module: dmel_insulin_like_receptor_signaling
title: Insulin-like receptor signaling pathway in Drosophila melanogaster
label: Insulin-like receptor signaling
module_type: SIGNALING_PATHWAY
description: >-
  Drosophila insulin-like peptides (Ilps), several of them secreted by the
  insulin-producing cells of the brain, bind the single insulin-like receptor
  InR, a receptor tyrosine kinase. Activated InR phosphorylates the adaptor
  Chico (IRS) and acts with the adaptor Lnk (SH2B), recruiting the class IA
  phosphatidylinositol 3-kinase made of the catalytic subunit Pi3K92E (Dp110)
  and the regulatory subunit Pi3K21B (p60). The resulting PIP3 recruits Pdk1
  and Akt; Akt phosphorylates and excludes the transcription factor FOXO from
  the nucleus and promotes TORC1 activity through Rheb, leading to S6 kinase
  activation and inhibition of the translational repressor Thor (4E-BP). The
  pathway controls cell and organismal growth, carbohydrate and lipid
  metabolism, reproduction and lifespan.
summary: >-
  Insulin-like peptides activate InR, Chico/Lnk and class IA PI3K, then
  Pdk1-Akt, which inhibits FOXO and activates TORC1-S6K growth signaling.
concepts:
  - {id: GO:0008286, label: insulin receptor signaling pathway}
parts:
  - id: insulin_like_peptides
    label: Insulin-like peptides
    role: secreted ligands
    genes: [Ilp2, Ilp3, Ilp5, Ilp6]
    complex: false
    function: {id: GO:0005179, label: hormone activity}
  - id: insulin_like_receptor
    label: InR
    role: receptor tyrosine kinase
    genes: [InR]
    complex: false
    function: {id: GO:0005009, label: insulin receptor activity}
  - id: inr_adaptors
    label: Receptor adaptors
    role: phosphotyrosine adaptors
    description: Chico (IRS) and Lnk (SH2B) are InR adaptors; Drk (Grb2) links InR to Ras-MAPK.
    genes: [chico, Lnk, drk]
    complex: false
  - id: class_ia_pi3k
    label: Class IA phosphatidylinositol 3-kinase
    role: lipid kinase complex
    description: Pi3K92E (Dp110) catalytic and Pi3K21B (p60) regulatory subunits.
    group: PI3K-IA
    complex: true
    complex_term: {id: GO:0005943, label: "phosphatidylinositol 3-kinase complex, class IA"}
    unit_functions:
      Pi3K92E: {id: GO:0046934, label: "1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity"}
  - id: pdk1_akt
    label: Pdk1 and Akt
    role: PIP3-dependent protein kinases
    genes: [Pdk1, Akt]
    complex: false
    unit_functions:
      Pdk1: {id: GO:0004676, label: 3-phosphoinositide-dependent protein kinase activity}
      Akt: {id: GO:0004674, label: protein serine/threonine kinase activity}
  - id: foxo_output
    label: FOXO transcriptional output
    role: transcription factors
    description: >-
      FOXO is the main transcriptional effector repressed by Akt. Fork head is
      a FlyBase core component acting in some tissues.
    genes: [foxo, fkh]
    complex: false
    function: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"}
  - id: torc1_branch
    label: Rheb-TORC1-S6K growth branch
    role: growth and translation control
    description: >-
      Rheb activates TORC1 (mTor with Raptor), which phosphorylates S6 kinase
      and the 4E-BP Thor.
    genes: [Rheb, mTor, raptor, S6k, Thor]
    complex: false
    unit_functions:
      Rheb: {id: GO:0003924, label: GTPase activity}
      mTor: {id: GO:0004674, label: protein serine/threonine kinase activity}
      S6k: {id: GO:0004711, label: ribosomal protein S6 kinase activity}
  - id: inr_mapk_branch
    label: Ras-MAPK branch
    role: MAP kinase cascade components
    genes: [cnk, Dsor1, rl]
    complex: false
    unit_functions:
      Dsor1: {id: GO:0004708, label: MAP kinase kinase activity}
      rl: {id: GO:0004707, label: MAP kinase activity}
  - id: other_effectors
    label: Other downstream effectors
    role: kinases, transcriptional and metabolic effectors
    description: >-
      FlyBase core components acting downstream of InR in particular tissues
      or physiological contexts: the salt-inducible kinases Sik2 and Sik3,
      HDAC4, Myc, the hypoxia factor Sima with its partner Tango, and glycogen
      phosphorylase (Glyp).
    genes: [Sik2, Sik3, HDAC4, Myc, sima, tgo, Glyp]
    complex: false
connections:
  - {source: insulin_like_peptides, target: insulin_like_receptor, connection_type: POSITIVELY_REGULATES,
     description: "Ilp binding activates the InR tyrosine kinase."}
  - {source: insulin_like_receptor, target: inr_adaptors, connection_type: POSITIVELY_REGULATES,
     description: "InR phosphorylates Chico and engages Lnk and Drk."}
  - {source: inr_adaptors, target: class_ia_pi3k, connection_type: POSITIVELY_REGULATES,
     description: "Phosphorylated Chico recruits and activates class IA PI3K."}
  - {source: class_ia_pi3k, target: pdk1_akt, connection_type: POSITIVELY_REGULATES,
     description: "PIP3 recruits Pdk1 and Akt; Pdk1 phosphorylates Akt."}
  - {source: pdk1_akt, target: foxo_output, connection_type: NEGATIVELY_REGULATES,
     description: "Akt phosphorylates FOXO and excludes it from the nucleus."}
  - {source: pdk1_akt, target: torc1_branch, connection_type: POSITIVELY_REGULATES,
     description: "Akt promotes Rheb-TORC1 activity."}
  - {source: inr_adaptors, target: inr_mapk_branch, connection_type: POSITIVELY_REGULATES,
     description: "Drk couples InR to the Ras-MAPK cascade."}
notes: >-
  Boundary. Core components (FlyBase INS-C) and the class IA PI3K complex
  (PI3K-IA). Ilp1, Ilp4, Ilp7 and Ilp8 are not FlyBase core members and are not
  included. The TORC1 and MAPK branches are shared with TOR and Ras signaling
  modules. Pten, Tsc1/gigas, ImpL2 and other FlyBase regulators are not parts.
  The other-effectors part collects FlyBase core members whose position in the
  pathway is tissue-specific; no activities are asserted for them.