module: dmel_hippo_signaling
title: Hippo signaling pathway in Drosophila melanogaster
label: Hippo signaling pathway
module_type: SIGNALING_PATHWAY
description: >-
  The Hippo pathway restricts tissue growth by limiting the activity of the
  transcriptional coactivator Yorkie. At the apical cortex of epithelial cells,
  the Kibra-Expanded-Merlin complex promotes activation of the Ste20-like
  kinase Hippo, which with its scaffold Salvador phosphorylates and activates
  the NDR family kinase Warts and its coactivator Mats. Warts phosphorylates
  Yorkie, which leads to its retention in the cytoplasm. When the pathway is
  off, Yorkie enters the nucleus and, with the TEAD transcription factor
  Scalloped, activates genes that promote cell proliferation and inhibit
  apoptosis, such as cycE, diap1 and bantam.
summary: >-
  Kinase cascade (Hippo-Salvador, Warts-Mats) activated by the Kibra-Ex-Mer
  complex that inhibits the growth-promoting coactivator Yorkie.
concepts:
  - {id: GO:0035329, label: hippo signaling}
parts:
  - id: kibra_ex_mer
    label: Kibra-Expanded-Merlin complex
    role: apical upstream activator
    complex: true
    group: KEM
    complex_term: {id: GO:0036375, label: Kibra-Ex-Mer complex}
  - id: hpo_sav
    label: Hippo-Salvador kinase module
    role: upstream kinase
    complex: true
    genes: [hpo, sav]
    unit_functions:
      hpo: {id: GO:0004674, label: protein serine/threonine kinase activity}
    roles:
      hpo: Ste20-like kinase
      sav: scaffold
  - id: wts_mats
    label: Warts-Mats kinase module
    role: core kinase phosphorylating Yorkie
    complex: true
    genes: [wts, mats]
    unit_functions:
      wts: {id: GO:0004674, label: protein serine/threonine kinase activity}
    roles:
      wts: NDR family kinase
      mats: MOB kinase activator
  - id: rae1
    label: Rae1
    role: FlyBase core component
    description: >-
      Rae1 is listed by FlyBase among core components of the pathway; its
      mechanism is less well characterized than that of the kinase core.
    genes: [Rae1]
  - id: yki_sd
    label: Yorkie-Scalloped transcriptional output
    role: transcriptional output
    genes: [yki, sd]
    unit_functions:
      yki: {id: GO:0003713, label: transcription coactivator activity}
      sd: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
connections:
  - {source: kibra_ex_mer, target: hpo_sav, connection_type: POSITIVELY_REGULATES, description: The Kibra-Ex-Mer complex promotes Hippo activation at the apical cortex.}
  - {source: hpo_sav, target: wts_mats, connection_type: POSITIVELY_REGULATES, description: Hippo phosphorylates and activates Warts and Mats.}
  - {source: wts_mats, target: yki_sd, connection_type: NEGATIVELY_REGULATES, description: Warts phosphorylates Yorkie and keeps it in the cytoplasm.}
notes: >-
  Boundary. The module contains the Kibra-Ex-Mer complex, the core kinase
  cassette and the Yorkie output. Scalloped (sd) is not a member of the FlyBase
  Hippo groups and is added as the textbook DNA-binding partner of Yorkie.
  Upstream inputs (Fat-Dachsous, Crumbs, Tao-1, Echinoid) and the many
  positive and negative regulators are FlyBase regulator sets and not parts.