module: dmel_notch_signaling
title: Notch signaling pathway in Drosophila melanogaster
label: Notch signaling pathway
module_type: SIGNALING_PATHWAY
description: >-
  Notch signaling is a juxtacrine pathway in which the transmembrane ligands
  Delta and Serrate on one cell bind the Notch receptor on a neighbouring cell.
  Ligand binding, together with ligand endocytosis in the signal-sending cell,
  exposes Notch to cleavage by the ADAM10 metalloprotease Kuzbanian (S2
  cleavage), after which the gamma-secretase complex (Presenilin, Nicastrin,
  Aph-1 and Pen-2) cleaves within the transmembrane domain (S3 cleavage) and
  releases the Notch intracellular domain. The intracellular domain enters the
  nucleus and forms a transcriptional activation complex with the CSL DNA-binding
  protein Suppressor of Hairless and the coactivator Mastermind, switching Su(H)
  target genes such as the Enhancer of split complex genes from repression to
  activation. The pathway controls lateral inhibition, boundary formation and
  binary cell-fate decisions throughout development.
summary: >-
  Juxtacrine pathway in which Delta/Serrate binding triggers sequential
  cleavage of Notch and activation of Su(H)-Mastermind target genes by the
  Notch intracellular domain.
concepts:
  - {id: GO:0007219, label: Notch signaling pathway}
parts:
  - id: notch_ligands
    label: DSL ligands Delta and Serrate
    role: transmembrane ligands
    description: Transmembrane DSL-domain ligands presented by the signal-sending cell.
    genes: [Delta, Ser]
    function: {id: GO:0005112, label: Notch binding}
  - id: weary
    label: Weary
    role: FlyBase core component of uncharacterized mechanism
    description: >-
      Single-pass membrane protein with EGF-like repeats that FlyBase lists among
      the core components of Notch signaling; how it acts in the pathway is not
      well characterized.
    genes: [wry]
  - id: notch_receptor
    label: Notch receptor
    role: receptor
    genes: [N]
    function: {id: GO:0004888, label: transmembrane signaling receptor activity}
  - id: s2_cleavage
    label: ADAM metalloproteases for S2 cleavage
    role: S2 cleavage of ligand-bound Notch
    description: >-
      Kuzbanian (ADAM10) performs the ligand-dependent S2 cleavage of Notch; the
      ADAM17 homolog Tace also cleaves Notch, mainly in ligand-independent
      contexts.
    genes: [kuz, Tace]
    function: {id: GO:0004222, label: metalloendopeptidase activity}
    processes:
      - {id: GO:0007220, label: Notch receptor processing}
  - id: gamma_secretase
    label: Gamma-secretase complex
    role: S3 intramembrane cleavage releasing the Notch intracellular domain
    complex: true
    genes: [Psn, Nct, aph-1, pen-2]
    complex_term: {id: GO:0070765, label: gamma-secretase complex}
    unit_functions:
      Psn: {id: GO:0042500, label: "aspartic endopeptidase activity, intramembrane cleaving"}
    roles:
      Psn: catalytic subunit
    processes:
      - {id: GO:0007220, label: Notch receptor processing}
  - id: csl_nicd_mam_complex
    label: CSL-Notch-Mastermind transcription complex
    role: nuclear transcriptional activation complex
    description: >-
      The Notch intracellular domain, the CSL DNA-binding protein Suppressor of
      Hairless and the coactivator Mastermind form the activation complex on
      Su(H) binding sites of target genes.
    complex: true
    group: CNM
    complex_term: {id: GO:0002193, label: MAML1-RBP-Jkappa- ICN1 complex}
    unit_functions:
      Su(H): {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
      mam: {id: GO:0003713, label: transcription coactivator activity}
    roles:
      N: Notch intracellular domain
      Su(H): CSL DNA-binding protein
      mam: coactivator
connections:
  - {source: notch_ligands, target: notch_receptor, connection_type: POSITIVELY_REGULATES, description: DSL ligands bind and activate Notch on the adjacent cell.}
  - {source: notch_receptor, target: s2_cleavage, connection_type: PROVIDES_INPUT_FOR, description: Ligand-bound Notch is the substrate for ADAM S2 cleavage.}
  - {source: s2_cleavage, target: gamma_secretase, connection_type: PROVIDES_INPUT_FOR, description: The S2-cleaved membrane-tethered fragment is the substrate for gamma-secretase.}
  - {source: gamma_secretase, target: csl_nicd_mam_complex, connection_type: POSITIVELY_REGULATES, description: S3 cleavage releases the Notch intracellular domain that assembles the nuclear complex.}
notes: >-
  Boundary. The module contains ligands, receptor, the two proteolytic steps and
  the nuclear CSL complex. Notch appears twice, as the receptor and as the
  intracellular domain within the nuclear complex. E3 ligases that drive ligand
  endocytosis (Neuralized, Mind bomb 1), glycosyltransferases that modify
  Notch (Ofut1, Fringe, Rumi), the corepressor Hairless and the Enhancer of
  split target genes are FlyBase regulators and are not modelled as parts.
  Weary (wry) is included because FlyBase lists it among the core components,
  but its mechanism is not established.