module: dmel_eiger_tnf_signaling
title: Eiger (TNF) signaling pathway in Drosophila melanogaster
label: Eiger-TNF signaling pathway
module_type: SIGNALING_PATHWAY
description: >-
  Eiger is the single Drosophila member of the tumor necrosis factor
  superfamily. It is a type II transmembrane protein that can be released as a
  soluble ligand by the metalloprotease Tace. Eiger binds the TNF receptors
  Grindelwald and Wengen, which signal through Traf proteins and the
  Tak1-Tab2 kinase complex to the JNK kinase kinases Hemipterous and Mkk4 and
  the JNK Basket. The Ste20-family kinase Misshapen acts upstream in the JNK
  cascade. JNK activation by Eiger induces apoptosis and cell elimination in
  development and tumour suppression, and also contributes to tissue growth,
  regeneration, pain sensitization and immune responses.
summary: >-
  TNF-like ligand Eiger and its receptors Grindelwald and Wengen, which activate
  JNK through Traf6, Tak1-Tab2 and the JNK kinase kinases Hep and Mkk4.
concepts:
  - {id: GO:0033209, label: tumor necrosis factor-mediated signaling pathway}
parts:
  - id: eiger_shedding
    label: Tace ectodomain shedding
    role: release of soluble Eiger
    genes: [Tace]
    function: {id: GO:0004222, label: metalloendopeptidase activity}
  - id: eiger_ligand
    label: Eiger
    role: ligand
    genes: [egr]
    function: {id: GO:0005164, label: tumor necrosis factor receptor binding}
  - id: eiger_receptors
    label: TNF receptors Grindelwald and Wengen
    role: receptors
    genes: [grnd, wgn]
  - id: traf_tak1_relay
    label: Traf6 and Tak1-Tab2 relay
    role: receptor-proximal signal relay to MAP3K
    description: >-
      Traf6 and the Tak1-Tab2 complex relay receptor signals to the MAP kinase
      kinase kinase Tak1; the MAP4K Misshapen also acts upstream of the JNK
      kinase kinases.
    genes: [Traf6, Tab2, Tak1, msn]
    unit_functions:
      Tak1: {id: GO:0004709, label: MAP kinase kinase kinase activity}
      msn: {id: GO:0008349, label: MAP kinase kinase kinase kinase activity}
  - id: mapkk_tier
    label: MAP kinase kinases Hep, Mkk4 and Licorne
    role: MAP2K tier
    genes: [hep, Mkk4, lic]
    unit_functions:
      hep: {id: GO:0008545, label: JUN kinase kinase activity}
      Mkk4: {id: GO:0008545, label: JUN kinase kinase activity}
      lic: {id: GO:0004708, label: MAP kinase kinase activity}
  - id: jnk
    label: JNK Basket
    role: JNK
    genes: [bsk]
    function: {id: GO:0004705, label: JUN kinase activity}
    processes:
      - {id: GO:0007254, label: JNK cascade}
connections:
  - {source: eiger_shedding, target: eiger_ligand, connection_type: POSITIVELY_REGULATES, description: Tace cleavage releases soluble Eiger.}
  - {source: eiger_ligand, target: eiger_receptors, connection_type: POSITIVELY_REGULATES, description: Eiger binds and activates Grindelwald and Wengen.}
  - {source: eiger_receptors, target: traf_tak1_relay, connection_type: POSITIVELY_REGULATES, description: Activated receptors engage Traf proteins and Tak1-Tab2.}
  - {source: traf_tak1_relay, target: mapkk_tier, connection_type: POSITIVELY_REGULATES, description: Tak1 phosphorylates and activates the MAP2Ks.}
  - {source: mapkk_tier, target: jnk, connection_type: POSITIVELY_REGULATES, description: Hep and Mkk4 phosphorylate and activate Basket.}
notes: >-
  Boundary. The module stops at the JNK Basket; the AP-1 transcription factors
  (Jra, Kay) and JNK target genes are not FlyBase members of this group and are
  left out. Licorne (MKK3) belongs to the p38 branch and is included because
  FlyBase lists it among the core components. Traf6 is also in the FlyBase
  positive regulator set; Traf4 is not a FlyBase member, although it has been
  implicated in Eiger signaling. The JNK phosphatase Puckered and other
  regulators are FlyBase regulator sets and not parts.