module: dmel_fgfr_signaling
title: FGFR signaling pathway in Drosophila melanogaster
label: FGFR signaling
module_type: SIGNALING_PATHWAY
description: >-
  Drosophila has two FGF receptor tyrosine kinases with distinct ligands.
  Breathless (Btl) is activated by Branchless (Bnl) and guides tracheal
  branch migration, and Heartless (Htl) is activated by Pyramus and Thisbe and
  directs the spreading and migration of mesoderm and glial cells. Both
  receptors use the FGFR-specific cytoplasmic adaptor Stumps (Downstream of
  FGFR, Dof). Signaling proceeds through Drk, Sos, Ras85D and the
  Raf-Dsor1-Rolled MAP kinase cascade, ending in ETS factor output (Pointed
  activation, Yan/Aop relief). Pebble, a Rho exchange factor, acts in
  Heartless-dependent mesoderm migration.
summary: >-
  Branchless-Breathless and Pyramus/Thisbe-Heartless FGF signaling through
  Stumps, Ras and the Raf-Dsor1-Rolled cascade to ETS transcriptional output.
concepts:
  - {id: GO:0008543, label: fibroblast growth factor receptor signaling pathway}
parts:
  - id: fgf_ligand_receptor_pairs
    label: FGF ligand-receptor pairs
    role: ligands and receptor tyrosine kinases
    variant_sets:
      - id: fgf_branches
        label: Breathless or Heartless branch
        selection: ONE_OR_MORE
        variants:
          - id: breathless_branch
            label: Branchless-Breathless
            description: Tracheal FGF signaling.
            genes: [bnl, btl]
            complex: false
            unit_functions:
              bnl: {id: GO:0008083, label: growth factor activity}
              btl: {id: GO:0005007, label: fibroblast growth factor receptor activity}
          - id: heartless_branch
            label: Pyramus/Thisbe-Heartless
            description: Mesodermal and glial FGF signaling.
            genes: [pyr, ths, htl]
            complex: false
            unit_functions:
              pyr: {id: GO:0008083, label: growth factor activity}
              ths: {id: GO:0008083, label: growth factor activity}
              htl: {id: GO:0005007, label: fibroblast growth factor receptor activity}
  - id: fgfr_adaptors_and_ras_activation
    label: Receptor adaptors and Ras activation
    role: FGFR-specific and general adaptors, phosphatase and exchange factor
    description: >-
      Stumps (Dof) is the FGFR-specific adaptor; Drk, Shc, Corkscrew (SHP2)
      and Sos link the receptors to Ras.
    genes: [stumps, drk, Shc, csw, Sos]
    complex: false
    unit_functions:
      csw: {id: GO:0004725, label: protein tyrosine phosphatase activity}
      Sos: {id: GO:0005085, label: guanyl-nucleotide exchange factor activity}
  - id: fgfr_ras
    label: Ras85D
    role: small GTPase switch
    genes: [Ras85D]
    complex: false
    function: {id: GO:0003924, label: GTPase activity}
  - id: fgfr_mapk_cascade
    label: Raf-Dsor1-Rolled MAP kinase cascade
    role: kinase cascade and scaffolds
    genes: [Raf, Dsor1, rl, ksr, cnk]
    complex: false
    unit_functions:
      Raf: {id: GO:0004709, label: MAP kinase kinase kinase activity}
      Dsor1: {id: GO:0004708, label: MAP kinase kinase activity}
      rl: {id: GO:0004707, label: MAP kinase activity}
  - id: fgfr_nuclear_output
    label: Nuclear transcriptional output
    role: transcription factors and co-repressor
    description: >-
      Pointed (activator) and Yan/Aop (repressor) are ETS factors acting
      downstream of ERK. Grainyhead, Groucho and Zpr1 are FlyBase core
      components whose roles in FGFR signaling are less defined.
    genes: [pnt, aop, grh, gro, Zpr1]
    complex: false
    unit_functions:
      pnt: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
      aop: {id: GO:0001227, label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"}
  - id: pebble
    label: Pebble
    role: Rho exchange factor in mesoderm migration
    genes: [pbl]
    complex: false
connections:
  - {source: fgf_ligand_receptor_pairs, target: fgfr_adaptors_and_ras_activation, connection_type: POSITIVELY_REGULATES,
     description: "Activated Breathless or Heartless recruits Stumps and Drk/Sos."}
  - {source: fgfr_adaptors_and_ras_activation, target: fgfr_ras, connection_type: POSITIVELY_REGULATES,
     description: "Sos catalyses GDP-GTP exchange on Ras85D."}
  - {source: fgfr_ras, target: fgfr_mapk_cascade, connection_type: POSITIVELY_REGULATES,
     description: "GTP-bound Ras activates Raf."}
  - {source: fgfr_mapk_cascade, target: fgfr_nuclear_output, connection_type: POSITIVELY_REGULATES,
     description: "Rolled (ERK) regulates the ETS factors Pointed and Yan."}
  - {source: fgf_ligand_receptor_pairs, target: pebble, connection_type: POSITIVELY_REGULATES,
     description: "Heartless signaling engages Pebble during mesoderm spreading."}
notes: >-
  Boundary. Core components only (FlyBase FGFR-C). The adaptors, Ras and the
  MAP kinase cascade are shared with EGFR, Sevenless and Torso signaling.
  Heparan sulfate proteoglycans (Dally, Dlp, Trol), Sprouty and other FlyBase
  regulators are not parts.