id: MODULE:mtor_complex_signaling title: mTOR complex signaling — mTORC1 (MTOR-RPTOR-MLST8, PRAS40, DEPTOR) and mTORC2 (MTOR-RICTOR-MAPKAP1-MLST8, PRR5/PRR5L) kinases, RHEB activation on the lysosome under TSC control, and amino acid sensing through Rag-Ragulator, GATOR1, GATOR2, FLCN-FNIP, Sestrin2, CASTOR1 and SAMTOR description: >- The serine/threonine kinase mTOR acts in two multiprotein complexes. mTOR complex 1 (mTORC1) contains mTOR, the substrate-recruiting scaffold raptor (RPTOR) and mLST8, and is held in check by two inhibitory subunits, PRAS40 (AKT1S1) and DEPTOR. mTOR complex 2 (mTORC2) contains mTOR, mLST8, the scaffold rictor (RICTOR), mSIN1 (MAPKAP1) and one of the Protor proteins (PRR5 or PRR5L), and DEPTOR also binds and inhibits it. mTORC1 is the growth controller: it phosphorylates S6K1 and S6K2, 4E-BP1, ULK1, TFEB and lipin-1, promoting translation, ribosome biogenesis and lipid synthesis and suppressing autophagy and lysosome biogenesis. mTORC2 phosphorylates the hydrophobic motifs of AGC kinases, most notably AKT on Ser473, SGK1 and protein kinase C, and so feeds into PI3K-AKT signalling and cytoskeletal control. mTORC1 is activated on the cytosolic face of lysosomes only when two inputs coincide. Growth factor and energy signals act through the small GTPase RHEB, which binds mTOR and allosterically activates the kinase; the TSC1-TSC2-TBC1D7 complex is the GTPase-activating protein that turns RHEB off, and AKT and AMPK act on it in opposite directions. Amino acid sufficiency acts through the heterodimeric Rag GTPases (RagA or RagB with RagC or RagD), which are anchored to the lysosome by the pentameric Ragulator complex (LAMTOR1-5) and, in the RagA/B-GTP and RagC/D-GDP state, bind raptor and recruit mTORC1 to the lysosomal surface where RHEB resides. The nucleotide state of the Rags is set by GATOR1 (DEPDC5, NPRL2, NPRL3), a GTPase-activating protein for RagA/B that inhibits the pathway; by GATOR2 (MIOS, WDR24, WDR59, SEH1L, SEC13), which inhibits GATOR1; and by the folliculin-FNIP complex, a GTPase-activating protein for RagC/D that is needed for mTORC1 activation and especially for TFEB phosphorylation. Cytosolic sensors connect specific amino acids to GATOR: Sestrin2 binds GATOR2 until leucine binds Sestrin2, CASTOR1 binds GATOR2 until arginine binds CASTOR1, and SAMTOR binds GATOR1 until S-adenosylmethionine binds SAMTOR. Folding and assembly of mTOR into both complexes depends on the TEL2-TTI1-TTI2 co-chaperone complex. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000180 title: mTOR signaling pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its interactive diagram, which draws the mTORC1 and mTORC2 complexes; Akt1s1 negatively affecting mTORC1; Rheb activating mTORC1 and Tsc2 inhibiting Rheb; the Rrag members activating mTORC1 under positive control of the Ragulator complex and Flcn-Fnip and negative control of the Gator1 complex; Gator2 inhibiting Gator1 and itself inhibited by Sesn2, Gatsl3 (CASTOR1) and Gatsl2 (CASTOR2), with leucine and arginine relieving those inhibitions; rapamycin with Fkbp1a inhibiting mTORC1; and outputs to Rps6kb1, Eif4ebp1, autophagy, Nfe2l2 signalling and, for mTORC2, the PI3K-Akt pathway and cytoskeletal rearrangements. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000180.yaml). - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000180.yaml title: RGD PW:0000180 record (cached pathway text, diagram and gene links) statement: >- The RGD record text names the two complexes and their composition, which the first two parts of the module follow. supporting_text: >- The highly conserved Ser/Thr mTOR kinase is found in two distinct complexes: the rapamycin-sensitive mTORC1 and the largely rapamycin-insensitive mTORC2. - source_id: GO:0031929 title: TOR signaling statement: >- The GO process mapped to PW:0000180 (skos:relatedMatch from the PW definition xref, recorded in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml) and the module's process concept. Its two children, TORC1 signaling (GO:0038202) and TORC2 signaling (GO:0038203), are used on the two complex nodes. - source_id: gomodel:646ff70100000391 title: Canonical mTORC1 signaling (Human) statement: >- The reference human GO-CAM for the lysosomal mTORC1 core: Ragulator guanyl-nucleotide exchange factor activity and LAMTOR1 protein-membrane adaptor activity, RRAGA and RRAGC protein-membrane adaptor activity, RHEB protein serine/threonine kinase activator activity, RPTOR enzyme-substrate adaptor activity and MTOR protein serine/threonine kinase activity, all on the lysosomal membrane, with S6K1/S6K2 and 4E-BP1 downstream. - source_id: gomodel:66e382fb00001412 title: mTORC2 signaling (Human). statement: >- The reference human GO-CAM for mTORC2: MTOR protein serine/threonine kinase activity with RICTOR and MAPKAP1 enzyme-substrate adaptor activity and MLST8 protein-macromolecule adaptor activity at the plasma membrane, acting on AKT1. - source_id: gomodel:6482692800001029 title: Activation of the canonical mTORC1 signaling by GATOR2, which inactivates GATOR1 in response to abundant amino acids (Human) statement: >- The best GO-CAM lead recorded for PW:0000180 in the RGD seed file (overlap 10 genes), checked and relevant: it models WDR24 ubiquitin protein ligase activity acting on the GATOR1 GAP (NPRL2 GTPase activator activity, DEPDC5 small GTPase binding) upstream of the Rag heterodimer, RHEB and mTORC1. - source_id: PMID:15467718 title: Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. statement: >- Establishes the two-complex organisation of mammalian TOR that the module's first two parts follow. supporting_text: >- Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth. - source_id: PMID:20381137 title: Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. statement: >- Establishes lysosomal recruitment by Rag-Ragulator as the amino acid step, and that it works by bringing mTORC1 to RHEB rather than by bypassing RHEB, which is why the module requires both the RHEB part and the amino acid sensing part. supporting_text: >- Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000180 (mTOR signaling pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. RGD curates 43 human genes to PW:0000180 (AKT1S1 CASTOR1 CASTOR2 CXCL8 DEPDC5 DEPTOR EIF4EBP1 FKBP1A FLCN FNIP1 FNIP2 LAMTOR1 LAMTOR2 LAMTOR3 LAMTOR4 LAMTOR5 LPIN1 MAPKAP1 MIOS MLST8 MTOR NPRL2 NPRL3 PRR5 PRR5L RHEB RICTOR RPS6KB1 RPS6KB2 RPTOR RRAGA RRAGB RRAGC RRAGD SESN2 SLC7A5 TBC1D7 TELO2 TSC1 TSC2 TTI1 WDR24 WDR59). Thirty-four are modelled here as participants; TSC1 and TSC2 are covered by module_ref to the TSC relay of ampk_energy_sensing; EIF4EBP1, RPS6KB1, RPS6KB2 and LPIN1 are recorded as kinase targets, not participants; CXCL8, FKBP1A and SLC7A5 are excluded (reasons below). Three participants are added although RGD does not list them: SEH1L and SEC13, because they are two of the five subunits of the GATOR2 complex RGD draws and GO:0061700 is the complex term used, and SAMTOR, the S-adenosylmethionine sensor that acts on GATOR1 alongside the leucine and arginine sensors that RGD draws, with a primary paper and a human GO-CAM. The only PW id used as an evidence source is PW:0000180. The other PW ids the RGD diagram links to (translation, Raf/Mek/Erk, insulin signaling, PI3K-Akt, autophagy, NRF2, AMPK, translation initiation and ribosome biogenesis pathways) are other diagrams; the PI3K-Akt and AMPK ones are realised here only through module_ref to existing modules. The mapped GO process GO:0031929 TOR signaling is the module concept; its children TORC1 signaling and TORC2 signaling sit on the complex nodes. Boundary decisions. (1) Relationship to pi3k_akt_mtor. That module models the growth factor axis and has a coarse mTORC1 activation step (an unnamed mTORC1 complex with protein serine/threonine kinase activity). This module is the decomposition of the mTOR complexes themselves and their non-AKT inputs, so the PI3K-AKT input is included by module_ref to pi3k_akt_mtor#akt_activation and is not re-modelled; PI3K, PDK1, PTEN and the AKT effector tier stay in that module. Its mtorc1_activation step is not referenced, because this module's mtorc1 node is the fuller model of the same complex; a follow-up could make that step a module_ref to mtor_complex_signaling#mtorc1 (not done here, since this change touches only this file). (2) TSC. The TSC1-TSC2 complex, with TSC2 GTPase activator activity on RHEB, is already modelled in ampk_energy_sensing#ampk_tsc_relay and is included by module_ref, not duplicated. TBC1D7, which RGD lists and the referenced step lacks, is modelled as a separate optional part with a POSITIVELY_REGULATES connection to the TSC part; it would sit better as a third unit of that TSC complex in the AMPK module. The TSC, AKT and AMPK parts are optional because they regulate rather than perform the activation of mTORC1; loss of TSC gives constitutive activity. The AMPK heterotrimer is referenced (ampk_energy_sensing#ampk_heterotrimer) for the direct raptor phosphorylation, and its TSC2 arm is the TSC part. The Raf/Mek/Erk (and RSK) phosphorylation of TSC2 that RGD mentions is not modelled; it is described here only. (3) Substrates are targets, not participants. S6K1, S6K2, 4E-BP1, ULK1, TFEB/TFE3, lipin-1 (mTORC1) and AKT, SGK1 and PKC (mTORC2) are phosphorylated by the complexes and are listed under the kinase function's targets. This follows CLAUDE.md's substrate-versus-participant rule and the GO-CAM convention: in gomodel:646ff70100000391 the S6Ks and 4E-BP1 carry their own activities in translation initiation, downstream of MTOR, not TORC1 signaling. The RGD outputs that are other diagrams (translation initiation, ribosome biogenesis, autophagy, NRF2 via SQSTM1-KEAP1, cytoskeletal rearrangement, the S6K1-IRS1 feedback) are outside the boundary. The S6K-IRS1 feedback in particular is S6K acting on the insulin receptor pathway, not mTOR acting. (4) Excluded RGD genes. FKBP1A (FKBP12) is the intracellular receptor for rapamycin; the FKBP12-rapamycin complex inhibits mTORC1, but that is drug action, and no endogenous role of FKBP12 in mTOR signalling is modelled. SLC7A5 (LAT1) imports leucine; it supplies the signal rather than sensing it, and RGD itself says the lysosomal amino acid transporters that may act as sensors are not shown. CXCL8 appears on the RGD gene list without a role in the record text or diagram, and is treated as a downstream or annotation-propagated association. (5) Amino acid sensing is one root part with eight sub-parts. Ragulator, the Rag heterodimer, GATOR1, GATOR2 and FLCN-FNIP are required (FLCN because RagC/D-GDP is needed for raptor binding); the three sensors are optional, since each relays one amino acid and none is required for the others. KICSTOR (which holds GATOR1 and SAMTOR at the lysosome), SLC38A9 and the v-ATPase are outside the RGD list and are named here only; the v-ATPase-Ragulator link is modelled in gomodel:698e557b00000129. The TTT co-chaperone (TELO2, TTI1) is an optional assembly part: it is required for mTOR stability but also serves the other PIKKs, so it is not specific to this pathway. Molecular functions follow experimental GOA rows (QuickGO, checked November 2026) and the human GO-CAMs, and gene-review core functions where reviews exist (AKT1S1, DEPDC5, FLCN, FNIP1). Choices needing comment: (a) Ragulator. All five LAMTOR subunits carry contributes_to guanyl-nucleotide exchange factor activity GO:0005085 (IDA, PMID:22980980 and one later paper), and the mTORC1 GO-CAMs type the complex that way. The module instead gives the complex protein-membrane adaptor activity GO:0043495 (LAMTOR1 IDA), the anchoring role established by PMID:20381137, because lysosomal anchoring of the Rag heterodimer is the step this node represents in the module. This is a modelling choice for that step, not a judgement against the GEF annotation: the GEF rows are not disputed here, only not chosen as the module's step. (b) Rag heterodimer: complex-level protein-membrane adaptor activity, as in the GO-CAMs (RRAGA and RRAGC IDA), with GTPase activity on the two paralogue-pair units. The GO-CAMs type RRAGA as GTP binding and RRAGC as GDP binding to encode the active state; the module records that state in prose. RRAGC also has enzyme-substrate adaptor activity (IDA) for TFEB recruitment, noted in its unit role. (c) Sensors. SESN2 and CASTOR1 are given protein sequestering activity GO:0140311 (IDA, and the activity their GO-CAMs give the GATOR2 interaction); their amino acid binding terms (L-leucine binding, arginine binding, both IDA) are described in the role text. GO's amino acid sensor activity GO:0140785 has no leucine or arginine child (both are requested in proposed_new_terms) and no experimental rows on these proteins, so it is not used. CASTOR1 also carries molecular sensor activity GO:0140299 (IDA). CASTOR2 has NOT arginine binding (IDA) and is given no function. SAMTOR is given S-adenosyl-L-methionine binding GO:1904047 (IDA). (d) mLST8 is given protein serine/threonine kinase activator activity GO:0043539 (IDA, PMID:12718876) in both complexes; the mTORC2 GO-CAM uses protein-macromolecule adaptor activity (also IDA). (e) Units without an experimental molecular function carry a role statement and no GO id: PRR5/PRR5L (protein kinase regulator activity IBA only), NPRL3, MIOS, WDR59 (signaling adaptor activity IBA only), SEH1L, SEC13, LAMTOR2-5 (only the contributes_to GEF and adaptor rows), TBC1D7 (see its part) and CASTOR2. No function is authored that is not backed by an experimental GOA row or a gene-review core function. Process terms. Following the GO-CAM convention, only the kinase complexes carry TORC1 signaling GO:0038202 and TORC2 signaling GO:0038203; activators (RHEB, Rags, Ragulator, GATOR2, FLCN-FNIP) carry positive regulation of TORC1 signaling GO:1904263, and inhibitors (GATOR1, Sestrin2, CASTOR1/2, TBC1D7's TSC complex) negative regulation GO:1904262, which is how GOA annotates them (e.g. SESN2, CASTOR1, CASTOR2 GO:1904262 IDA/IMP; FLCN GO:1904263 IDA). SAMTOR is given the neutral regulation of TORC1 signaling GO:1903432 (IDA), see below. No NEW annotations are implied by the module. GO-CAM coverage. Human models were checked in gocams/index.tsv: the canonical mTORC1 model gomodel:646ff70100000391 grounds MTOR, RPTOR, RHEB, RRAGA, RRAGC, LAMTOR1 and Ragulator; the mTORC2 model gomodel:66e382fb00001412 grounds MTOR, RICTOR, MAPKAP1 and MLST8; the RGD seed's best lead gomodel:6482692800001029 (GATOR2 inactivating GATOR1) grounds WDR24, NPRL2 and DEPDC5; separate models ground AKT1S1, DEPTOR, SESN2, CASTOR1, SAMTOR, FLCN and FNIP1 and the ULK1 and TFEB substrate branches. No production GO-CAM contains PRR5, PRR5L, RRAGB, RRAGD, LAMTOR2-5 as individual genes, NPRL3, MIOS, WDR59, SEH1L, SEC13, CASTOR2, FNIP2, TELO2, TTI1 or TBC1D7. Possible upstream issues noticed. SAMTOR carries positive regulation of TORC1 signaling GO:1904263 by IDA (PMID:29123071), although that paper shows SAMTOR inhibits mTORC1 and is relieved by SAM; the positive sign fits SAM binding relieving inhibition (as the GO-CAM encodes it) but reads oddly as a gene-level annotation. SESN2 carries both enables and NOT|enables for GO:0032542 sulfiredoxin activity (IDA, different papers). TBC1D7's GTPase activator activity GO:0005096 IDA comes from PMID:17646400, a Rab GTPase screen in cilium formation; it may be read as Rheb GAP activity, which PMID:22795129 assigns to the TSC-TBC complex rather than to TBC1D7 alone. The Ragulator GEF typing discussed above is a modelling difference, not an error. Gene reviews exist for AKT1S1, DEPDC5, FLCN, FNIP1, LPIN1 and AKT1; the other participants have none. PANTHER family ids and PTNs are deliberately not asserted. proposed_new_terms: - proposed_name: L-leucine sensor activity proposed_definition: >- An amino acid sensor activity in which binding of L-leucine at physiological concentrations changes the protein's interaction with, or activity toward, a signalling partner, conveying intracellular leucine availability. justification: >- GO:0140785 amino acid sensor activity has no leucine child. Sestrin2 is therefore given protein sequestering activity GO:0140311 in this module, with its leucine binding described only in its role text. proposed_parent: id: GO:0140785 label: amino acid sensor activity supported_by: - reference_id: PMID:26449471 supporting_text: We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. - proposed_name: L-arginine sensor activity proposed_definition: >- An amino acid sensor activity in which binding of L-arginine at physiological concentrations changes the protein's interaction with, or activity toward, a signalling partner, conveying intracellular arginine availability. justification: >- GO:0140785 amino acid sensor activity has no arginine child. CASTOR1 is therefore given protein sequestering activity GO:0140311 in this module, with its arginine binding described only in its role text. proposed_parent: id: GO:0140785 label: amino acid sensor activity supported_by: - reference_id: PMID:26972053 supporting_text: Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. module: id: mtor_complex_signaling label: mTOR complexes and their lysosomal and amino acid inputs module_type: SIGNALING_PATHWAY description: >- mTORC1 and mTORC2 kinase complexes, RHEB activation of mTORC1 under TSC control, and the Rag-Ragulator amino acid sensing machinery with its GATOR1, GATOR2, FLCN-FNIP and amino acid sensor regulators. Growth factor (PI3K-AKT) and energy (AMPK) inputs are included by reference to their own modules. concepts: - preferred_term: TOR signaling term: id: GO:0031929 label: TOR signaling context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: mTORC1 growth-control kinase node: id: mtorc1 label: mTOR complex 1 (mTORC1) module_type: PROTEIN_COMPLEX description: >- The rapamycin-sensitive mTOR complex. Raptor binds TOS motifs in substrates and presents them to the mTOR kinase domain; mLST8 binds the kinase domain and is needed for activity; PRAS40 and DEPTOR are inhibitory subunits whose release (PRAS40 after phosphorylation by AKT and by mTORC1 itself, DEPTOR after mTOR-primed SCF(betaTrCP) degradation) increases activity. Active mTORC1 on the lysosome phosphorylates its substrates, which are recorded as targets of the kinase annoton and not as parts. concepts: - preferred_term: TORC1 signaling term: id: GO:0038202 label: TORC1 signaling - preferred_term: TORC1 complex term: id: GO:0031931 label: TORC1 complex annotons: - id: mtorc1_kinase label: mTORC1 protein serine/threonine kinase participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TORC1 complex term: id: GO:0031931 label: TORC1 complex active_units: - id: mtorc1_mtor label: mTOR catalytic subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MTOR term: id: UniProtKB:P42345 label: Serine/threonine-protein kinase mTOR role: PIKK-family catalytic subunit shared with mTORC2. function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity - id: mtorc1_rptor label: raptor substrate-recruiting scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RPTOR term: id: UniProtKB:Q8N122 label: Regulatory-associated protein of mTOR role: >- Defining mTORC1 subunit; binds TOS motifs of S6K1 and 4E-BP1 and is the docking site for the Rag heterodimer and for PRAS40. function: preferred_term: enzyme-substrate adaptor activity term: id: GO:0140767 label: enzyme-substrate adaptor activity - id: mtorc1_mlst8 label: mLST8 kinase-domain-binding subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MLST8 term: id: UniProtKB:Q9BVC4 label: Target of rapamycin complex subunit LST8 role: Binds the mTOR kinase domain and stimulates kinase activity; shared with mTORC2. function: preferred_term: protein serine/threonine kinase activator activity term: id: GO:0043539 label: protein serine/threonine kinase activator activity - id: mtorc1_akt1s1 label: PRAS40 inhibitory subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKT1S1 term: id: UniProtKB:Q96B36 label: Proline-rich AKT1 substrate 1 role: >- Raptor-bound inhibitor that competes with substrates; relieved when AKT (and mTORC1) phosphorylate it and 14-3-3 binds. function: preferred_term: protein serine/threonine kinase inhibitor activity term: id: GO:0030291 label: protein serine/threonine kinase inhibitor activity - id: mtorc1_deptor label: DEPTOR inhibitory subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DEPTOR term: id: UniProtKB:Q8TB45 label: DEP domain-containing mTOR-interacting protein role: mTOR-binding inhibitor of both complexes. function: preferred_term: protein serine/threonine kinase inhibitor activity term: id: GO:0030291 label: protein serine/threonine kinase inhibitor activity function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: S6K1 (RPS6KB1) and S6K2 (RPS6KB2), hydrophobic-motif threonine - preferred_term: 4E-BP1 (EIF4EBP1) - preferred_term: ULK1 (and ATG13) - preferred_term: TFEB and TFE3 (Rag-dependent, RHEB-insensitive substrates) - preferred_term: lipin-1 (LPIN1) - preferred_term: PRAS40 (AKT1S1) and DEPTOR (feedback on its own inhibitors) processes: - preferred_term: TORC1 signaling term: id: GO:0038202 label: TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Integrates RHEB and Rag inputs on the lysosomal surface and phosphorylates the growth, translation, autophagy and lysosome-biogenesis substrates. Unit functions follow experimental GOA rows: MTOR GO:0004674 (IDA/EXP), RPTOR GO:0140767 (IDA), MLST8 GO:0043539 (IDA), AKT1S1 and DEPTOR GO:0030291 (IDA; AKT1S1 core in its gene review). evidence: - source_id: PMID:12150926 statement: Raptor binds mTOR and its substrates and is required for mTOR-catalysed 4E-BP1 phosphorylation. supporting_text: Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo. - source_id: PMID:12718876 statement: mLST8 (GbetaL) binds the mTOR kinase domain and stabilises the raptor-mTOR interaction. supporting_text: a protein named GbetaL that binds to the kinase domain of mTOR and stabilizes the interaction of raptor with mTOR - source_id: PMID:17386266 statement: PRAS40 is a raptor-binding inhibitor of mTORC1 that AKT phosphorylation relieves. supporting_text: Insulin stimulates Akt/PKB-mediated phosphorylation of PRAS40, which prevents its inhibition of mTORC1 in cells and in vitro. - source_id: PMID:19446321 statement: DEPTOR binds mTOR and its loss activates both mTORC1 and mTORC2. supporting_text: Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. - source_id: PMID:19211835 statement: mTORC1 associates with the ULK1-ATG13-FIP200 complex and phosphorylates ULK1 and ATG13, which places ULK1 among the kinase targets. supporting_text: mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. - source_id: PMID:32612235 statement: TFEB is an mTORC1 substrate whose phosphorylation depends on the Rags and on FLCN rather than on RHEB. supporting_text: is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases gocam_associations: - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000530 title: Canonical mTORC1 signaling (Human) description: MTOR protein serine/threonine kinase activity (GO:0004674) in TORC1 signaling on the lysosomal membrane. - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100002533 title: Canonical mTORC1 signaling (Human) description: RPTOR enzyme-substrate adaptor activity (GO:0140767). - model: gomodel:646ff70100004220 activity: gomodel:646ff70100004220/646ff70100004444 title: Inhibition of the canonical mTORC1 signaling by AKT1S1/PRAS40 in absence of insulin (Human) description: AKT1S1 protein serine/threonine kinase inhibitor activity (GO:0030291) on mTORC1. - model: gomodel:648d0dc100000075 activity: gomodel:648d0dc100000075/648d0dc100000252 title: Positive regulation of autophagy via inhibition of MTOR by DEPTOR (Human) description: DEPTOR protein serine/threonine kinase inhibitor activity (GO:0030291) on mTORC1. - model: gomodel:646ff70100002557 activity: gomodel:646ff70100002557/646ff70100002676 title: Negative regulation of autophagy via phosphorylation of ULK1 by canonical mTORC1 signaling (Human) description: MTOR kinase activity with ULK1 as substrate. - model: gomodel:6482692800002614 activity: gomodel:6482692800002614/6482692800002713 title: Non-canonical mTORC1 signaling leading to TFEB and TFE3 phosphorylation and inactivation (Human) description: MTOR kinase activity with TFEB/TFE3 as substrates. - order: 2 role: mTORC2 AGC-kinase hydrophobic-motif kinase node: id: mtorc2 label: mTOR complex 2 (mTORC2) module_type: PROTEIN_COMPLEX description: >- The largely rapamycin-insensitive mTOR complex. Rictor and mSIN1 are its defining subunits and are needed for complex integrity and for substrate recruitment; the mSIN1 PH domain binds phosphoinositides and restrains the kinase until it reaches the membrane. Protor-1/2 (PRR5, PRR5L) are peripheral rictor-binding subunits; PRR5L selectively restrains PKC-delta phosphorylation. mTORC2 phosphorylates the hydrophobic motif of AGC kinases (AKT Ser473, SGK1, PKC), which are recorded as targets, not parts. concepts: - preferred_term: TORC2 signaling term: id: GO:0038203 label: TORC2 signaling - preferred_term: TORC2 complex term: id: GO:0031932 label: TORC2 complex annotons: - id: mtorc2_kinase label: mTORC2 protein serine/threonine kinase participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TORC2 complex term: id: GO:0031932 label: TORC2 complex active_units: - id: mtorc2_mtor label: mTOR catalytic subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MTOR term: id: UniProtKB:P42345 label: Serine/threonine-protein kinase mTOR role: Catalytic subunit shared with mTORC1. function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity - id: mtorc2_rictor label: rictor scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RICTOR term: id: UniProtKB:Q6R327 label: Rapamycin-insensitive companion of mTOR role: Defining mTORC2 subunit; required for complex assembly and AGC-kinase substrate recruitment. function: preferred_term: enzyme-substrate adaptor activity term: id: GO:0140767 label: enzyme-substrate adaptor activity - id: mtorc2_mapkap1 label: mSIN1 scaffold with phosphoinositide-binding PH domain participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MAPKAP1 term: id: UniProtKB:Q9BPZ7 label: Target of rapamycin complex 2 subunit MAPKAP1 role: Essential mTORC2 subunit; recruits substrates and couples the complex to membrane phosphoinositides. function: preferred_term: enzyme-substrate adaptor activity term: id: GO:0140767 label: enzyme-substrate adaptor activity - id: mtorc2_mlst8 label: mLST8 kinase-domain-binding subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MLST8 term: id: UniProtKB:Q9BVC4 label: Target of rapamycin complex subunit LST8 role: Kinase-domain-binding subunit shared with mTORC1. function: preferred_term: protein serine/threonine kinase activator activity term: id: GO:0043539 label: protein serine/threonine kinase activator activity - id: mtorc2_protor label: Protor-1/2 peripheral subunit participant: selector_type: FAMILY family: preferred_term: Protor (PRR5, PRR5L) description: >- Rictor-binding peripheral mTORC2 subunits; a given complex carries one of the two paralogues. representative_members: - preferred_term: PRR5 term: id: UniProtKB:P85299 label: Proline-rich protein 5 - preferred_term: PRR5L term: id: UniProtKB:Q6MZQ0 label: Proline-rich protein 5-like role: >- Peripheral rictor-binding subunit; PRR5L suppresses mTORC2 phosphorylation of PKC-delta but not of AKT. No experimental molecular function is annotated (protein kinase regulator activity is IBA only), so none is asserted. - id: mtorc2_deptor label: DEPTOR inhibitory subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DEPTOR term: id: UniProtKB:Q8TB45 label: DEP domain-containing mTOR-interacting protein role: mTOR-binding inhibitor shared with mTORC1. function: preferred_term: protein serine/threonine kinase inhibitor activity term: id: GO:0030291 label: protein serine/threonine kinase inhibitor activity function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity targets: - preferred_term: AKT1-3, hydrophobic-motif Ser473 (AKT1 numbering) - preferred_term: SGK1 - preferred_term: protein kinase C (PKC-alpha, PKC-delta) processes: - preferred_term: TORC2 signaling term: id: GO:0038203 label: TORC2 signaling locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Hydrophobic-motif kinase for AGC kinases, giving full AKT activation and acting on SGK1 and PKC. Unit functions follow experimental GOA rows and the mTORC2 GO-CAM: RICTOR and MAPKAP1 GO:0140767 (IDA), MLST8 GO:0043539 (IDA), DEPTOR GO:0030291 (IDA). The mTORC2 GO-CAM types MLST8 as protein-macromolecule adaptor activity (GO:0030674, IDA in GOA); the activator term is used here so that both complexes give mLST8 the same role. evidence: - source_id: PMID:15467718 statement: mTORC2 contains mTOR, mLST8 and rictor (mAVO3) but not raptor. supporting_text: mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. - source_id: PMID:17043309 statement: mSIN1 is an essential mTORC2-specific subunit needed for complex formation and kinase activity. supporting_text: Sin1 is an essential component of TORC2 but not of TORC1, and functions similarly to Rictor, the defining member of TORC2, in complex formation and kinase activity. - source_id: PMID:15718470 statement: The rictor-mTOR complex phosphorylates AKT Ser473 directly. supporting_text: The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. - source_id: PMID:15268862 statement: The rictor-mTOR complex controls PKC-alpha phosphorylation and the actin cytoskeleton. supporting_text: We find that the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) and the actin cytoskeleton - source_id: PMID:22609986 statement: PRR5L is an mTORC2 subunit that restrains PKC-delta, but not AKT, hydrophobic-motif phosphorylation. supporting_text: Destabilization of PRR5L, a suppressor of mTORC2-mediated hydrophobic motif phosphorylation of PKC-δ, but not AKT, results in PKC-δ hydrophobic motif phosphorylation and activation. gocam_associations: - model: gomodel:66e382fb00001412 activity: gomodel:66e382fb00001412/66e382fb00001413 title: mTORC2 signaling (Human). description: MTOR protein serine/threonine kinase activity (GO:0004674) in TORC2 signaling at the plasma membrane. - model: gomodel:66e382fb00001412 activity: gomodel:66e382fb00001412/66e382fb00001432 title: mTORC2 signaling (Human). description: RICTOR enzyme-substrate adaptor activity (GO:0140767). - model: gomodel:66e382fb00001412 activity: gomodel:66e382fb00001412/66e382fb00001422 title: mTORC2 signaling (Human). description: MAPKAP1 enzyme-substrate adaptor activity (GO:0140767). - model: gomodel:66e382fb00001412 activity: gomodel:66e382fb00001412/66e382fb00001457 title: mTORC2 signaling (Human). description: MLST8 protein-macromolecule adaptor activity (GO:0030674). - order: 3 role: direct activation of mTORC1 by RHEB on the lysosome node: id: rheb_activation label: RHEB-GTP activation of mTORC1 module_type: REGULATORY_STEP description: >- GTP-bound RHEB on the lysosomal surface binds mTOR away from the active site and allosterically realigns the catalytic residues, accelerating catalysis. RHEB is the point at which growth factor and energy signals, relayed through the TSC complex, converge on mTORC1. mTORC2 is not activated by RHEB. annotons: - id: rheb_kinase_activator label: RHEB mTORC1 activator participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RHEB term: id: UniProtKB:Q15382 label: GTP-binding protein Rheb function: preferred_term: protein serine/threonine kinase activator activity term: id: GO:0043539 label: protein serine/threonine kinase activator activity targets: - preferred_term: mTORC1 (MTOR) processes: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- GO:0043539 is IDA for RHEB and is the activity the human mTORC1 GO-CAMs use. RHEB also carries GTPase activity GO:0003924 (IDA); that intrinsic activity is what the TSC GAP accelerates, but the step RHEB performs in this module is kinase activation. evidence: - source_id: PMID:29236692 statement: RHEB binds mTOR and allosterically activates mTORC1. supporting_text: RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. gocam_associations: - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000496 title: Canonical mTORC1 signaling (Human) description: RHEB protein serine/threonine kinase activator activity (GO:0043539) on the lysosomal membrane. - order: 4 optional: true role: TSC1-TSC2 GTPase-activating complex for RHEB (negative regulator) node: id: tsc_rheb_gap label: TSC1-TSC2 RHEB GAP description: >- Included by reference to the TSC relay step of the AMPK energy-sensing module, which models the TSC1-TSC2 complex with TSC2 GTPase activator activity on RHEB. AKT phosphorylation of TSC2 inhibits it and AMPK phosphorylation activates it. Optional because it restrains rather than performs mTORC1 activation; loss of TSC gives constitutive mTORC1 activity. module_ref: ampk_energy_sensing#ampk_tsc_relay evidence: - source_id: PMID:12172553 statement: AKT phosphorylates and inactivates TSC2, the step by which growth factors relieve TSC inhibition of mTOR. supporting_text: TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. - order: 5 optional: true role: TBC1D7, third core subunit of the TSC complex node: id: tsc_tbc1d7 label: TBC1D7 TSC-complex subunit module_type: PROTEIN_COMPLEX description: >- TBC1D7 is a stable third core subunit of the TSC1-TSC2 complex that binds TSC1 and supports TSC1-TSC2 association and so RHEB-GAP activity. It is modelled here because the referenced TSC step does not include it. annotons: - id: tbc1d7_subunit label: TBC1D7 stabilising subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TBC1D7 term: id: UniProtKB:Q9P0N9 label: TBC1 domain family member 7 locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Stabilises the TSC1-TSC2 association. No molecular function is asserted: the GTPase activator activity row for TBC1D7 (IDA) comes from a Rab GTPase screen in cilium formation, not from RHEB, and TSC1-TSC2 complex binding is IBA only. evidence: - source_id: PMID:22795129 statement: TBC1D7 is a third core TSC subunit; its knockdown weakens TSC1-TSC2 association and Rheb-GAP activity. supporting_text: TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. - order: 6 role: amino acid sensing and lysosomal recruitment of mTORC1 node: id: amino_acid_sensing label: Rag-Ragulator amino acid sensing module_type: SIGNALING_PATHWAY description: >- Amino acids act on mTORC1 by changing the nucleotide state of the Rag GTPase heterodimer, which Ragulator anchors to the lysosome. RagA/B-GTP with RagC/D-GDP binds raptor and brings mTORC1 to the lysosomal surface, where RHEB activates it. The Rags do not activate the kinase themselves. concepts: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling - preferred_term: cellular response to amino acid stimulus term: id: GO:0071230 label: cellular response to amino acid stimulus parts: - order: 1 role: lysosomal anchor for the Rag heterodimer node: id: ragulator label: Ragulator (LAMTOR1-5) module_type: PROTEIN_COMPLEX annotons: - id: ragulator_anchor label: Ragulator lysosomal membrane anchor participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Ragulator complex term: id: GO:0071986 label: Ragulator complex active_units: - id: lamtor1 label: LAMTOR1 lipidated membrane scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMTOR1 term: id: UniProtKB:Q6IAA8 label: Ragulator complex protein LAMTOR1 role: >- N-terminally myristoylated and palmitoylated belt that wraps the two roadblock heterodimers and tethers the complex to the lysosomal membrane. function: preferred_term: protein-membrane adaptor activity term: id: GO:0043495 label: protein-membrane adaptor activity - id: lamtor2 label: LAMTOR2 roadblock subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMTOR2 term: id: UniProtKB:Q9Y2Q5 label: Ragulator complex protein LAMTOR2 role: Roadblock-domain subunit paired with LAMTOR3. - id: lamtor3 label: LAMTOR3 roadblock subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMTOR3 term: id: UniProtKB:Q9UHA4 label: Ragulator complex protein LAMTOR3 role: Roadblock-domain subunit paired with LAMTOR2. - id: lamtor4 label: LAMTOR4 roadblock subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMTOR4 term: id: UniProtKB:Q0VGL1 label: Ragulator complex protein LAMTOR4 role: Roadblock-domain subunit paired with LAMTOR5. - id: lamtor5 label: LAMTOR5 roadblock subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMTOR5 term: id: UniProtKB:O43504 label: Ragulator complex protein LAMTOR5 role: Roadblock-domain subunit paired with LAMTOR4. function: preferred_term: protein-membrane adaptor activity term: id: GO:0043495 label: protein-membrane adaptor activity targets: - preferred_term: Rag GTPase heterodimer processes: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Anchors the Rags to the lysosome. LAMTOR1 GO:0043495 is IDA. All five subunits also carry contributes_to guanyl-nucleotide exchange factor activity (GO:0005085, IDA), and the human mTORC1 GO-CAMs type the complex with that activity; see notes for why the anchor role is used here. evidence: - source_id: PMID:20381137 statement: Ragulator binds the Rags, recruits them to lysosomes and is required for mTORC1 activation. supporting_text: A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. - source_id: PMID:22980980 statement: The five-subunit Ragulator shows nucleotide exchange activity toward RagA and RagB in vitro. supporting_text: The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. gocam_associations: - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000402 title: Canonical mTORC1 signaling (Human) description: LAMTOR1 protein-membrane adaptor activity (GO:0043495). - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000392 title: Canonical mTORC1 signaling (Human) description: Ragulator complex guanyl-nucleotide exchange factor activity (GO:0005085). - order: 2 role: amino acid-regulated recruitment of mTORC1 to the lysosome node: id: rag_heterodimer label: Rag GTPase heterodimer (RagA/B with RagC/D) module_type: PROTEIN_COMPLEX annotons: - id: rag_mtorc1_recruitment label: Rag heterodimer recruitment of mTORC1 participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Rag GTPase heterodimer term: id: GO:1990131 label: Gtr1-Gtr2 GTPase complex description: >- Obligate heterodimer of one RagA/B and one RagC/D subunit; the active state is RagA/B-GTP with RagC/D-GDP. active_units: - id: rag_ab label: RagA or RagB participant: selector_type: FAMILY family: preferred_term: RagA/RagB representative_members: - preferred_term: RRAGA term: id: UniProtKB:Q7L523 label: Ras-related GTP-binding protein A - preferred_term: RRAGB term: id: UniProtKB:Q5VZM2 label: Ras-related GTP-binding protein B role: GTP-loaded in amino acid sufficiency; the GATOR1 substrate. function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity - id: rag_cd label: RagC or RagD participant: selector_type: FAMILY family: preferred_term: RagC/RagD representative_members: - preferred_term: RRAGC term: id: UniProtKB:Q9HB90 label: Ras-related GTP-binding protein C - preferred_term: RRAGD term: id: UniProtKB:Q9NQL2 label: Ras-related GTP-binding protein D role: >- GDP-loaded in the active state; the FLCN-FNIP substrate; also recruits TFEB to mTORC1. function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity function: preferred_term: protein-membrane adaptor activity term: id: GO:0043495 label: protein-membrane adaptor activity targets: - preferred_term: mTORC1 (via RPTOR) processes: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Binds raptor and tethers mTORC1 to the Ragulator-anchored lysosomal pool. GO:0043495 is IDA for RRAGA and RRAGC and is the activity the mTORC1 GO-CAMs give both. GTPase activity GO:0003924 is IDA/EXP for RRAGA, RRAGB and RRAGC and IMP for RRAGD. evidence: - source_id: PMID:18497260 statement: The Rags bind mTORC1 in an amino acid-dependent way and act by relocalising it, not by stimulating the kinase. supporting_text: The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb. - source_id: PMID:31601764 statement: Structure of RagA/RagC bound to raptor in mTORC1, showing the nucleotide-state requirement. supporting_text: Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. gocam_associations: - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000463 title: Canonical mTORC1 signaling (Human) description: RRAGA protein-membrane adaptor activity (GO:0043495). - model: gomodel:646ff70100000391 activity: gomodel:646ff70100000391/646ff70100000478 title: Canonical mTORC1 signaling (Human) description: RRAGC protein-membrane adaptor activity (GO:0043495). - order: 3 role: GTPase-activating protein for RagA/B (negative regulator) node: id: gator1 label: GATOR1 (DEPDC5, NPRL2, NPRL3) module_type: PROTEIN_COMPLEX annotons: - id: gator1_rag_gap label: GATOR1 RagA/B GAP participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: GATOR1 complex term: id: GO:1990130 label: GATOR1 complex active_units: - id: gator1_nprl2 label: NPRL2 catalytic-arginine subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NPRL2 term: id: UniProtKB:Q8WTW4 label: GATOR1 complex protein NPRL2 role: Provides the arginine finger for GTP hydrolysis by RagA/B. function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity - id: gator1_depdc5 label: DEPDC5 Rag-binding subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DEPDC5 term: id: UniProtKB:O75140 label: GATOR1 complex protein DEPDC5 role: Largest subunit; binds the Rag heterodimer in the inhibitory mode. function: preferred_term: small GTPase binding term: id: GO:0031267 label: small GTPase binding - id: gator1_nprl3 label: NPRL3 subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NPRL3 term: id: UniProtKB:Q12980 label: GATOR1 complex protein NPRL3 role: Longin-domain heterodimer partner of NPRL2; no experimental molecular function is annotated. function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: RagA and RagB processes: - preferred_term: negative regulation of TORC1 signaling term: id: GO:1904262 label: negative regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Switches RagA/B off when amino acids are scarce. NPRL2 GO:0005096 is IDA; DEPDC5 GO:0031267 is IDA and its gene-review core function. GATOR1 is held at the lysosome by KICSTOR, which RGD does not list and is not modelled. evidence: - source_id: PMID:23723238 statement: GATOR1 (DEPDC5, NPRL2, NPRL3) is a GAP for RagA/B and GATOR2 acts upstream of it. supporting_text: GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. - source_id: PMID:35338845 statement: Cryo-EM of GATOR1 with Rag-Ragulator shows separate inhibitory and GAP binding modes. supporting_text: One negative regulator, GATOR1, is a GTPase activating protein (GAP) for RagA. gocam_associations: - model: gomodel:6482692800001029 activity: gomodel:6482692800001029/6482692800001184 title: Activation of the canonical mTORC1 signaling by GATOR2, which inactivates GATOR1 in response to abundant amino acids (Human) description: NPRL2 GTPase activator activity (GO:0005096) in negative regulation of TORC1 signaling. - model: gomodel:6482692800001029 activity: gomodel:6482692800001029/6482692800001203 title: Activation of the canonical mTORC1 signaling by GATOR2, which inactivates GATOR1 in response to abundant amino acids (Human) description: DEPDC5 small GTPase binding (GO:0031267). - order: 4 role: inhibitor of GATOR1 (positive regulator) node: id: gator2 label: GATOR2 (MIOS, WDR24, WDR59, SEH1L, SEC13) module_type: PROTEIN_COMPLEX annotons: - id: gator2_gator1_inhibition label: GATOR2 inhibition of GATOR1 participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: GATOR2 complex term: id: GO:0061700 label: GATOR2 complex active_units: - id: gator2_wdr24 label: WDR24 RING E3 subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: WDR24 term: id: UniProtKB:Q96S15 label: GATOR2 complex protein WDR24 role: >- RING-domain E3 that, with UBE2D3, ubiquitinates NPRL2 once leucine has released Sestrin2; AMPK phosphorylation of WDR24 suppresses it. function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity - id: gator2_mios label: MIOS RING hub subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MIOS term: id: UniProtKB:Q9NXC5 label: GATOR2 complex protein MIOS role: RING-domain hub that holds WDR24 and WDR59 together; no experimental molecular function is annotated. - id: gator2_wdr59 label: WDR59 RING subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: WDR59 term: id: UniProtKB:Q6PJI9 label: GATOR2 complex protein WDR59 role: RING-domain subunit; signaling adaptor activity is IBA only, so none is asserted. - id: gator2_seh1l label: SEH1L structural subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SEH1L term: id: UniProtKB:Q96EE3 label: Nucleoporin SEH1 role: Beta-propeller subunit shared with the nuclear pore Nup107-160 subcomplex. - id: gator2_sec13 label: SEC13 structural subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SEC13 term: id: UniProtKB:P55735 label: Protein SEC13 homolog role: Beta-propeller subunit shared with COPII and the nuclear pore. function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity targets: - preferred_term: NPRL2 (GATOR1) processes: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Inhibits GATOR1 when amino acids are abundant. WDR24 GO:0061630 is IDA from two papers and is the activity the GATOR2 GO-CAM uses; the other subunits have no experimental molecular function and carry role statements only. evidence: - source_id: PMID:23723238 statement: GATOR2 subunits are required for mTORC1 signalling and act by negatively regulating DEPDC5. supporting_text: inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 - source_id: PMID:36528027 statement: Leucine-released WDR24 ubiquitinates NPRL2, which contributes to GATOR1 inactivation. supporting_text: leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. gocam_associations: - model: gomodel:6482692800001029 activity: gomodel:6482692800001029/6482692800001232 title: Activation of the canonical mTORC1 signaling by GATOR2, which inactivates GATOR1 in response to abundant amino acids (Human) description: WDR24 ubiquitin protein ligase activity (GO:0061630) acting on GATOR1. - order: 5 role: GTPase-activating protein for RagC/D (positive regulator) node: id: flcn_fnip label: Folliculin-FNIP RagC/D GAP module_type: PROTEIN_COMPLEX annotons: - id: flcn_fnip_rag_gap label: FLCN-FNIP RagC/D GAP participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: FNIP-folliculin RagC/D GAP term: id: GO:1990877 label: FNIP-folliculin RagC/D GAP active_units: - id: flcn_unit label: folliculin GAP subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FLCN term: id: UniProtKB:Q8NFG4 label: Folliculin role: Supplies the catalytic arginine for GTP hydrolysis by RagC/D. function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity - id: fnip_unit label: FNIP1 or FNIP2 partner subunit participant: selector_type: FAMILY family: preferred_term: FNIP1/FNIP2 description: Folliculin-interacting proteins; a complex carries one of the two paralogues. representative_members: - preferred_term: FNIP1 term: id: UniProtKB:Q8TF40 label: Folliculin-interacting protein 1 - preferred_term: FNIP2 term: id: UniProtKB:Q9P278 label: Folliculin-interacting protein 2 role: Binds FLCN through its longin and DENN domains and completes the GAP. function: preferred_term: GTPase activating protein binding term: id: GO:0032794 label: GTPase activating protein binding function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity targets: - preferred_term: RagC and RagD processes: - preferred_term: positive regulation of TORC1 signaling term: id: GO:1904263 label: positive regulation of TORC1 signaling locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: >- Converts RagC/D to the GDP state needed for raptor binding; required strictly for TFEB/TFE3 phosphorylation and partly for S6K and 4E-BP1. FLCN GO:0005096 is IDA in six papers and its gene-review core function; FNIP1 GO:0032794 is the core function of the FNIP1 review in the FLCN-FNIP complex. evidence: - source_id: PMID:24095279 statement: FLCN with FNIP1/2 is a GAP for RagC/D but not RagA/B. supporting_text: We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. - source_id: PMID:31672913 statement: Structure of the lysosomal FLCN-FNIP2-Rag-Ragulator complex in the starved state. supporting_text: The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. gocam_associations: - model: gomodel:6482692800002614 activity: gomodel:6482692800002614/6482692800002838 title: Non-canonical mTORC1 signaling leading to TFEB and TFE3 phosphorylation and inactivation (Human) description: FLCN GTPase activator activity (GO:0005096) on the lysosomal membrane. - model: gomodel:648d0dc100001272 activity: gomodel:648d0dc100001272/648d0dc100001513 title: Inhibition of the non-canonical mTORC1 signaling following phosphorylation of FNIP1 by AMPK in response to mitochondrial stress (Human). description: FNIP1 enzyme activator activity (GO:0008047) supporting FLCN. - order: 6 optional: true role: leucine sensor acting on GATOR2 node: id: sestrin2_leucine_sensor label: Sestrin2 leucine sensor module_type: REGULATORY_STEP annotons: - id: sesn2_gator2_sequestration label: Sestrin2 sequestration of GATOR2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SESN2 term: id: UniProtKB:P58004 label: Sestrin-2 function: preferred_term: protein sequestering activity term: id: GO:0140311 label: protein sequestering activity targets: - preferred_term: GATOR2 processes: - preferred_term: negative regulation of TORC1 signaling term: id: GO:1904262 label: negative regulation of TORC1 signaling locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Leucine-free Sestrin2 binds and inhibits GATOR2; leucine binding (L-leucine binding GO:0070728, IDA) releases it. GO:0140311 is IDA and is the activity the Sestrin2 GO-CAMs use for the GATOR2 interaction. evidence: - source_id: PMID:26449471 statement: Leucine binds Sestrin2 at the concentration that half-maximally activates mTORC1 and disrupts the Sestrin2-GATOR2 interaction. supporting_text: We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. - source_id: PMID:26586190 statement: Crystal structure of Sestrin2 bound to leucine. supporting_text: Sestrin2 interacts with GATOR2 and is a leucine sensor. gocam_associations: - model: gomodel:6482692800002068 activity: gomodel:6482692800002068/6482692800002070 title: Activation of the mTORC1 signaling by SESN2 in response to abundant leucine (Human). description: SESN2 protein sequestering activity (GO:0140311). - model: gomodel:6482692800002068 activity: gomodel:6482692800002068/6482692800002109 title: Activation of the mTORC1 signaling by SESN2 in response to abundant leucine (Human). description: SESN2 L-leucine binding (GO:0070728). - order: 7 optional: true role: arginine sensor acting on GATOR2 node: id: castor_arginine_sensor label: CASTOR1/CASTOR2 arginine sensor module_type: REGULATORY_STEP annotons: - id: castor1_gator2_sequestration label: CASTOR1 arginine sensor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CASTOR1 term: id: UniProtKB:Q8WTX7 label: Cytosolic arginine sensor for mTORC1 subunit 1 function: preferred_term: protein sequestering activity term: id: GO:0140311 label: protein sequestering activity targets: - preferred_term: GATOR2 processes: - preferred_term: negative regulation of TORC1 signaling term: id: GO:1904262 label: negative regulation of TORC1 signaling locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Arginine-free CASTOR1 homodimers or CASTOR1-CASTOR2 heterodimers bind and inhibit GATOR2; arginine binding (GO:0034618, IDA) releases them. GO:0140311 (IDA) is the activity the CASTOR1 GO-CAMs use for the GATOR2 interaction. evidence: - source_id: PMID:26972053 statement: Arginine binds CASTOR1 and disrupts the CASTOR1-GATOR2 complex; CASTOR1 heterodimerises with CASTOR2. supporting_text: Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. gocam_associations: - model: gomodel:6482692800002004 activity: gomodel:6482692800002004/6482692800002023 title: Activation of the mTORC1 signaling by CASTOR1 in response to abundant arginine (Human) description: CASTOR1 protein sequestering activity (GO:0140311). - model: gomodel:6482692800002004 activity: gomodel:6482692800002004/6482692800002016 title: Activation of the mTORC1 signaling by CASTOR1 in response to abundant arginine (Human) description: CASTOR1 arginine binding (GO:0034618). - id: castor2_partner label: CASTOR2 heterodimer partner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CASTOR2 term: id: UniProtKB:A6NHX0 label: Cytosolic arginine sensor for mTORC1 subunit 2 processes: - preferred_term: negative regulation of TORC1 signaling term: id: GO:1904262 label: negative regulation of TORC1 signaling role_description: >- Heterodimerises with CASTOR1 and binds GATOR2 but does not bind arginine (NOT arginine binding, IDA), so no sensor function is asserted for it. evidence: - source_id: PMID:26972053 statement: CASTOR1 forms homodimers and heterodimers with CASTOR2. supporting_text: CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. - order: 8 optional: true role: S-adenosylmethionine sensor acting on GATOR1 node: id: samtor_sam_sensor label: SAMTOR S-adenosylmethionine sensor module_type: REGULATORY_STEP annotons: - id: samtor_sam_binding label: SAMTOR S-adenosylmethionine sensor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SAMTOR term: id: UniProtKB:Q1RMZ1 label: S-adenosylmethionine sensor upstream of mTORC1 function: preferred_term: S-adenosyl-L-methionine binding term: id: GO:1904047 label: S-adenosyl-L-methionine binding processes: - preferred_term: regulation of TORC1 signaling term: id: GO:1903432 label: regulation of TORC1 signaling locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- SAM-free SAMTOR binds GATOR1 (and KICSTOR) and inhibits mTORC1; SAM binding (GO:1904047, IDA) disrupts the complex, linking methionine availability to mTORC1. SAMTOR is not in the RGD gene list and is added on the strength of the primary paper and a human GO-CAM. evidence: - source_id: PMID:29123071 statement: SAMTOR binds GATOR1 and inhibits mTORC1 until SAM binds SAMTOR. supporting_text: We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. gocam_associations: - model: gomodel:6482692800000701 activity: gomodel:6482692800000701/6482692800000904 title: Activation of the canonical mTORC1 signaling by BMT2/SAMTOR in response to S-adenosyl-L-methionine influx (Human) description: SAMTOR S-adenosyl-L-methionine binding (GO:1904047). connections: - source: ragulator target: rag_heterodimer connection_type: POSITIVELY_REGULATES description: Ragulator anchors the Rag heterodimer to the lysosomal membrane. - source: gator1 target: rag_heterodimer connection_type: NEGATIVELY_REGULATES description: GATOR1 stimulates GTP hydrolysis by RagA/B, inactivating the heterodimer. - source: gator2 target: gator1 connection_type: NEGATIVELY_REGULATES description: GATOR2 inhibits GATOR1, in part by WDR24-dependent ubiquitination of NPRL2. - source: flcn_fnip target: rag_heterodimer connection_type: POSITIVELY_REGULATES description: FLCN-FNIP converts RagC/D to the GDP-bound state required for raptor binding. - source: sestrin2_leucine_sensor target: gator2 connection_type: NEGATIVELY_REGULATES description: Leucine-free Sestrin2 binds and inhibits GATOR2; leucine relieves this. - source: castor_arginine_sensor target: gator2 connection_type: NEGATIVELY_REGULATES description: Arginine-free CASTOR1 binds and inhibits GATOR2; arginine relieves this. - source: samtor_sam_sensor target: gator1 connection_type: POSITIVELY_REGULATES description: SAM-free SAMTOR binds GATOR1 and promotes its inhibition of mTORC1; SAM relieves this. - order: 7 optional: true role: mTOR folding and complex assembly node: id: ttt_mtor_assembly label: TEL2-TTI1-TTI2 (TTT) co-chaperone module_type: PROTEIN_COMPLEX description: >- The TTT complex, with the R2TP complex and HSP90, is needed for the stability and assembly of PIKK-family kinases including mTOR, and so for both mTOR complexes. It is not specific to mTOR (it also serves ATM, ATR, DNA-PKcs, SMG1 and TRRAP) and is optional here. annotons: - id: ttt_complex_stabilization label: TTT stabilisation of mTOR participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TTT Hsp90 cochaperone complex term: id: GO:0110078 label: TTT Hsp90 cochaperone complex active_units: - id: ttt_telo2 label: TEL2 scaffold subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TELO2 term: id: UniProtKB:Q9Y4R8 label: Telomere length regulation protein TEL2 homolog role: CK2-phosphorylated scaffold that recruits R2TP to newly made PIKKs. function: preferred_term: protein-containing complex stabilizing activity term: id: GO:0140777 label: protein-containing complex stabilizing activity - id: ttt_tti1 label: TTI1 subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TTI1 term: id: UniProtKB:O43156 label: TELO2-interacting protein 1 homolog role: TEL2 partner required for PIKK stability. function: preferred_term: protein-containing complex stabilizing activity term: id: GO:0140777 label: protein-containing complex stabilizing activity function: preferred_term: protein-containing complex stabilizing activity term: id: GO:0140777 label: protein-containing complex stabilizing activity targets: - preferred_term: MTOR (mTORC1 and mTORC2) locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- TELO2 and TTI1 both carry GO:0140777 (IMP). TTI2, the third TTT subunit, is not in the RGD gene list and is not modelled. evidence: - source_id: PMID:20864032 statement: TEL2 coordinates R2TP and HSP90 and is required for mTOR stability. supporting_text: failure to interact with the R2TP/prefoldin-like complex results in instability of the PIKKs, principally mTOR and SMG1. - order: 8 optional: true role: growth factor input through AKT node: id: akt_input label: AKT activation (PI3K-AKT input) description: >- Included by reference to the AKT activation step of the PI3K-AKT-mTOR module. Active AKT phosphorylates TSC2 (inhibiting the RHEB GAP) and PRAS40 (relieving its inhibition of mTORC1). mTORC2 supplies the Ser473 phosphorylation that AKT needs for full activity, so this node is also an mTORC2 output. module_ref: pi3k_akt_mtor#akt_activation evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000180.yaml statement: RGD draws PI3K-Akt inhibiting Tsc2 and Akt1s1, and mTORC2 phosphorylating Akt. supporting_text: Akt can also activate mTOR downstream of Tsc2 by relieving the inhibition by Akt1s1, (known as Pras40). Interestingly, Akt is among the substrates of mTORC2. - order: 9 optional: true role: energy input through AMPK node: id: ampk_input label: AMPK heterotrimer (energy-stress input) description: >- Included by reference to the AMPK heterotrimer of the AMPK energy-sensing module. AMPK activates TSC2 (modelled in that module's TSC relay, referenced as part 4) and directly phosphorylates raptor, which inhibits mTORC1. module_ref: ampk_energy_sensing#ampk_heterotrimer evidence: - source_id: PMID:18439900 statement: AMPK phosphorylation of raptor is required for mTORC1 inhibition by energy stress. supporting_text: The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. connections: - source: rheb_activation target: mtorc1 connection_type: POSITIVELY_REGULATES description: RHEB-GTP binds mTOR and allosterically activates mTORC1 on the lysosome. - source: amino_acid_sensing target: mtorc1 connection_type: POSITIVELY_REGULATES description: The active Rag heterodimer binds raptor and recruits mTORC1 to the lysosome, where RHEB is. - source: tsc_rheb_gap target: rheb_activation connection_type: NEGATIVELY_REGULATES description: TSC2 stimulates GTP hydrolysis by RHEB. - source: tsc_tbc1d7 target: tsc_rheb_gap connection_type: POSITIVELY_REGULATES description: TBC1D7 stabilises the TSC1-TSC2 association and so its RHEB-GAP activity. - source: akt_input target: tsc_rheb_gap connection_type: NEGATIVELY_REGULATES description: AKT phosphorylates and inactivates TSC2. - source: akt_input target: mtorc1 connection_type: POSITIVELY_REGULATES description: AKT phosphorylates PRAS40, releasing its inhibition of mTORC1. - source: mtorc2 target: akt_input connection_type: POSITIVELY_REGULATES description: mTORC2 phosphorylates AKT Ser473, required for full AKT activity. - source: ampk_input target: tsc_rheb_gap connection_type: POSITIVELY_REGULATES description: AMPK phosphorylates TSC2 and increases its GAP activity. - source: ampk_input target: mtorc1 connection_type: NEGATIVELY_REGULATES description: AMPK phosphorylates raptor, inhibiting mTORC1. - source: ttt_mtor_assembly target: mtorc1 connection_type: POSITIVELY_REGULATES description: TTT is required for mTOR stability and assembly into mTORC1. - source: ttt_mtor_assembly target: mtorc2 connection_type: POSITIVELY_REGULATES description: TTT is required for mTOR stability and assembly into mTORC2.