Affinage

NOTCH3

Neurogenic locus notch homolog protein 3 · UniProt Q9UM47

Length
2321 aa
Mass
243.6 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOTCH3 is a single-pass transmembrane receptor expressed predominantly in vascular smooth muscle cells and mural/pericyte populations, where it governs mural cell investment and stabilization of the developing and mature vasculature (PMID:10712431, PMID:20689064, PMID:28698285). Ligand engagement triggers sequential proteolysis—an ADAM10 metalloprotease cut followed by intramembranous cleavage by the presenilin-containing γ-secretase complex—releasing a ~210-kDa ectodomain and a ~97-kDa intracellular domain (N3-ICD), both of which are cleared through lysosome-dependent rather than proteasomal degradation (PMID:10712431, PMID:24842903, PMID:19735738). Canonically NOTCH3 signals through RBP-Jk to specify smooth muscle/mural cell programs, and this activity drives mural cell coverage of arteries and cooperates with endothelial NOTCH1 to maintain VE-cadherin junctions (PMID:28698285, PMID:34878922); ligand availability is shaped by extracellular intermediaries including Thrombospondin-2, which bridges NOTCH3 to Jagged1 (PMID:19147503), and by Jagged1 produced within smooth muscle, which drives NOTCH3 activation in elastin deficiency (PMID:34990407). Beyond this canonical axis, NOTCH3 acts non-canonically through PI3K-Akt to promote tumor cell survival in cholangiocarcinoma (PMID:27791012) and behaves as a dependence receptor in endothelial cells, inducing apoptosis when Jagged-1 is absent (PMID:28719575). NOTCH3 is the causative gene in CADASIL, where stereotyped cysteine-altering missense mutations in the EGF-like repeats of the ectodomain create unpaired cysteines (PMID:8878478, PMID:9388399); these mutations impair Fringe-mediated glycosylation and dramatically enhance disulfide-bonded ectodomain multimerization, causing selective surface accumulation of the 210-kDa ectodomain together with co-aggregating wild-type ectodomain (PMID:15857853, PMID:19417009, PMID:38386425). This aggregation, rather than loss of canonical signaling, drives arterial smooth muscle cell loss—canonical RBP-Jk activity is preserved in mutant receptors—and operates by sequestering matrix proteins such as LTBP-1 and engaging a Nox5/ER stress/Rho-kinase cascade (PMID:17331978, PMID:25190493, PMID:31647781, PMID:38386425).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Having established NOTCH3 as the CADASIL gene, the question became what kind of lesion the mutations represent; finding that they are stereotyped cysteine gains/losses clustered in ectodomain EGF repeats defined a mutational signature and predicted abnormal disulfide bridging.

    Evidence Mutational screening of CADASIL patients and controls by SSCP, heteroduplex analysis, and Sanger sequencing, following positional cloning

    PMID:8878478 PMID:9388399

    Open questions at the time
    • Did not show how unpaired cysteines lead to protein-level dysfunction
    • No demonstration of aggregation in tissue at this stage
  2. 2000 High

    It was unknown which NOTCH3 fragment is affected in disease; demonstrating that the 210-kDa ectodomain selectively accumulates at the VSMC surface in CADASIL brains while the intracellular domain does not established a clearance defect specific to the ectodomain.

    Evidence IHC, Western blot, and transfected cell analysis of post-mortem CADASIL brain tissue

    PMID:10712431

    Open questions at the time
    • Did not establish whether accumulation is cause or consequence of disease
    • Mechanism of impaired ectodomain clearance not defined
  3. 2005 High

    To explain how cysteine mutations cause accumulation, glycosylation and dimerization were tested; mutations were shown to spare O-fucose addition but impair Fringe-mediated chain elongation and to drive aberrant homo/heterodimerization, implicating glycosylation and abnormal self-association in pathology.

    Evidence In vitro biochemical glycosylation and dimerization assays on Notch3 EGF-like repeat fragments

    PMID:15857853

    Open questions at the time
    • Used isolated fragments rather than full-length receptor
    • Did not quantify multimerization or link to tissue accumulation
  4. 2007 High

    A central question was whether CADASIL is loss- or gain-of-function; in vivo rescue showing R90C retains normal RBP-Jk activity and lacks dominant-negative effect established that pathogenesis involves a novel toxic role rather than canonical signaling loss.

    Evidence Genetic rescue in Notch3-/- mice with WT or R90C human NOTCH3 at physiological levels, with in vivo signaling readout

    PMID:17331978

    Open questions at the time
    • Did not identify the toxic mechanism downstream of ectodomain accumulation
    • Single mutation tested
  5. 2009 High

    The biophysical basis of accumulation was unresolved; single-molecule and biochemical assays showed both WT and mutant ectodomains form disulfide-linked multimers with mutations markedly enhancing multimerization, providing direct evidence for a neomorphic self-association defect, while parallel work assigned NOTCH3 turnover to the lysosome.

    Evidence In vitro multimerization and single-molecule fluorescence assays; pharmacological lysosome vs proteasome inhibitor experiments across multiple cell lines

    PMID:19417009 PMID:19735738

    Open questions at the time
    • Did not reconstitute multimerization in vivo at this stage
    • Lysosomal targeting signal/machinery not identified
  6. 2009 High

    How NOTCH3-ligand engagement is modulated extracellularly was unclear; identifying Thrombospondin-2 as a direct binder of NOTCH3 and Jagged1 that augments their interaction defined an extracellular amplifier of NOTCH3 signaling.

    Evidence Direct binding/pulldown assays, TSP2 knockout mouse analysis, and Notch target gene expression

    PMID:19147503

    Open questions at the time
    • TSP2 role in CADASIL or vascular maintenance not tested
    • Structural basis of the ternary interaction unknown
  7. 2010 High

    The physiological vascular role of NOTCH3 was incompletely defined; knockout mice revealed it is required in mural cells for retinal vascularization, sprouting, and vessel coverage, and regulates angiopoietin-2, placing NOTCH3 in mural cell investment of vessels.

    Evidence Notch3 knockout mice, oxygen-induced retinopathy model, in vitro angiopoietin-2 induction assays, immunostaining

    PMID:20689064

    Open questions at the time
    • Did not resolve which ligands drive this in vivo
    • Connection to CADASIL SMC loss not established
  8. 2012 Medium

    Whether mutant NOTCH3 might also impair canonical function was revisited; co-IP and reporter assays showed mutant heterodimers are detergent-resistant and poorly cleared and that NOTCH3 overexpression represses smooth muscle transcripts, raising a possible interference with canonical function in SMCs.

    Evidence Reciprocal co-IP for heterodimer detection, NOTCH3-luciferase clearance assays, and smooth muscle promoter reporter assays

    PMID:23028706

    Open questions at the time
    • Relied on overexpression, which may not reflect physiological signaling
    • Apparent tension with in vivo rescue showing preserved signaling not resolved
  9. 2014 High

    The proteases required for NOTCH3 activation were undefined; functional assays established ligand-induced activation requires ADAM10 then presenilin/γ-secretase, with ADAM17/TACE playing no role, defining the canonical processing pathway.

    Evidence Cell-based proteolytic activation assays with ADAM10/presenilin knockdown-knockout and signaling readouts

    PMID:24842903

    Open questions at the time
    • Did not address ligand-independent or aberrant processing in disease
    • Regulation of protease access not studied
  10. 2014 Medium

    The matrix consequences of ectodomain aggregation were unknown; identifying LTBP-1 as a direct binder that co-aggregates specifically with mutant Notch3-ECD deposits, with increased TGF-β prodomain levels, established sequestration of matrix/TGF-β components as a pathogenic mechanism.

    Evidence IHC of post-mortem CADASIL tissue plus in vitro direct interaction and co-aggregation assays

    PMID:25190493

    Open questions at the time
    • Functional consequence of TGF-β dysregulation for SMC loss not demonstrated
    • Single-lab IHC correlation
  11. 2015 High

    NOTCH3's role in non-vascular tissue was unclear; airway studies showed endogenous NOTCH3 signaling via Jag1/Jag2 controls undifferentiated progenitor pools and precedes NOTCH1/NOTCH2-driven fate selection, extending NOTCH3 function to epithelial progenitor regulation.

    Evidence Genetic knockouts, pharmacological inhibition, airway organotypic culture, and human lung tissue analysis

    PMID:25564622

    Open questions at the time
    • Downstream transcriptional targets in airway not detailed
    • Relevance to vascular NOTCH3 biology not connected
  12. 2016 High

    Whether NOTCH3 signals only canonically was tested in cancer; cholangiocarcinoma studies showed NOTCH3 drives tumor survival and growth via an RBPJ-independent PI3K-Akt pathway, establishing a non-canonical NOTCH3 mode.

    Evidence Notch3 genetic knockout in mouse and rat models, PI3K-Akt pathway analysis, human tumor characterization

    PMID:27791012

    Open questions at the time
    • Molecular link between NOTCH3 and PI3K-Akt not defined
    • Generality across tumor types untested here
  13. 2016 Medium

    Post-translational control of N3-ICD was probed pharmacologically; CHAC1 was shown to bind NOTCH3 and inhibit its activation, and N-acetylcysteine was shown to lower cleaved N3-ICD via lysosomal degradation, identifying modulators of NOTCH3 protein levels and signaling.

    Evidence Co-IP of CHAC1 with NOTCH3 and signaling assays; NAC treatment with lysosome/proteasome inhibitors, silencing, and N3ICD overexpression across cancer cell lines

    PMID:27102435 PMID:27986595

    Open questions at the time
    • CHAC1-NOTCH3 interaction is single-lab co-IP without structural detail
    • NAC mechanism on endogenous N3ICD versus ectopic differs and is unexplained
  14. 2017 High

    The vascular dependence of NOTCH3 and its therapeutic accessibility were addressed together; genetic rescue and agonist antibody studies showed NOTCH3 is necessary and sufficient for arterial mural cell coverage and that agonism prevents mural cell loss in CADASIL mice, while separate work defined NOTCH3 as an endothelial dependence receptor inducing ligand-free apoptosis, and as essential for hemangioma stem cell-to-mural differentiation.

    Evidence Genetic rescue in Notch3 KO mice and agonist antibody treatment in CADASIL mice; dependence-receptor apoptosis assays in tumor models; NOTCH3 knockdown/Decoy in HemSCs and IH mouse model

    PMID:28698285 PMID:28719575 PMID:29093274

    Open questions at the time
    • How the same receptor balances survival/mural-supportive and pro-apoptotic outputs not mechanistically unified
    • Agonist antibody durability and specificity not fully characterized
  15. 2019 High

    A downstream effector cascade for CADASIL vasculopathy was missing; mutant NOTCH3 was shown to upregulate Nox5, raising ER stress, ROCK activity, and superoxide, with inhibitors of each step ameliorating aberrant vascular responses in patient arteries and mutant mice, defining a Nox5/ER stress/ROCK axis. In parallel, ligand-induced NOTCH3 cleavage and nuclear translocation were linked to glioblastoma stemness via MMP14/DLL4.

    Evidence CADASIL patient and mouse small-artery isolation with pharmacological inhibitors and functional vascular assays; subcellular localization and stemness assays in GBM models

    PMID:31443114 PMID:31647781

    Open questions at the time
    • Connection between ectodomain aggregation and intracellular Nox5 induction not fully resolved
    • GBM MMP14/DLL4/NOTCH3 axis is single-lab and Medium confidence
  16. 2020 High

    A causal test of aggregation as the disease driver and a therapeutic strategy emerged together; natural exon 9 skipping in a Gly498Cys patient excluded the mutant cysteine and yielded attenuated aggregation and milder disease, with antisense and CRISPR approaches reproducing cysteine-corrective skipping, providing proof-of-concept that reducing aggregation is beneficial.

    Evidence Patient fibroblast RT-PCR/sequencing, skin biopsy EM/IHC, and antisense and CRISPR/Cas9 exon-skipping in cell models

    PMID:31960911

    Open questions at the time
    • In vivo efficacy of therapeutic exon skipping not demonstrated
    • Applicability beyond skippable exons unclear
  17. 2021 High

    How NOTCH3 cooperates across the vessel wall was unresolved; pericyte-endothelial coculture showed pericyte NOTCH3 and endothelial NOTCH1 cooperate to stabilize VE-cadherin junctions, with DLL4 (NOTCH1 ligand) expression in pericytes dependent on NOTCH3, defining a cross-talk circuit for vascular stabilization.

    Evidence In vitro pericyte-endothelial coculture with NOTCH3/NOTCH1 loss-of-function, VE-cadherin imaging, and DLL4 expression analysis

    PMID:34878922

    Open questions at the time
    • In vivo validation of the NOTCH3→DLL4→NOTCH1 circuit not shown
    • Relevance to CADASIL pathology not established
  18. 2022 High

    Context-specific drivers of NOTCH3 activation in disease were defined; in elastin deficiency, reduced elastin epigenetically upregulates NOTCH3 with SMC-derived (not endothelial) JAGGED1 driving N3-ICD generation via increased γ-secretase, and Notch3 deletion or γ-secretase inhibition rescued aortic hypermuscularization and stenosis.

    Evidence Human aortic cells, Eln-/- mice, iPSC-derived patient SMCs, Notch3 deletion, cell-type-specific Jag1 deletion, and γ-secretase inhibition

    PMID:34990407

    Open questions at the time
    • Epigenetic mechanism linking elastin loss to NOTCH3 not fully detailed
    • Whether this axis operates in CADASIL untested
  19. 2024 High

    The definitive test of whether accumulation versus signaling loss drives CADASIL was performed; showing wild-type ectodomain co-aggregates with mutant and that removing one wild-type Notch3 copy attenuates ECD accumulation and arterial SMC loss while gene expression is unchanged established ectodomain accumulation as the major pathogenic driver.

    Evidence Transgenic and knockin Notch3 mouse models with multiscale imaging, quantitative SMC-loss measurement, gene expression profiling, and co-aggregation assays

    PMID:38386425

    Open questions at the time
    • Molecular trigger converting surface aggregates to SMC death not fully defined
    • Translatability of wild-type-allele reduction to patients unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the same NOTCH3 receptor reconciles its canonical RBP-Jk mural-cell program, non-canonical PI3K-Akt survival signaling, and dependence-receptor pro-apoptotic activity, and what molecular event converts surface ectodomain aggregates into the downstream Nox5/ER-stress/ROCK cascade that kills smooth muscle cells.
  • No unifying model linking the three signaling modes
  • Mechanistic bridge from extracellular aggregation to intracellular stress cascade undefined
  • Structural basis of mutant ectodomain self-association not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005576 extracellular region 2 GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM10CHAC1DLL4JAG1JAG2LTBP1NOTCH1THBS2

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Mutations in the NOTCH3 gene were identified as causative for CADASIL; the mutations map to the CADASIL critical region on chromosome 19 and cause serious disruption of the Notch3 receptor, establishing NOTCH3 as the defective gene in CADASIL patients. Positional cloning, sequence analysis, genetic linkage analysis Nature High 8878478
1997 CADASIL mutations in NOTCH3 are strongly clustered within the EGF-like repeats of the extracellular domain and are stereotyped missense mutations that all cause loss or gain of a cysteine residue, resulting in an unpaired number of cysteine residues within a given EGF domain; this suggests aberrant dimerization of Notch3 via abnormal disulfide bridging. SSCP, heteroduplex analysis, Sanger sequencing of 50 unrelated CADASIL patients and 100 controls Lancet High 9388399
2000 In normal tissues NOTCH3 expression is restricted to vascular smooth muscle cells; NOTCH3 undergoes proteolytic cleavage producing a 210-kDa extracellular fragment and a 97-kDa intracellular fragment; in CADASIL brains the 210-kDa ectodomain selectively accumulates at the cytoplasmic membrane of vascular smooth muscle cells, while the cytosolic domain does not accumulate, indicating that CADASIL mutations specifically impair clearance of the Notch3 ectodomain from the cell surface. Immunohistochemistry, Western blot, transfected cell analysis, post-mortem CADASIL brain tissue analysis Journal of Clinical Investigation High 10712431
2005 CADASIL mutations in NOTCH3 do not affect the addition of O-fucose to EGF-like repeats but do impair carbohydrate chain elongation by Fringe (O-fucosyltransferase-dependent glycosylation); additionally, CADASIL mutations induce aberrant homodimerization of mutant Notch3 fragments and heterodimerization with Lunatic Fringe, implicating Fringe in CADASIL pathophysiology. Biochemical glycosylation assays on Notch3 EGF-like repeat fragments, in vitro dimerization assays Human Molecular Genetics High 15857853
2007 The archetypal CADASIL mutation R90C in NOTCH3 retains normal canonical Notch signaling activity in brain arteries in vivo (normal RBP-Jk-mediated activity) and does not exhibit dominant-negative activity even when the ectodomain accumulates; this suggests CADASIL pathogenesis involves novel pathogenic roles of mutant NOTCH3 rather than loss of canonical NOTCH3 signaling function. Genetic rescue experiments in Notch3-/- mice using transgenic expression of wild-type or R90C mutant human NOTCH3 at physiological levels; in vivo NOTCH3/RBP-Jk activity assessment Human Molecular Genetics High 17331978
2009 Both wild-type and CADASIL-mutated NOTCH3 ectodomain spontaneously form oligomers and higher-order multimers via disulfide bonds in vitro; CADASIL-associated mutations significantly enhance multimerization compared to wild-type, providing experimental evidence for a neomorphic effect of CADASIL mutations promoting N3ECD self-association and accumulation. In vitro multimerization assays, single-molecule analysis ('scanning for intensely fluorescent targets'), biochemical characterization Human Molecular Genetics High 19417009
2009 Thrombospondin-2 (TSP2), but not TSP1, directly binds to NOTCH3 and Jagged1 and augments the interaction between Notch3 and Jagged1, thereby enhancing Notch3 signal transduction potency; loss of TSP2 in knockout mice reduces Notch target gene expression, identifying TSP2 as an extracellular intermediary that facilitates Notch3-Jagged1 receptor-ligand interactions. Direct binding assays (TSP2 pulldown with Notch3 and Jagged1), TSP2 knockout mouse analysis, Notch target gene expression measurement, cancer cell proliferation assays Journal of Biological Chemistry High 19147503
2009 Degradation of both the intracellular domain (N3-ICD) and the extracellular domain (N3-ECD) of Notch3 is mediated by lysosomes, not by the ubiquitin-proteasome system; lysosome inhibitors (chloroquine, NH4Cl) caused accumulation and delayed degradation of N3-ICD, while proteasome inhibitors (MG132, lactacystin) had no effect, distinguishing Notch3 turnover from Notch1 and Notch4. Pharmacological inhibitor experiments (lysosome vs. proteasome inhibitors) in transfected 293 cells and endogenous N3-ICD in C2C12, H460, and HeLa cell lines; Western blot International Journal of Biochemistry & Cell Biology High 19735738
2010 Notch3 is required in mural cells for retinal vascular development; Notch3-deficient mice exhibit reduced retinal vascularization, diminished sprouting, reduced mural cell investment, and loss of vessel coverage; Notch3 also regulates angiopoietin-2 expression in mural cells (Notch3 is sufficient for angiopoietin-2 induction, enhanced by HIF-1α), and pathological neovascularization in oxygen-induced retinopathy is decreased in Notch3-null mice. Notch3 knockout mice, oxygen-induced retinopathy model, in vitro Notch3 overexpression assays for angiopoietin-2 induction, immunostaining Circulation Research High 20689064
2012 NOTCH3 forms heterodimers with NOTCH1, NOTCH3, and NOTCH4; CADASIL mutant NOTCH3 (R90C, C49Y) forms complexes more resistant to detergents than wild-type; mutant NOTCH3 shows significantly inhibited clearance; overexpressed wild-type and mutant NOTCH3 protein repress NOTCH-regulated smooth muscle transcripts and impair the activity of smooth muscle promoters, suggesting that NOTCH3 accumulation interferes with canonical Notch function in smooth muscle cells. Co-immunoprecipitation for heterodimer detection, quantitative NOTCH3-luciferase clearance assays, coculture NOTCH functional assays, smooth muscle promoter reporter assays PLoS One Medium 23028706
2014 Ligand-induced proteolytic activation of NOTCH3 (and NOTCH2) requires sequential cleavage by ADAM10 metalloprotease followed by intramembranous cleavage by the presenilin-containing γ-secretase complex; ADAM17/TACE plays no role in ligand-induced NOTCH2 or NOTCH3 signaling, establishing canonical ligand-induced processing of NOTCH3 as strictly ADAM10- and presenilin-dependent. Cell-based proteolytic activation assays with Delta-Jagged-type ligands, ADAM10 and presenilin knockdown/knockout, signaling readouts Molecular and Cellular Biology High 24842903
2014 LTBP-1 (latent TGF-β binding protein 1) directly interacts with NOTCH3-ECD and co-aggregates specifically with mutant Notch3-ECD deposits in CADASIL vessel walls; fibronectin and fibrillin-1 are also enriched in CADASIL vessels but do not co-localize with Notch3-ECD deposits; TGF-β prodomain (LAP) levels are increased in CADASIL, indicating dysregulation of TGF-β pathway via sequestration by Notch3-ECD aggregates. Immunohistochemistry of post-mortem CADASIL brain tissue, in vitro direct interaction assay between LTBP-1 and Notch3-ECD, co-aggregation assays Acta Neuropathologica Communications Medium 25190493
2015 Endogenous Notch3 signaling via Jag1 and Jag2 ligands selectively controls the pool of undifferentiated progenitors of upper airways; disruption of Notch3 signaling (genetic and pharmacological) causes aberrant expansion of basal cells and altered pseudostratification; Notch3-dependent parabasal cells subsequently activate Notch1 and Notch2 for secretory-multiciliated cell fate selection. Genetic knockouts, pharmacological inhibition, airway organotypic culture, human lung tissue analysis Development High 25564622
2016 Notch3 drives cholangiocarcinoma development and progression via a non-canonical pathway independent of RBPJ; Notch3 promotes tumor cell survival via activation of PI3K-Akt; genetic knockout of Notch3 significantly attenuates tumor growth. Notch3 genetic knockout studies in transgenic mouse model and rat model, PI3K-Akt pathway analysis, human CC characterization Proceedings of the National Academy of Sciences High 27791012
2017 Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries; systemic administration of an agonist Notch3 antibody prevents mural cell loss in CADASIL mice (C455R mutation) and modifies plasma proteins including endostatin/collagen 18α1 and Notch3 ECD; genetic rescue in Notch3 knockout mice demonstrated necessity and sufficiency of Notch3 for mural cell maintenance. Genetic rescue in Notch3 knockout mice, agonist antibody treatment in CADASIL mouse model, plasma protein analysis Journal of Experimental Medicine High 28698285
2017 Notch3 functions as a dependence receptor in endothelial cells, inducing apoptosis in the absence of its ligand Jagged-1; Jagged-1 produced by cancer cells blocks this pro-apoptotic activity; using Notch3 mutant mice, tumor growth and angiogenesis increase when Notch3 is silenced in stroma, and the anti-tumor effect of γ-secretase inhibition is partly dependent on Notch3-triggered apoptosis in endothelial cells. Notch3 mutant mice, genetic silencing, endothelial cell apoptosis assays, tumor implantation models Nature Communications High 28719575
2017 NOTCH3 is expressed in NG2+PDGFRβ+ perivascular hemangioma stem cells (HemSCs) and is necessary for HemSC-to-mural cell differentiation; NOTCH3 knockdown in HemSCs inhibits mural cell differentiation and perturbs αSMA expression; in a mouse IH model, NOTCH3 knockdown or NOTCH3 Decoy expression decreases IH blood flow, vessel caliber, and αSMA+ perivascular cell coverage. NOTCH3 knockdown in HemSCs, mouse IH model, NOTCH3 Decoy transgenic expression, flow cytometry, immunostaining JCI Insight High 29093274
2019 CADASIL vasculopathy involves a Notch3-Nox5/ER stress/ROCK signaling mechanism; NOTCH3 mutations in VSMCs induce Nox5 upregulation, leading to increased ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation; inhibitors of Notch3 (γ-secretase inhibitor), Nox5, ER stress, and ROCK each ameliorate aberrant vascular responses in CADASIL patient arteries and TgNotch3R169C mice. Peripheral small artery isolation from CADASIL patients and CADASIL mouse model, pharmacological inhibitors, gene expression analysis, functional vascular assays JCI Insight High 31647781
2019 MMP14 nuclear translocation following TMZ treatment promotes extracellular release of DLL4, which stimulates cleavage of Notch3 and its nuclear translocation, inducing sphering capacity and stemness in glioblastoma cells. Subcellular localization studies, Kiloplex ELISA-based array, functional stemness assays in PDX GBM models and established cell lines International Journal of Cancer Medium 31443114
2021 Pericyte NOTCH3 and endothelial NOTCH1 cooperate for pericyte-induced stabilization of the vasculature; loss of either NOTCH3 or NOTCH1 decreases VE-cadherin accumulation at endothelial adherens junctions and increases junction motility; DLL4 is the key ligand for NOTCH1 activation in endothelial cells, and DLL4 expression in pericytes is dependent on NOTCH3. In vitro vascular models with pericyte-endothelial coculture, NOTCH3 and NOTCH1 loss-of-function, VE-cadherin imaging, DLL4 expression analysis American Journal of Physiology: Cell Physiology High 34878922
2022 In elastin deficiency, reduced elastin induces epigenetic upregulation of the NOTCH pathway in SMCs, specifically activating NOTCH3 intracellular domain via increased γ-secretase; JAGGED1 produced by SMCs (not endothelial cells) is the key ligand driving NOTCH3 activation; Notch3 deletion or γ-secretase inhibition attenuates aortic hypermuscularization and stenosis in Eln-/- mice. Human aortic vascular cells, Eln-/- mouse models, iPSC-derived SMCs from ELN-deficient patients, Notch3 genetic deletion, Jag1 conditional deletion in SMCs vs ECs, pharmacological γ-secretase inhibition Journal of Clinical Investigation High 34990407
2024 Wild-type Notch3-ECD co-aggregates with mutant Notch3-ECD; elimination of one copy of wild-type Notch3 in TgNotch3R169C mice is sufficient to attenuate Notch3-ECD accumulation and arterial pathology (SMC loss); Notch3-regulated gene expression is essentially unchanged in TgNotch3R169C arteries, indicating that ECD accumulation (not loss of signaling) is the major driver of arterial SMC loss in CADASIL. Dedicated histopathological and multiscale imaging modalities in transgenic and knockin Notch3 mouse models, quantitative SMC loss measurement, Notch3-regulated gene expression profiling, co-aggregation assays Journal of Clinical Investigation High 38386425
2016 CHAC1, upregulated by TMZ via the JNK1/c-JUN pathway, binds directly to the Notch3 protein and inhibits Notch3 activation, attenuating Notch3-mediated downstream signaling; TMZ also significantly reduces Notch3 levels in glioma cells. Transcriptome microarray, CHAC1 overexpression/knockdown, co-immunoprecipitation of CHAC1 with Notch3, signaling pathway analysis in GBM cell lines Neuropharmacology Medium 27986595
2016 N-acetylcysteine (NAC) reduces Notch3 (specifically the cleaved intracellular domain N3ICD) protein levels through lysosome-dependent degradation in a manner independent of γ-secretase or glutathione; NAC does not affect full-length Notch3 precursor or ectopically expressed N3ICD, and does not alter Notch3 mRNA, indicating post-translational regulation at the level of processed N3ICD. Pharmacological inhibition (lysosome vs. proteasome inhibitors), NAC treatment in HeLa and multiple cancer cell lines, Western blot, mRNA analysis, Notch3 silencing and N3ICD overexpression Oncotarget Medium 27102435
2018 Deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4+CD8+ thymocytes; Notch3 regulates CXCR4 surface expression through β-arrestin in human leukemia cells; in vivo CXCR4 antagonism prevents bone marrow colonization by CD4+CD8+ cells in young Notch3 transgenic mice. Notch3 intracellular domain transgenic mice, transplantation assays, CXCR4 surface expression analysis, β-arrestin mechanistic studies in human leukemia cells, in vivo CXCR4 antagonism Oncogene Medium 30038265
2020 Naturally occurring NOTCH3 exon 9 skipping in a patient with a Gly498Cys NOTCH3 variant effectively excludes the mutation from the majority of transcripts, resulting in attenuated NOTCH3 protein aggregation (no GOM detected, minimal NOTCH3 staining in skin biopsy) and a milder CADASIL phenotype; therapeutic exon 9 skipping can be achieved in cell models using antisense oligonucleotides and CRISPR/Cas9, providing proof-of-concept that cysteine-corrective exon skipping reduces NOTCH3 aggregation. RT-PCR and Sanger sequencing of patient fibroblast RNA, skin biopsy electron microscopy and immunohistochemistry, antisense-mediated exon skipping in cell models, CRISPR/Cas9 genome editing Human Molecular Genetics High 31960911

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 1650 8878478
2009 Cadasil. The Lancet. Neurology 857 19539236
1997 Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet (London, England) 548 9388399
2000 The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. The Journal of clinical investigation 479 10712431
2006 Notch3 gene amplification in ovarian cancer. Cancer research 231 16778208
2010 Notch3 is critical for proper angiogenesis and mural cell investment. Circulation research 156 20689064
2016 Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Annals of clinical and translational neurology 155 27844030
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) 151 25323668
2015 Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development (Cambridge, England) 130 25564622
2007 An overview of Notch3 function in vascular smooth muscle cells. Progress in biophysics and molecular biology 113 17854869
2010 Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature. BioEssays : news and reviews in molecular, cellular and developmental biology 106 20967782
2014 Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert review of molecular diagnostics 99 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
1997 Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia. Annals of the New York Academy of Sciences 94 9329692
2006 Cortical neuronal apoptosis in CADASIL. Stroke 90 17008611
2006 Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Neurology 84 16717210
2007 The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. Human molecular genetics 78 17331978
2016 Notch3 drives development and progression of cholangiocarcinoma. Proceedings of the National Academy of Sciences of the United States of America 75 27791012
2016 Notch signaling in lung diseases: focus on Notch1 and Notch3. Therapeutic advances in respiratory disease 74 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
2020 Notch3 in Development, Health and Disease. Biomolecules 70 32210034
2018 The Role of Notch3 in Cancer. The oncologist 69 29622701
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
2010 NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. Journal of neurology, neurosurgery, and psychiatry 68 20935329
2008 Notch3: from subtle structural differences to functional diversity. Oncogene 68 18758477
2010 Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology 66 20038773
2009 CADASIL mutations enhance spontaneous multimerization of NOTCH3. Human molecular genetics 66 19417009
1999 CADASIL: hereditary disease of arteries causing brain infarcts and dementia. Neuropathology and applied neurobiology 63 10476042
2014 Notch3 pathway alterations in ovarian cancer. Cancer research 62 24743243
2020 Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology 60 32732295
2006 CADASIL: a critical look at a Notch disease. Developmental neuroscience 60 16508299
2020 Clinical and Genetic Aspects of CADASIL. Frontiers in aging neuroscience 58 32457593
2017 Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. The Journal of experimental medicine 57 28698285
2009 Thrombospondin 2 potentiates notch3/jagged1 signaling. The Journal of biological chemistry 57 19147503
2010 CADASIL: experimental insights from animal models. Stroke 56 20876488
2010 CADASIL. Journal of geriatric psychiatry and neurology 55 21045164
2004 The pathogenesis of CADASIL: an update. Journal of the neurological sciences 55 15537516
2014 Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits. Acta neuropathologica communications 53 25190493
2005 CADASIL mutations impair Notch3 glycosylation by Fringe. Human molecular genetics 48 15857853
2018 CADASIL. Handbook of clinical neurology 47 29478611
2010 CADASIL and migraine: A narrative review. Cephalalgia : an international journal of headache 47 21038489
2006 Cholinergic neuronal deficits in CADASIL. Stroke 47 17122431
2018 Severe white matter astrocytopathy in CADASIL. Brain pathology (Zurich, Switzerland) 46 29757481
2016 The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology 45 27986595
2020 CADASIL: yesterday, today, tomorrow. European journal of neurology 42 32348626
2012 Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3. PloS one 40 23028706
2024 CADASIL: A NOTCH3-associated cerebral small vessel disease. Journal of advanced research 39 38176524
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
2022 Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL. Neurology 38 35641310
2019 ER stress and Rho kinase activation underlie the vasculopathy of CADASIL. JCI insight 38 31647781
2018 Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice. Annals of neurology 38 30014602
2021 NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature. Neuropathology and applied neurobiology 37 34297860
2021 Notch1 and Notch3 coordinate for pericyte-induced stabilization of vasculature. American journal of physiology. Cell physiology 36 34878922
2022 Effect of NOTCH3 EGFr Group, Sex, and Cardiovascular Risk Factors on CADASIL Clinical and Neuroimaging Outcomes. Stroke 34 35862191
2006 Notch3 intracellular domain accumulates in HepG2 cell line. Anticancer research 33 16827154
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
2022 Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 31 36254369
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
2003 Incipient CADASIL. Archives of neurology 30 12756134
2022 Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS neuroscience & therapeutics 29 35822697
2015 Clinical significance of cerebral microbleeds locations in CADASIL with R544C NOTCH3 mutation. PloS one 29 25692567
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
2017 CADASIL: Treatment and Management Options. Current treatment options in neurology 27 28741120
2024 Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL. The Journal of clinical investigation 26 38386425
2021 Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases. The American journal of pathology 26 33895122
2017 NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma. JCI insight 26 29093274
2017 Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas. Journal of Cancer 26 29158806
2009 CADASIL: extended polymorphisms and mutational analysis of the NOTCH3 gene. Journal of neuroscience research 25 19006080
2007 Neuropsychiatric manifestations in CADASIL. Dialogues in clinical neuroscience 25 17726918
2024 Most common NOTCH3 mutations causing CADASIL or CADASIL-like cerebral small vessel disease: A systematic review. Cerebral circulation - cognition and behavior 24 38966425
2022 Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model. EMBO molecular medicine 24 36524456
2021 The pericyte: A critical cell in the pathogenesis of CADASIL. Cerebral circulation - cognition and behavior 24 34950895
2022 Cognition, mood and behavior in CADASIL. Cerebral circulation - cognition and behavior 23 36324403
2021 NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Frontiers in genetics 23 34335700
2019 NOTCH3 and CADASIL syndrome: a genetic and structural overview. EMBnet.journal 23 31218211
2014 Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features. Neurobiology of aging 23 25260852
2019 TMZ regulates GBM stemness via MMP14-DLL4-Notch3 pathway. International journal of cancer 22 31443114
2000 CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. Annals of the New York Academy of Sciences 22 10818516
2002 Lessons from CADASIL. Annals of the New York Academy of Sciences 20 12480754
2013 Headache among CADASIL patients with R544C mutation: prevalence, characteristics, and associations. Cephalalgia : an international journal of headache 19 23847153
2022 Elderly CADASIL patients with intact neurological status. Journal of stroke 18 36221938
2020 Naturally occurring NOTCH3 exon skipping attenuates NOTCH3 protein aggregation and disease severity in CADASIL patients. Human molecular genetics 18 31960911
2018 Regulation of pancreatic stellate cell activation by Notch3. BMC cancer 18 29304760
2007 CADASIL in Arabs: clinical and genetic findings. BMC medical genetics 18 17996090
2022 Genotype and Phenotype Differences in CADASIL from an Asian Perspective. International journal of molecular sciences 17 36232798
2010 Glial vascular degeneration in CADASIL. Journal of Alzheimer's disease : JAD 17 21504125
2009 On the diagnosis of CADASIL. Journal of Alzheimer's disease : JAD 17 19542611
2002 Clinical Features of CADASIL. Annals of the New York Academy of Sciences 17 12480760
2014 Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state. Brain research 16 25150590
2024 Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease. Biomolecules 15 38254727
2017 Recognizing CADASIL: a Secondary Cause of Migraine with Aura. Current pain and headache reports 15 28281108
2016 N-acetylcysteine negatively regulates Notch3 and its malignant signaling. Oncotarget 15 27102435
2016 Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiology of aging 15 27890607

Missed literature

Know a paper Affinage missed for NOTCH3? Flag it for the maintainers and the community.

No submissions yet.