module: dmel_torc1_nutrient_sensing
title: TORC1 nutrient- and growth-factor-sensing machinery in Drosophila melanogaster
label: TORC1 upstream sensing machinery
module_type: SIGNALING_PATHWAY
description: >-
  TORC1 is activated on the lysosome surface only when two inputs coincide.
  Amino acid sufficiency is relayed through the heterodimeric Rag GTPases
  (RagA-B with RagC-D), which are anchored to the lysosome by the pentameric
  Ragulator complex and recruit TORC1 when RagA-B is GTP-bound. The GATOR1
  complex (Iml1, Nprl2, Nprl3) acts as a GTPase-activating protein for RagA-B
  and so inhibits TORC1, and the GATOR2 complex (Mio, Wdr24, Wdr59, Seh1 and
  Sec13) inhibits GATOR1. Growth-factor and energy signals are relayed through
  the TSC1-TSC2 complex (Tsc1 and Gigas), a GTPase-activating protein for the
  small GTPase Rheb, which directly activates TORC1. In Drosophila, GATOR1 and
  GATOR2 regulate TORC1 activity in the ovary and other tissues, and
  TSC mutations cause cell overgrowth.
summary: >-
  GATOR1, GATOR2, Ragulator, Rag GTPase and TSC-Rheb modules that couple amino
  acid and growth-factor signals to TORC1 activity.
concepts:
  - {id: GO:1903432, label: regulation of TORC1 signaling}
parts:
  - id: gator2
    label: GATOR2 complex
    role: inhibitor of GATOR1
    complex: true
    group: GAT2
    complex_term: {id: GO:0061700, label: GATOR2 complex}
  - id: gator1
    label: GATOR1 complex
    role: GTPase-activating protein for RagA-B
    complex: true
    group: GAT1
    complex_term: {id: GO:1990130, label: GATOR1 complex}
    function: {id: GO:0005096, label: GTPase activator activity}
  - id: ragulator
    label: Ragulator complex
    role: lysosomal anchor for the Rag GTPases
    description: >-
      Pentameric Lamtor1-5 complex; FlyBase separately groups Lamtor2 and
      Lamtor3 as Rag guanine nucleotide exchange factors (RAGGEF).
    complex: true
    groups: [LAMTOR, RAGGEF]
    complex_term: {id: GO:0071986, label: Ragulator complex}
  - id: rag_gtpases
    label: Rag GTPase heterodimer
    role: amino acid-dependent TORC1 recruitment
    complex: true
    group: RAG
    complex_term: {id: GO:1990131, label: Gtr1-Gtr2 GTPase complex}
    function: {id: GO:0003924, label: GTPase activity}
  - id: tsc_complex
    label: TSC1-TSC2 complex
    role: GTPase-activating protein for Rheb
    complex: true
    group: TSC1-2C
    complex_term: {id: GO:0033596, label: TSC1-TSC2 complex}
    unit_functions:
      gig: {id: GO:0005096, label: GTPase activator activity}
    roles:
      gig: TSC2 ortholog, GAP subunit
      Tsc1: TSC1 ortholog, stabilizing subunit
  - id: rheb
    label: Rheb
    role: direct TORC1 activator
    genes: [Rheb]
    function: {id: GO:0003924, label: GTPase activity}
connections:
  - {source: gator2, target: gator1, connection_type: NEGATIVELY_REGULATES, description: GATOR2 inhibits GATOR1.}
  - {source: gator1, target: rag_gtpases, connection_type: NEGATIVELY_REGULATES, description: GATOR1 stimulates GTP hydrolysis by RagA-B.}
  - {source: ragulator, target: rag_gtpases, connection_type: POSITIVELY_REGULATES, description: Ragulator anchors the Rag heterodimer at the lysosome.}
  - {source: tsc_complex, target: rheb, connection_type: NEGATIVELY_REGULATES, description: TSC2/Gigas stimulates GTP hydrolysis by Rheb.}
notes: >-
  Boundary. TORC1 itself is modelled in dmel_tor_complexes; this module holds
  the upstream regulators that act on the Rag and Rheb GTPases. Rheb is not a
  member of these FlyBase groups and is added as the textbook substrate of the
  TSC complex and direct activator of TORC1. The GATOR1 GAP activity and the
  Ragulator structure are best characterized in mammalian and yeast orthologs.