module: dmel_pvr_signaling
title: PVR receptor tyrosine kinase signaling in Drosophila melanogaster
label: PVR signaling pathway
module_type: SIGNALING_PATHWAY
description: >-
  PVR is the single Drosophila receptor tyrosine kinase related to vertebrate
  PDGF and VEGF receptors. It is activated by three secreted ligands, Pvf1,
  Pvf2 and Pvf3. PVR signaling guides the migration of border cells in the
  ovary and of other cells during development, and supports the survival,
  proliferation and migration of embryonic and larval hemocytes, and acts in
  dorsal closure and thorax closure. Downstream of the receptor, signaling runs
  through several branches: the Ras-Raf-MEK-ERK cascade, a Crk-Myoblast city-Ced-12
  route to the Rac GTPase that drives actin-based migration, a PI3K-Akt-TOR
  branch that supports growth and survival, and JNK and p38 kinase cascades.
summary: >-
  PDGF/VEGF-related receptor tyrosine kinase pathway activated by Pvf1-3 that
  signals through Ras-ERK, Rac, PI3K-TOR and JNK branches.
concepts:
  - {id: GO:0048008, label: platelet-derived growth factor receptor signaling pathway}
  - {id: GO:0048010, label: vascular endothelial growth factor receptor signaling pathway}
parts:
  - id: pvf_ligands
    label: Pvf ligands
    role: secreted ligands
    genes: [Pvf1, Pvf2, Pvf3]
  - id: pvr_receptor
    label: PVR receptor tyrosine kinase
    role: receptor
    genes: [Pvr]
    function: {id: GO:0004714, label: transmembrane receptor protein tyrosine kinase activity}
  - id: pvr_adaptors
    label: Receptor-proximal adaptors
    role: phosphotyrosine adaptors and signaling modulators
    description: >-
      Adaptor proteins that FlyBase places at the receptor. Drk (Grb2) and Shc
      couple the receptor to Sos; PVRAP and Socs16D are further FlyBase core
      members whose precise position in the pathway is less well defined.
    genes: [drk, Shc, PVRAP, Socs16D]
  - id: ras_erk_branch
    label: Ras-ERK branch
    role: Ras-MAPK cascade
    genes: [Sos, Ras85D, Raf, ksr, mask, Dsor1, rl, aop]
    unit_functions:
      Sos: {id: GO:0005085, label: guanyl-nucleotide exchange factor activity}
      Ras85D: {id: GO:0003924, label: GTPase activity}
      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}
      aop: {id: GO:0001227, label: "DNA-binding transcription repressor activity, RNA polymerase II-specific"}
    processes:
      - {id: GO:0000165, label: MAPK cascade}
  - id: rac_branch
    label: Crk-Mbc-Ced-12 Rac branch
    role: Rac activation for cell migration
    description: >-
      Crk links the receptor to the bipartite Rac exchange factor Myoblast
      city/Ced-12 (DOCK180/ELMO); Vav is a further Rac/Cdc42 exchange factor.
    genes: [Crk, mbc, Ced-12, Vav, Rac1, Cdc42]
    unit_functions:
      Rac1: {id: GO:0003924, label: GTPase activity}
      Cdc42: {id: GO:0003924, label: GTPase activity}
  - id: pi3k_tor_branch
    label: PI3K-Akt-TOR branch
    role: growth and survival signaling
    genes: [Lnk, Pi3K92E, Akt, Rheb, mTor, S6k, Thor]
    unit_functions:
      Akt: {id: GO:0004674, label: protein serine/threonine kinase activity}
      mTor: {id: GO:0004674, label: protein serine/threonine kinase activity}
      S6k: {id: GO:0004674, label: protein serine/threonine kinase activity}
  - id: stress_mapk_branch
    label: JNK and p38 kinase branches
    role: stress-activated MAPK cascades
    genes: [slpr, hep, bsk, lic]
    unit_functions:
      slpr: {id: GO:0004709, label: MAP kinase kinase kinase activity}
      hep: {id: GO:0008545, label: JUN kinase kinase activity}
      bsk: {id: GO:0004705, label: JUN kinase activity}
      lic: {id: GO:0004708, label: MAP kinase kinase activity}
connections:
  - {source: pvf_ligands, target: pvr_receptor, connection_type: POSITIVELY_REGULATES, description: Pvf ligands bind and activate PVR.}
  - {source: pvr_receptor, target: pvr_adaptors, connection_type: POSITIVELY_REGULATES, description: Phosphorylated PVR recruits phosphotyrosine adaptors.}
  - {source: pvr_adaptors, target: ras_erk_branch, connection_type: POSITIVELY_REGULATES, description: Drk-Sos activates Ras and the ERK cascade.}
  - {source: pvr_receptor, target: rac_branch, connection_type: POSITIVELY_REGULATES, description: PVR activates Rac through Crk and Mbc/Ced-12 during cell migration.}
  - {source: pvr_receptor, target: pi3k_tor_branch, connection_type: POSITIVELY_REGULATES, description: PVR activates PI3K-Akt-TOR signaling.}
  - {source: pvr_receptor, target: stress_mapk_branch, connection_type: POSITIVELY_REGULATES, description: PVR feeds into JNK and p38 kinase cascades in some contexts.}
notes: >-
  Boundary. The downstream branches are shared with many other receptor
  pathways and are modelled here only as the FlyBase PVR core components. The
  branches are drawn as parallel outputs of the receptor; which branch is used
  depends on cell type (Ras-ERK and Rac in migrating cells, PI3K-TOR in
  hemocyte survival and growth).