module: dmel_hedgehog_signaling
title: Hedgehog signaling pathway in Drosophila melanogaster
label: Hedgehog signaling
module_type: SIGNALING_PATHWAY
description: >-
  Hedgehog (Hh) is a secreted morphogen that is autoprocessed and modified with
  cholesterol and, by the acyltransferase Rasp, with palmitate. The
  transmembrane protein Dispatched releases lipid-modified Hh from producing
  cells. In receiving cells Hh binds its receptor Patched together with the
  co-receptors Ihog and Boi. In the absence of Hh, Patched keeps the
  seven-pass transmembrane protein Smoothened inactive, and the Hedgehog
  signaling complex of the kinesin-like protein Costal-2 (Cos), the kinase
  Fused and the zinc-finger transcription factor Cubitus interruptus (Ci)
  promotes processing of Ci into a repressor form. Hh binding relieves Patched
  inhibition, Smoothened accumulates at the plasma membrane and recruits the
  Cos-Fused complex, Ci processing is blocked and full-length Ci activates Hh
  target genes. The pathway patterns embryonic segments and the
  anterior-posterior axis of imaginal discs.
summary: >-
  Lipid-modified Hedgehog released by Dispatched binds Patched and Ihog/Boi,
  activating Smoothened and the Cos-Fused-Ci complex to switch Ci from repressor
  to activator.
concepts:
  - {id: GO:0007224, label: smoothened signaling pathway}
parts:
  - id: hh_production_and_release
    label: Hedgehog lipid modification and release
    role: ligand modification and secretion
    description: >-
      Rasp palmitoylates Hh in the secretory pathway; Dispatched is required
      for release of lipid-modified Hh from producing cells.
    group: HH-PRO
    complex: false
  - id: hh_ligand
    label: Hedgehog
    role: secreted morphogen
    genes: [hh]
    complex: false
    function: {id: GO:0048018, label: receptor ligand activity}
  - id: hh_reception
    label: Hedgehog reception
    role: receptor and co-receptors
    description: >-
      Patched is the Hh receptor; Ihog and Boi are cell-surface co-receptors
      that bind Hh and Patched.
    genes: [ptc, ihog, boi]
    complex: false
    unit_functions:
      ptc: {id: GO:0008158, label: hedgehog receptor activity}
  - id: smoothened
    label: Smoothened
    role: seven-pass transmembrane signal transducer
    genes: [smo]
    complex: false
  - id: hedgehog_signaling_complex
    label: Hedgehog signaling complex
    role: cytoplasmic transducer complex and transcription factor
    description: >-
      Costal-2, Fused and Cubitus interruptus form a microtubule-associated
      complex that controls Ci processing and activity. Ci is the
      transcriptional effector of the pathway.
    group: HSC
    complex: true
    complex_term: {id: GO:0035301, label: Hedgehog signaling complex}
    unit_functions:
      fu: {id: GO:0004674, label: protein serine/threonine kinase activity}
      ci: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
connections:
  - {source: hh_production_and_release, target: hh_ligand, connection_type: PROVIDES_INPUT_FOR,
     description: "Palmitoylation by Rasp and release by Dispatched produce active, secreted Hh."}
  - {source: hh_ligand, target: hh_reception, connection_type: POSITIVELY_REGULATES,
     description: "Hh binds Patched with the co-receptors Ihog and Boi."}
  - {source: hh_reception, target: smoothened, connection_type: NEGATIVELY_REGULATES,
     description: "Unliganded Patched inhibits Smoothened; Hh binding relieves this inhibition."}
  - {source: smoothened, target: hedgehog_signaling_complex, connection_type: POSITIVELY_REGULATES,
     description: "Active Smoothened recruits Cos-Fused, blocking Ci processing and activating full-length Ci."}
notes: >-
  Boundary. Core components (FlyBase HH-SMOC), Hh production (HH-PRO) and the
  Hedgehog signaling complex (HSC). Patched is listed by FlyBase only as a
  negative regulator (HH-SMON); it is added here as the Hh receptor because the
  pathway cannot be decomposed without it. Other regulators (PKA, CK1, Sgg,
  Su(fu), Slimb, glypicans) are not parts. Costal-2 and Fused are also listed
  by FlyBase as negative regulators, reflecting their roles in Ci processing.