Whether impaired Fringe glycosylation contributes to pathology in vivo was untested
    • The contribution of multimerization to ectodomain accumulation was not established
  5. 2009 High

    Multiple advances converged: single-molecule analysis confirmed CADASIL mutations enhance ectodomain multimerization via disulfide bonds (neomorphic gain-of-function); lysosomal (not proteasomal) degradation of NOTCH3 ICD was established; TSP2 was identified as a direct NOTCH3/Jagged1 interaction facilitator; and CADASIL mutations in the ligand-binding domain were shown to have dominant-negative properties distinct from common mutations.

    Evidence Single-molecule fluorescence multimerization assays; pharmacological lysosome/proteasome inhibition pulse-chase; direct binding assays with TSP2-knockout validation; transgenic mouse epistasis for ligand-binding domain mutations

    PMID:19147503 PMID:19293235 PMID:19417009 PMID:19735738

    Open questions at the time
    • Whether multimerization is the primary pathogenic event versus ectodomain deposition remained unclear
    • In vivo relevance of lysosomal degradation pathway for NOTCH3 ICD not shown
    • TSP2-NOTCH3 interaction not validated in vascular cells
  6. 2009 Medium

    NOTCH3 was placed within cancer survival pathways when its inhibition in lung cancer was shown to induce apoptosis via MAPK-Bim regulation, demonstrating NOTCH3 function beyond the vasculature.

    Evidence γ-secretase inhibitor treatment, shRNA knockdown, xenograft model

    PMID:19881544

    Open questions at the time
    • Whether this is a direct transcriptional target pathway of NOTCH3 ICD or indirect was unclear
    • Generalizability to other tumor types not established
  7. 2010 High

    NOTCH3 was established as essential for mural cell investment and vascular development through knockout mouse studies showing reduced retinal vascularization and angiopoietin-2 as a downstream effector linking NOTCH3 to vessel maturation.

    Evidence Notch3 knockout mice; oxygen-induced retinopathy model; in vitro Ang2 induction assays

    PMID:20689064

    Open questions at the time
    • Whether angiopoietin-2 regulation is direct or via intermediate transcription factors was not resolved
    • Phenotype in other vascular beds not characterized
  8. 2013 High

    Zebrafish studies expanded NOTCH3's role to oligodendrocyte precursor cell development and myelin gene expression, linking NOTCH3 to white matter biology via canonical hey1-dependent signaling, while cancer studies showed NOTCH3 ICD drives mesenchymal/motile phenotypes.

    Evidence Forward genetic screen with two independent zebrafish notch3 alleles; inducible NOTCH3-IC transgene in neuroblastoma with migration assays

    PMID:23649002 PMID:23720232

    Open questions at the time
    • Whether OPC defects contribute to CADASIL white matter lesions was not tested
    • Motility regulation mechanism not defined at signaling level
  9. 2014 High

    The proteolytic activation cascade was definitively resolved: ADAM10 (not ADAM17) performs the S2 cleavage, followed by presenilin-1/2 (γ-secretase) for S3 cleavage; separately, LTBP-1 was identified as a NOTCH3 ECD interactor sequestered into CADASIL deposits.

    Evidence Genetic knockout/knockdown of ADAM10, ADAM17, presenilin-1/2 with signaling readouts; co-localization immunohistochemistry and direct binding assays for LTBP-1

    PMID:24842903 PMID:25190493

    Open questions at the time
    • Whether LTBP-1 sequestration functionally impairs TGF-β signaling in CADASIL vessels was not demonstrated
    • S1 cleavage site and furin processing details remained incomplete
  10. 2016 High

    Downstream effectors of NOTCH3 ECD accumulation in CADASIL were genetically dissected: TIMP3 drives cerebral blood flow deficits via impaired myogenic responses, while vitronectin independently causes white matter lesions; separately, NOTCH3 was shown to promote cholangiocarcinoma via non-canonical PI3K-Akt signaling independent of RBPJ.

    Evidence Genetic reduction of Timp3 and vitronectin in TgNotch3R169C mice with CBF and white matter readouts; NOTCH3 knockout in rat/mouse cholangiocarcinoma models

    PMID:26648042 PMID:27791012

    Open questions at the time
    • How NOTCH3 ECD deposition induces TIMP3 and vitronectin accumulation mechanistically was unclear
    • Non-canonical PI3K-Akt mechanism of NOTCH3 activation not defined
  11. 2017 High

    NOTCH3 was shown to be both necessary and sufficient for arterial mural cell coverage (with therapeutic rescue by agonist antibody), and to act as a non-canonical dependence receptor inducing endothelial apoptosis in the absence of ligand, expanding its functional repertoire beyond transcriptional signaling.

    Evidence NOTCH3 KO genetic rescue and agonist antibody in CADASIL mice; NOTCH3 mutant mice tumor implantation with endothelial apoptosis assays

    PMID:28698285 PMID:28719575

    Open questions at the time
    • Dependence receptor apoptotic signaling pathway downstream of NOTCH3 not molecularly defined
    • Whether agonist antibody rescues CADASIL white matter lesions was not tested
  12. 2021 Medium

    A NOTCH3-DLL4-NOTCH1 intercellular signaling axis between pericytes and endothelium was delineated: pericyte NOTCH3 induces DLL4, which activates endothelial NOTCH1 to stabilize VE-cadherin junctions, providing a molecular mechanism for NOTCH3-mediated vessel stabilization.

    Evidence In vitro vascular co-culture with siRNA knockdown; live imaging of VE-cadherin junction dynamics

    PMID:34878922

    Open questions at the time
    • In vivo validation of this axis in intact vessels not performed
    • Whether this mechanism is disrupted in CADASIL not tested
  13. 2022 High

    Elastin insufficiency was found to epigenetically upregulate JAG1-NOTCH3 signaling in aortic SMCs, and Notch3 deletion attenuated aortic hypermuscularization, demonstrating that NOTCH3 hyperactivation drives pathological smooth muscle proliferation in non-CADASIL contexts.

    Evidence Eln-/- mice with Notch3 KO and Jag1 SMC-specific KO; γ-secretase inhibition; iPSC-derived SMCs from ELN-deficient patients

    PMID:34990407

    Open questions at the time
    • Epigenetic mechanism connecting elastin loss to γ-secretase upregulation not molecularly defined
    • Whether this pathway operates in human supravalvular aortic stenosis patients not confirmed
  14. 2024 High

    Wild-type NOTCH3 ECD was shown to co-aggregate with mutant ECD, and reducing wild-type Notch3 copy number decreased both ECD accumulation and arterial pathology in CADASIL mice, establishing co-aggregation as a major driver of smooth muscle cell loss and redefining CADASIL as a protein aggregation disease involving both mutant and wild-type protein.

    Evidence Quantitative histopathology in transgenic and knockin mice; genetic reduction of wild-type Notch3 copy in TgNotch3R169C

    PMID:38386425

    Open questions at the time
    • Whether therapeutic strategies targeting wild-type ECD co-aggregation are feasible
    • Structural basis of wild-type/mutant ECD co-aggregation not resolved at atomic level

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of NOTCH3 ECD multimerization and co-aggregation, the molecular identity of the dependence receptor apoptotic pathway, how NOTCH3 ECD accumulation triggers TIMP3 and vitronectin deposition, and whether the pericyte NOTCH3-DLL4-NOTCH1 axis is disrupted in CADASIL.
  • No atomic-resolution structure of NOTCH3 ECD multimers
  • Dependence receptor downstream apoptotic signaling pathway undefined
  • Mechanism linking ECD deposits to extracellular matrix protein accumulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 2
Partners
ADAM10CHAC1DLL4JAGGED1LTBP1NOTCH1RBPJTHBS2

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 NOTCH3 mutations in CADASIL patients cause serious disruption of the Notch3 gene, which encodes a transmembrane receptor mapped to chromosome 19, identifying NOTCH3 as the defective gene in CADASIL. Genetic mapping and mutation analysis in CADASIL patients Nature High 8878478
1997 CADASIL mutations are strongly clustered within EGF-like repeats of the extracellular domain of NOTCH3 and all lead to loss or gain of a cysteine residue, creating an unpaired cysteine that may cause aberrant dimerization of NOTCH3 through abnormal disulfide bridging. SSCP, heteroduplex, and sequence analysis of 50 CADASIL patients; biochemical inference Lancet High 9388399
2000 NOTCH3 undergoes proteolytic cleavage producing a 210-kDa extracellular fragment and a 97-kDa intracellular fragment; in CADASIL, the 210-kDa ectodomain selectively accumulates at the cytoplasmic membrane of vascular smooth muscle cells, indicating CADASIL mutations specifically impair clearance of the NOTCH3 ectodomain from the cell surface. Immunoblotting of transfected cells and CADASIL brain tissue; immunohistochemistry Journal of Clinical Investigation High 10712431
2002 The intracellular domains of NOTCH1, NOTCH2, and NOTCH3 have distinct transcriptional activities for HES1 and HES5 promoters; NOTCH3-IC activity is modulated by RBP-Jκ expression levels and can be reduced by co-expression of NOTCH2-IC, demonstrating functional diversity among Notch receptors. Luciferase reporter assays with truncated intracellular domain constructs in transfected cells Biochemical and Biophysical Research Communications Medium 11866432
2005 CADASIL mutations in the EGF-like repeats of NOTCH3 do not affect O-fucosylation but impair Fringe-mediated carbohydrate chain elongation; additionally, CADASIL mutations induce aberrant homodimerization of mutant NOTCH3 fragments and heterodimerization with Lunatic Fringe. Biochemical glycosylation assays on NOTCH3 EGF-like repeat fragments; co-immunoprecipitation Human Molecular Genetics Medium 15857853
2005 A recurrent CADASIL missense mutation in NOTCH3 causes subtle abnormalities in furin processing, but the mutant receptor is still present on the cell surface, retains ability to bind Delta1, Delta4, and Jagged1 ligands, and can activate CBF1 in a ligand-dependent manner. Flow cytometry ligand-binding assay; co-culture CBF1-luciferase reporter assay; cell surface expression analysis Journal of Neurology, Neurosurgery, and Psychiatry Medium 16107360
2009 Both wild-type and CADASIL-mutated NOTCH3 ectodomain spontaneously form oligomers and higher-order multimers via disulfide bonds in vitro; CADASIL mutations significantly enhance multimerization compared with wild-type, providing evidence for a neomorphic gain-of-function effect. Single-molecule fluorescence analysis ('scanning for intensely fluorescent targets'); in vitro multimerization assays Human Molecular Genetics High 19417009
2009 Thrombospondin-2 (TSP2), but not TSP1, enhances NOTCH3 signal transduction; TSP2 binds directly to NOTCH3 and Jagged1 and augments the interaction between NOTCH3 and Jagged1, acting as an intermediary that facilitates receptor-ligand interactions. Direct binding assays, co-immunoprecipitation, TSP2 knockout mouse Notch target gene expression analysis, cancer cell proliferation assays Journal of Biological Chemistry High 19147503
2009 NOTCH3 inhibition in lung cancer cells induces apoptosis via regulation of Bim (a BH3-only protein) through MAPK signaling; NOTCH3 cooperates with the EGFR-MAPK pathway in modulating apoptosis, and loss of Bim prevents tumor apoptosis induced by NOTCH3 inhibition. Gamma-secretase inhibitor treatment, shRNA knockdown, xenograft model, immunoblotting Oncogene Medium 19881544
2009 CADASIL mutations located in the ligand-binding domain (EGF-like repeats 10-11) result in loss of wild-type NOTCH3 receptor activity and exhibit mild dominant-negative activity in multiple biological settings in vivo, unlike common CADASIL mutations that retain canonical signaling. Transgenic mouse generation; introduction of C428S transgene into NOTCH3-null background; epistasis testing in three biological settings Brain High 19293235
2009 The intracellular domain of NOTCH3 (N3-ICD) is degraded by lysosomes, not proteasomes, as demonstrated by accumulation upon lysosome inhibition (chloroquine, NH4Cl) but not proteasome inhibition (MG132, lactacystin); the NOTCH3 ectodomain is also subject to lysosome-dependent degradation. Pharmacological inhibition of lysosomes vs. proteasomes; pulse-chase degradation assays in multiple cell lines International Journal of Biochemistry & Cell Biology High 19735738
2010 NOTCH3 forms heterodimers with NOTCH1, NOTCH3, and NOTCH4; CADASIL mutant NOTCH3 (R90C and C49Y) forms complexes more resistant to detergent solubilization than wild-type; mutant NOTCH3 shows inhibited clearance; overexpressed wild-type and mutant NOTCH3 repress smooth muscle gene expression and impair Notch-regulated smooth muscle promoter activity. Co-immunoprecipitation; NOTCH3-luciferase clearance assay; smooth muscle cell co-culture transcriptional assays PLoS One Medium 23028706
2010 NOTCH3-deficient mice exhibit reduced retinal vascularization, impaired mural cell investment, and reduced angiopoietin-2 expression; in vitro, NOTCH3 is sufficient to induce angiopoietin-2, particularly in hypoxic conditions with HIF-1α. Notch3 knockout mouse analysis; oxygen-induced retinopathy model; in vitro angiopoietin-2 induction assays Circulation Research High 20689064
2012 CADASIL mutations in NOTCH3 and shRNA silencing of NOTCH3 both cause similar alterations in actin cytoskeleton organization in vascular smooth muscle cells, including increased branching, node formation, and smaller adhesion sites, suggesting hypomorphic NOTCH3 activity drives actin disorganization. Analysis of CADASIL patient-derived VSMCs; shRNA silencing of NOTCH3 in control VSMCs; microscopic analysis of actin cytoskeleton Journal of Cerebral Blood Flow and Metabolism Medium 22948298
2013 Inducible expression of constitutively active NOTCH3 intracellular domain (NOTCH3-IC) in neuroblastoma cells confers a highly motile mesenchymal phenotype and strongly induces expression of motility and mesenchymal marker genes, establishing NOTCH3 as a master regulator of motility. Inducible transgene expression; Transwell migration assays; gene expression profiling Clinical Cancer Research Medium 23649002
2013 Zebrafish notch3 regulates oligodendrocyte precursor cell (OPC) development and myelin basic protein expression in larvae, and maintains vascular integrity in adults; hey1 expression (canonical Notch target) is greatly reduced in notch3 mutant fins, indicating action via the canonical Notch signaling pathway. Forward genetic screen; retroviral insertion mutants; histological and ultrastructural analysis; in situ hybridization for Notch target genes Disease Models & Mechanisms High 23720232
2014 Canonical ligand-induced proteolytic activation of NOTCH3 requires sequential cleavage by ADAM10 metalloprotease followed by presenilin-1 or -2 (γ-secretase); ADAM17/TACE plays no role in ligand-induced NOTCH3 signaling. Cell-based signaling assays with genetic knockout/knockdown of ADAM10, ADAM17, presenilin-1/-2; Delta and Jagged ligand stimulation Molecular and Cellular Biology High 24842903
2014 Latent TGF-β binding protein 1 (LTBP-1) directly interacts with NOTCH3-ECD and specifically co-aggregates with mutant NOTCH3, leading to its sequestration into CADASIL-related vascular deposits and potential dysregulation of TGF-β signaling. Co-localization immunohistochemistry in CADASIL brain tissue; in vitro direct protein interaction assays; co-aggregation assays with mutant vs. wild-type NOTCH3 Acta Neuropathologica Communications Medium 25190493
2014 NOTCH3 signaling is both necessary and sufficient to support mural cell coverage in arteries; genetic rescue experiments in NOTCH3 knockout mice confirmed this, and a NOTCH3 agonist antibody prevented mural cell loss in CADASIL mice carrying the C455R mutation. NOTCH3 knockout mouse genetic rescue; systemic administration of agonist NOTCH3 antibody in CADASIL C455R mutant mice; quantitative histology Journal of Experimental Medicine High 28698285
2014 NOTCH3 signaling negatively regulates hippocampal precursor cell proliferation in a cell-autonomous manner; NOTCH3 overexpression impairs KCl-induced precursor cell activation; NOTCH3 is expressed in hippocampal precursor cells and maturing neurons. NOTCH3 overexpression and knockdown in hippocampal precursor cells; BrdU/cell proliferation assays; immunohistochemistry in CADASIL transgenic mice Neurobiology of Disease Medium 25555543
2015 Biglycan (BGN) directly interacts with NOTCH3 protein; NOTCH3 ectodomain exposure induces BGN upregulation in cerebrovascular smooth muscle cells via mTOR-sensitive mechanisms; BGN accumulates in CADASIL brain vasculature. Direct protein interaction assays; co-immunoprecipitation in cell culture; immunoblotting and IHC of CADASIL brain tissue; mTOR inhibitor (rapamycin) functional assay Translational Stroke Research Medium 25578324
2016 NOTCH3 promotes cholangiocarcinoma tumor cell survival via activation of the PI3K-Akt pathway through a non-canonical pathway independent of RBPJ; NOTCH3 genetic knockout significantly attenuates tumor growth. NOTCH3 knockout studies in rat and transgenic mouse CC models; pathway analysis; genetic rescue experiments PNAS Medium 27791012
2016 Elevated TIMP3 and vitronectin, downstream of NOTCH3 ECD deposition in CADASIL vessels, produce divergent effects: TIMP3 drives cerebral blood flow deficits (attenuated myogenic responses), while vitronectin drives white matter lesion formation, acting independently of NOTCH3 ECD deposition levels. Genetic reduction of Timp3 and vitronectin in TgNotch3R169C CADASIL mice; CBF measurements; white matter lesion quantification; transgenic TIMP3 overexpression model Annals of Neurology High 26648042
2017 NOTCH3 acts as a dependence receptor in endothelial cells, inducing apoptosis; this pro-apoptotic activity is blocked by Jagged-1 produced by cancer cells, operating independently of the canonical Notch pathway. NOTCH3 mutant mice tumor implantation; endothelial cell apoptosis assays; tumor growth and angiogenesis quantification; γ-secretase inhibitor studies Nature Communications Medium 28719575
2017 NOTCH3 is required for hemangioma stem cell (HemSC)-to-mural cell differentiation; NOTCH3 knockdown inhibits mural cell differentiation in vitro and perturbs αSMA expression; systemic expression of NOTCH3 Decoy or NOTCH3 knockdown in a mouse IH model decreased vessel caliber and αSMA+ perivascular cell coverage. NOTCH3 knockdown in HemSCs; in vitro mural cell differentiation assay; in vivo mouse IH model with NOTCH3 Decoy inhibitor JCI Insight Medium 29093274
2018 CADASIL vasculopathy involves ER stress and Rho kinase (ROCK) activation driven by NOTCH3-induced Nox5 upregulation; inhibition of NOTCH3 (γ-secretase inhibitor), Nox5, ER stress, or ROCK individually ameliorates aberrant vascular responses in CADASIL patient-derived arteries and mouse model. Human CADASIL patient peripheral arterial biopsies; TgNotch3R169C mouse model; pharmacological inhibition of Notch3, Nox5, ER stress, and ROCK; functional vascular assays JCI Insight High 31647781
2019 CHAC1 binds to NOTCH3 protein and inhibits NOTCH3 activation in glioma cells; TMZ treatment reduces NOTCH3 levels via CHAC1-mediated inhibition, attenuating NOTCH3-mediated downstream signaling and contributing to TMZ cytotoxicity. Co-immunoprecipitation; CHAC1 overexpression/knockdown; apoptosis assays; pharmacological treatment Neuropharmacology Medium 27986595
2021 Pericyte NOTCH3 and endothelial NOTCH1 cooperate for vascular stabilization; NOTCH3 in pericytes drives DLL4 expression, which activates endothelial NOTCH1, stabilizing VE-cadherin at endothelial adherens junctions; loss of either NOTCH3 or NOTCH1 increases junction motility. In vitro vascular co-culture models; siRNA knockdown of NOTCH3 and NOTCH1; live imaging of VE-cadherin junctions American Journal of Physiology - Cell Physiology Medium 34878922
2022 Elastin insufficiency epigenetically upregulates JAGGED1/NOTCH3 signaling in aortic smooth muscle cells by increasing γ-secretase levels and activating NOTCH3 intracellular domain; Notch3 deletion or γ-secretase inhibition attenuates aortic hypermuscularization and stenosis in Eln-/- mice; Jag1 deletion in SMCs (not endothelial cells) similarly mitigates the phenotype. Eln-/- mouse model; Notch3 knockout; Jag1 SMC-specific vs. EC-specific knockout; γ-secretase inhibitor; iPSC-derived aortic SMCs from ELN-deficient patients Journal of Clinical Investigation High 34990407
2024 Wild-type NOTCH3 ECD co-aggregates with mutant NOTCH3 ECD; protein aggregates containing both wild-type and mutant NOTCH3 are major drivers of arterial smooth muscle cell loss in CADASIL; elimination of one copy of wild-type Notch3 in TgNotch3R169C mice reduced Notch3ECD accumulation and arterial pathology. Quantitative histopathology in transgenic and knockin mouse models; multiscale imaging; genetic manipulation (wild-type Notch3 copy reduction in TgNotch3R169C); NOTCH3 regulated gene expression profiling Journal of Clinical Investigation High 38386425
2023 The m6A reader IGF2BP3 maintains NOTCH3 mRNA stability by suppressing CCR4-NOT complex-mediated deadenylation in an m6A-dependent manner, thereby sustaining NOTCH3 signaling and promoting NPC metastasis. RIP assay; mRNA stability assays; CCR4-NOT complex interaction studies; IGF2BP3 overexpression/knockdown in NPC cells in vitro and in vivo Oncogene Medium 37853162

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1640 8878478
2009 Cadasil. The Lancet. Neurology 845 19539236
1997 Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet (London, England) 544 9388399
2000 The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. The Journal of clinical investigation 474 10712431
2010 Notch3 is critical for proper angiogenesis and mural cell investment. Circulation research 155 20689064
2009 Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain : a journal of neurology 153 19174371
2014 CADASIL and CARASIL. Brain pathology (Zurich, Switzerland) 150 25323668
2016 Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Annals of clinical and translational neurology 147 27844030
2007 An overview of Notch3 function in vascular smooth muscle cells. Progress in biophysics and molecular biology 113 17854869
2014 Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert review of molecular diagnostics 97 24844136
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
2009 Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain : a journal of neurology 92 19293235
2002 Functional diversity among Notch1, Notch2, and Notch3 receptors. Biochemical and biophysical research communications 90 11866432
2006 Cortical neuronal apoptosis in CADASIL. Stroke 89 17008611
2006 Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Neurology 84 16717210
2016 Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. Annals of neurology 75 26648042
2016 Notch3 drives development and progression of cholangiocarcinoma. Proceedings of the National Academy of Sciences of the United States of America 75 27791012
2009 Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim. Oncogene 75 19881544
2016 Notch signaling in lung diseases: focus on Notch1 and Notch3. Therapeutic advances in respiratory disease 73 27378579
2005 The spectrum of mutations for CADASIL diagnosis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 72 15995828
2014 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins. Molecular and cellular biology 69 24842903
2017 Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. International journal of molecular sciences 68 28902129
2020 Notch3 in Development, Health and Disease. Biomolecules 67 32210034
2018 The Role of Notch3 in Cancer. The oncologist 67 29622701
2010 NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. Journal of neurology, neurosurgery, and psychiatry 67 20935329
2005 The spectrum of Notch3 mutations in 28 Italian CADASIL families. Journal of neurology, neurosurgery, and psychiatry 67 15834039
2009 CADASIL mutations enhance spontaneous multimerization of NOTCH3. Human molecular genetics 65 19417009
1999 CADASIL: hereditary disease of arteries causing brain infarcts and dementia. Neuropathology and applied neurobiology 63 10476042
2020 Clinical and Genetic Aspects of CADASIL. Frontiers in aging neuroscience 58 32457593
2003 Cerebral hemodynamics and white matter hyperintensities in CADASIL. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 58 12771575
2020 Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology 57 32732295
2009 Thrombospondin 2 potentiates notch3/jagged1 signaling. The Journal of biological chemistry 57 19147503
2010 CADASIL. Journal of geriatric psychiatry and neurology 55 21045164
2004 The pathogenesis of CADASIL: an update. Journal of the neurological sciences 55 15537516
2003 Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta neuropathologica 55 12756589
2017 Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. The Journal of experimental medicine 54 28698285
2014 Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits. Acta neuropathologica communications 53 25190493
2016 Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain : a journal of neurology 51 26912635
2014 Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL. Neoplasia (New York, N.Y.) 48 25499214
2005 CADASIL mutations impair Notch3 glycosylation by Fringe. Human molecular genetics 48 15857853
2006 Cholinergic neuronal deficits in CADASIL. Stroke 47 17122431
2018 Severe white matter astrocytopathy in CADASIL. Brain pathology (Zurich, Switzerland) 46 29757481
2015 Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. Stroke 46 25604251
2001 NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology 46 11706120
2018 CADASIL. Handbook of clinical neurology 45 29478611
2016 The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology 45 27986595
2014 Mutations of NOTCH3 in childhood pulmonary arterial hypertension. Molecular genetics & genomic medicine 44 24936512
2020 Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL). Frontiers in pharmacology 42 32231578
2013 notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish. Disease models & mechanisms 41 23720232
2012 Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3. PloS one 40 23028706
2020 CADASIL: yesterday, today, tomorrow. European journal of neurology 39 32348626
2019 CADASIL: new advances in basic science and clinical perspectives. Current opinion in hematology 39 30855338
2017 Non-canonical NOTCH3 signalling limits tumour angiogenesis. Nature communications 39 28719575
2015 The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations. Journal of the neurological sciences 39 25982499
2018 Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice. Annals of neurology 37 30014602
2022 Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL. Neurology 36 35641310
2021 Notch1 and Notch3 coordinate for pericyte-induced stabilization of vasculature. American journal of physiology. Cell physiology 36 34878922
2019 ER stress and Rho kinase activation underlie the vasculopathy of CADASIL. JCI insight 36 31647781
2018 Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease. Scientific reports 36 29463793
2013 A NOTCH3 transcriptional module induces cell motility in neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 36 23649002
2005 Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. Journal of neurology, neurosurgery, and psychiatry 35 16107360
2021 NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature. Neuropathology and applied neurobiology 33 34297860
2003 Notch3, another Notch in T cell development. Seminars in immunology 33 12681947
2018 Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation. Oncogene 32 30038265
2006 Notch3 intracellular domain accumulates in HepG2 cell line. Anticancer research 32 16827154
2024 CADASIL: A NOTCH3-associated cerebral small vessel disease. Journal of advanced research 31 38176524
2014 NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer. Medicina (Kaunas, Lithuania) 31 25060200
2022 JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. The Journal of clinical investigation 30 34990407
2017 Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma. Oncotarget 30 28416766
2018 Clinical correlates of longitudinal MRI changes in CADASIL. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 29 29400120
2015 Clinical significance of cerebral microbleeds locations in CADASIL with R544C NOTCH3 mutation. PloS one 29 25692567
2012 CADASIL mutations and shRNA silencing of NOTCH3 affect actin organization in cultured vascular smooth muscle cells. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 29 22948298
2023 The m6A reader IGF2BP3 preserves NOTCH3 mRNA stability to sustain Notch3 signaling and promote tumor metastasis in nasopharyngeal carcinoma. Oncogene 28 37853162
2016 CADASIL: Imaging Characteristics and Clinical Correlation. Current pain and headache reports 28 27591799
2009 Lysosome-dependent degradation of Notch3. The international journal of biochemistry & cell biology 28 19735738
2022 Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS neuroscience & therapeutics 27 35822697
2017 CADASIL: Treatment and Management Options. Current treatment options in neurology 27 28741120
2017 Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. Oncotarget 26 28968975
2017 Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas. Journal of Cancer 26 29158806
2005 Peripheral nerve and skeletal muscle involvement in CADASIL. Acta neuropathologica 26 16328531
2017 NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma. JCI insight 25 29093274
2015 The small leucine-rich proteoglycan BGN accumulates in CADASIL and binds to NOTCH3. Translational stroke research 25 25578324
2014 Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis. Neurobiology of disease 25 25555543
2007 Neuropsychiatric manifestations in CADASIL. Dialogues in clinical neuroscience 25 17726918
2011 Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis. Blood 24 21768299
2021 The pericyte: A critical cell in the pathogenesis of CADASIL. Cerebral circulation - cognition and behavior 23 34950895
2014 Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features. Neurobiology of aging 23 25260852
2022 Cognition, mood and behavior in CADASIL. Cerebral circulation - cognition and behavior 22 36324403
2022 Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model. EMBO molecular medicine 22 36524456
2021 NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Frontiers in genetics 22 34335700
2019 TMZ regulates GBM stemness via MMP14-DLL4-Notch3 pathway. International journal of cancer 22 31443114
2024 Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL. The Journal of clinical investigation 21 38386425
2016 Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients. Human genomics 21 27881154
2014 A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses. Journal of molecular biochemistry 21 31799216
2000 CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. Annals of the New York Academy of Sciences 21 10818516
2010 Capillary vessel wall in CADASIL angiopathy. Folia neuropathologica 20 20602291
2002 Lessons from CADASIL. Annals of the New York Academy of Sciences 20 12480754
2000 Arg133Cys mutation of Notch3 in two unrelated Japanese families with CADASIL. Internal medicine (Tokyo, Japan) 20 10969905
2013 Headache among CADASIL patients with R544C mutation: prevalence, characteristics, and associations. Cephalalgia : an international journal of headache 19 23847153
2002 Notch3 gene polymorphism and ischaemic cerebrovascular disease. Journal of neurology, neurosurgery, and psychiatry 19 11861701