Notch signaling pathway

(The nav label “Notch Signaling” resolves here.)

NOTCH receptors are single-pass transmembrane proteins classically activated by trans-presented DSL ligands (DLL1/3/4, JAG1/2) on neighboring cells. Ligand engagement triggers metalloprotease S2 cleavage followed by gamma-secretase S3 intramembrane proteolysis to release the Notch intracellular domain (NICD). NICD enters the nucleus with RBPJ (CSL) and MAML co-activators to drive HES/HEY programs—central to fate decisions, tip–stalk angiogenic patterning, immunity, and stem-cell niches; cancers may show NOTCH1 gain/truncation, PEST-domain loss, or ligand-driven microenvironment remodeling.

1. Key targets

Receptor–ligand–protease axis

  • NOTCH1–4

    EGF repeats mediate ligand engagement; NRR modules gate ADAM accessibility.

  • DLL / Jagged

    DSL ligand family; Fringe-type glycosylation tunes avidity and strength.

  • ADAM10 / ADAM17

    S2 shedding yields membrane-tethered NEXT for gamma-secretase.

γ-Secretase complex

  • PSEN1 / PSEN2、APH1、PEN2、NCSTN（Nicastrin）
  • Intramembrane cleavage releases NICD; also processes APP (off-target note)

Nuclear complex & negative regulation

  • RBPJ / CSL + MAML1–3 + NICD
  • Numb, Fbxw7, Deltex tune NICD amplitude/turnover

2. Suggested experimental readouts

NICD is short-lived—pair WB with proteasome inhibitors; nuclear fractionation or IF foci help. GSIs affect multiple substrates including APP-CTF.

  • Cleaved NOTCH1 (e.g., Val1744 epitopes—clone-dependent), NICD, total NOTCH1
  • DLL4, JAG1, DLL1 membrane levels / co-culture models
  • HES1/5, HEY1/2 transcriptional readouts
  • RBPJ ChIP–qPCR / reporters (project-dependent)
  • FBXW7, Numb (negative-regulation context)

3. DLL vs Jagged ligands (overview)

Ligand classExamplesCommon biology notes
Delta-likeDLL1, DLL3, DLL4Strong lateral inhibition bias; tip–stalk competition in angiogenesis.
JaggedJAG1, JAG2Cross-regulates with DLL in stem/TME contexts—strength depends on Fringe/receptor background.

4. Cancer, vascular & immune context

  • T-ALL / NOTCH1: HD or PEST lesions stabilize NICD; FBXW7 loss is a frequent collaborator.
  • DLL4–Notch: tumor vasculature tip–stalk programs; anti-DLL4 strategies balance efficacy vs vascular toxicity.
  • Immunity & stroma: frequent axis in thymic development, macrophage polarization, CAF crosstalk.

Notch pathway–related antibodies (curated)

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5. Product lines & on-site search

Primary & phospho antibodies

NOTCH1–4, cleaved NOTCH1, NICD, DLL1/3/4, JAG1/2, RBPJ, MAML1, HES1/5, HEY1, ADAM10, PSEN1, NCSTN—WB/IF/IHC/FC per datasheet.

Recombinant proteins & reporters

Fc-ligand fusions, reporter lines—availability-dependent; co-culture controls.

6. Inhibitors & tool compounds (summary)

Gamma-secretase inhibitors modulate APP processing and can carry CNS toxicity risk; clinical agents are prescription drugs.

DAPT / LY411575

Gamma-secretase inhibition—common in vitro Notch blockade.

RO4929097 / MK-0752

Clinical/clinical-stage GSIs—see public trial literature.

Semagacestat / Avagacestat

GSIs with major AD-trial safety lessons—interpret carefully.

GI254023X / GW280264X

ADAM10/17-biased tools for S2-step dissection.

DLL4 / NOTCH biologics

Biologic DLL4/NOTCH programs—availability varies.

SAHM mimics

MAML–RBPJ-interface stapled peptides (tool-dependent).

7. Pathway schematic

Ligand-induced Notch activation (canonical)
Notch signaling pathway schematic
Legend
  1. Trans-presented DSL ligands
  2. S2: ADAM shedding to NEXT
  3. S3: gamma-secretase releases NICD
  4. NICD–RBPJ–MAML drives HES/HEY

8. Pathway biology overview

Notch converts juxtacrine contact into nuclear transcription, underpinning lateral inhibition and lineage boundaries. The same receptor couples to different cofactors and chromatin states—annotate cell type for antibody/ChIP readouts. Non-canonical outputs (membrane-tethered fragments, cross-talk with mTOR, etc.) appear in select models.

  • Development: neural, vascular, endodermal patterning
  • Homeostasis: niche maintenance and differentiation gradients

9. Related pathways on this site

TGF-β/SmadWnt/β-cateninMAPK/ERKPI3K/Akt/mTORCell cycleAngiogenesisApoptosisJAK-STATNF-κBCellular autophagy

10. External databases & resources

11. References

Mechanism & reviews

  • • Kopan R, Ilagan MX. (2009). The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 137(2):216-33.
  • • Bray SJ. (2016). Notch signalling in context. Nat Rev Mol Cell Biol. 17(11):722-35.

Disease & targeting

  • • Aster JC, Pear WS, Blacklow SC. (2017). The varied roles of NOTCH in cancer. Annu Rev Pathol. 12:245-75.
  • • Gridley T. (2010). Notch signaling in vascular development and physiology. Development. 137(11):1837-47.