id: PW:0000180 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000180 title: mtor signaling pathway description: 'The mTOR signaling pathway responds to and integrates a range of environmental cues and is known for its role in the control of protein translation and ribosome biogenesis, autophagy, cytoskeleton, and metabolism. The highly conserved Ser/Thr mTOR kinase is found in two distinct complexes: the rapamycin-sensitive mTORC1 and the largely rapamycin-insensitive mTORC2. Rapamycin (sirolimus) - a macrolide produced by Streptomyces hygroscopicus , in complex with Fkbp1a (the 12-kDa FK506-bindingprotein) binds to and inhibits mTOR when the kinase is part of the mTORC1 complex. Sensitivity to rapamycin rendered mTORC1 an easier target to study and today, this is the best-characterized system. In addition to mTOR, the two complexes share several other components: Mlst8 (known as GbetaL) and the Tti1/Tel2 complex, both playing a role in complex assembly and stability, and the inhibitory Deptor protein. Raptor and Rictor are the mTOR-specific scaffold proteins of mTORC1 and mTORC2, respectively. mTORC1 also contains the inhibitory Akt1s1, (known as PRAS40). Mapkap1 (known as mSin1) and Prr5 and Prr5l (known as Protor1 and 2) are part of the mTORC2 complex. The upstream regulation, responses and outcomes mediated by the two complexes are described in more detail. mTORC1 complex, hormones and growth factors responses The mTORC1 system responds to and integrates many cues that include energy status, oxygen, stress, growth factors and amino acids. mTORC1 signaling positively controls ribosome biogenesis and protein translation, and negatively, autophagy. The activity of mTORC1 is promoted by the GTP-bound small G protein Rheb. Under unstimulated conditions Rheb is inhibited by the TSC complex which has inhibitory GAP activity towards it; the function is dependent on the Tsc2 component. While usually depicted as a trimer composed of Tsc1, Tsc2 (both shown separately) and Tbc1d7, evidence indicates that this complex is present as a large oligomeric structure with multiple copies of each subunit. Insulin and growth factors activate PI3K-Akt and the Raf/Mek/Erk intracellular signaling pathways, resulting in inhibition of Tsc2 and activation of mTorc1. 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. Eif4bp1 and Rps6k1, targets and effectors of mTORC1, lead to activation of translation initiation and ribosome biogenesis. mTORC1 signaling can negatively impact on insulin signaling and its downstream-activated events; a regulatory feedback loop is provided by the Rps6k1 effector which phosphorylates insulin receptor substrate 1. Phosphorylation of Ulk1 by mTORC1 leads to inhibition of autophagy. mTORC1 can stimulate the activity of Nfe2l2 (known as Nrf2) transcription factor by phosphorylating Sqstm1. When modified, Sqstm1 becomes a potent inhibitor of Keap1 protein, a redox sensor that under basal conditions targets Nfe2l2 for ubiquitination and proteasomal degradation. Nfe2l2 signaling is one of the most important regulators of antioxidant and electrophilic stress responses. mTORC1 is negatively regulated by a low energy status of the cell and positively regulated by amino acid availability, consistent with its role in protein biosynthesis and metabolism. The energy ''sensor'' Amp-activated protein kinase (AMPK) of the Lkb1-AMPK axis inhibits energy-consuming pathways while promoting ATP-generating ones. AMPK phosphorylates and activates Tsc2; downstream of Tsc2 it can inhibit mTORC1 by phosphorylating Raptor. mTORC1 complex, amino acid responses Amino acid availability stimulates mTORC1 and is dependent on the Rrag (known as Rag) proteins: RragA, B, C and D. The Rag proteins constitute a family of related small GTPases that function as obligate heterodimers. GTP-bound RragA or B complexed with GDP-bound RragC or D, are the heterodimers that stimulate mTORC1 activity. As such, they bind the Raptor component of mTORC1, prompting the translocation of the complex to lysosomal surfaces. There, Rags dock onto a multisubunit complex known as the ''Ragulator'', essential for the activation of mTORC1 by amino acids. The lysosome is the final destination of many catabolic events and a major recycling center. The lysosomal localization allows mTORC1 to respond to amino acid availability; several amino acid lysosomal protein transporters may act as ''sensors'' (not shown). The ''Ragulator'' is composed of five Lamtor protein subunits of which Lamtor1 acts as a scaffold for two heterodimers of Lamtor2/3 and Lamtor4/5. The complex can act as a guanine exchange factor (GEF) for RragA and B. Inhibitory GAP activity for RragA and B is provided by the Gator1 complex while regulatory GAP activity towards RragC and D is provided by folliculin (Flcn) in complex with its Fnip partners. Gator1 inhibition is relieved by the Gator2 complex. How Gator2 functions remains to be elucidated; however, it is known that the function is modulated by amino acid availability. In the absence of amino acids, Gator2 is inhibited by Gatsl3/2 (Castor1/2) and by sestrin2 proteins. The interaction of these proteins with Gator2 is inhibited when leucine binds sestrin2 or arginine binds Castor1. Castor1 functions as a homodimer or a heterodimer with Castor2, which by itself does not bind arginine. On the lysosomal surface, mTORC1 is activated by a GTP-loaded Rheb. Insulin, and likely growth factors, prompt the departure of inhibitory TSC from the lysosome, where it can be found in their absence. mTORC2 complex Growth factors activate mTorc2 by mechanisms that are incompletely understood. mTORC2 promotes PI3k-Akt signaling via Akt phosphorylation. Full activity of Akt members requires two phosphorylation events; the second phosphorylation is provided by mTORC2. mTORC2 regulates several members of the protein kinase C family and recently it has been shown that it negatively regulates a component of the Hippo signaling pathway (not shown). The mTORC2 arm of the pathway plays a role in cytoskeletal rearrangements and like mTORC1, can modulate cell growth. The detailed picture of mTOR signaling is still incomplete but research increasingly points to its central role in the modulation of cell growth and metabolism. mTOR can be deregulated at many levels and its alteration, including deregulation of its cross talk with the PI3K-Akt system, has been implicated in numerous conditions.' diagram_image: https://rgd.mcw.edu/pathway/PW0000180/mTOR%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000180/mTOR%20signaling%20pathway/mTOR%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000101 label: translation pathway - id: PW:0000102 label: the extracellular signal-regulated Raf/Mek/Erk signaling pathway - id: PW:0000143 label: insulin signaling pathway - id: PW:0000232 label: phosphatidylinositol 3-kinase-Akt signaling pathway - id: PW:0000278 label: autophagy pathway - id: PW:0000369 label: nuclear factor, erythroid 2 like 2 signaling pathway - id: PW:0000542 label: adenosine monophosphate-activated protein kinase (AMPK) signaling pathway - id: PW:0000580 label: translation initiation pathway - id: PW:0001066 label: ribosome biogenesis pathway diagram_gene_links: - id: RGD:1312049 label: Akt1s1 - id: RGD:620259 label: Eif4ebp1 - id: RGD:2617 label: Fkbp1a - id: RGD:1304672 label: Gatsl2 - id: RGD:1304774 label: Gatsl3 - id: RGD:2922 label: Irs1 - id: RGD:621840 label: Rheb - id: RGD:620683 label: Rps6kb1 - id: RGD:1566319 label: Sesn2 - id: RGD:620124 label: Tsc1 - id: RGD:3908 label: Tsc2 diagram_chemicals: - id: CHEBI:9168 label: rapamycin diagram_edges: - source: Akt1s1 relation: negatively_affects target: mTORC1 complex - source: Eif4ebp1 relation: negatively_affects target: translation initiation pathway - source: Fkbp1a relation: associated_with target: rapamycin - source: Gator1 complex relation: negatively_affects target: Rrag members - source: Gator2 complex relation: associated_with target: Gatsl2 - source: Gator2 complex relation: associated_with target: Gatsl3 - source: Gator2 complex relation: associated_with target: Sesn2 - source: Gator2 complex relation: negatively_affects target: Gator1 complex - source: Gatsl2 relation: associated_with target: Gatsl3 - source: Gatsl2 relation: negatively_affects target: Gator2 complex - source: Gatsl3 relation: negatively_affects target: Gator2 complex - source: Rps6kb1 relation: negatively_affects target: Irs1 - source: Rrag members relation: positively_affects target: mTORC1 complex - source: Sesn2 relation: negatively_affects target: Gator2 complex - source: Tsc2 relation: negatively_affects target: Rheb - source: adenosine monophosphate-activated protein kinase (AMPK) signaling pathway relation: negatively_affects target: mTORC1 complex - source: arginine relation: associated_with target: Gatsl3 - source: arginine relation: negatively_affects target: Gatsl3 - source: leucine relation: associated_with target: Sesn2 - source: leucine relation: negatively_affects target: Sesn2 - source: mTORC1 complex relation: negatively_affects target: Eif4ebp1 - source: mTORC1 complex relation: negatively_affects target: autophagy pathway - source: phosphatidylinositol 3-kinase-Akt signaling pathway relation: negatively_affects target: Akt1s1 - source: phosphatidylinositol 3-kinase-Akt signaling pathway relation: negatively_affects target: Tsc2 - source: rapamycin relation: negatively_affects target: mTORC1 complex - source: the extracellular signal-regulated Raf/Mek/Erk signaling pathway relation: negatively_affects target: Tsc2 - source: translation initiation pathway relation: positively_affects target: ribosome biogenesis pathway diagram_labels: - adenosine monophosphate-activated protein kinase (AMPK) signaling pathway --+> Tsc2 - cytoskeletal rearrangements - environmental cues - environmental cues --+> adenosine monophosphate-activated protein kinase (AMPK) signaling pathway - Flcn-Flip --+> Rrag members - GF - GF --+> mTORC2 complex - insulin signaling pathway --+> phosphatidylinositol 3-kinase-Akt signaling pathway - insulin signaling pathway --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - mTORC1 complex - mTORC1 complex --+> nuclear factor, erythroid 2 like 2 signaling pathway - mTORC1 complex --+> Rps6kb1 - mTORC2 complex - mTORC2 complex --+> cytoskeletal rearrangements - mTORC2 complex --+> phosphatidylinositol 3-kinase-Akt signaling pathway - Ragulator complex --+> Rrag members - Rheb --+> mTORC1 complex - Rps6kb1 --+> translation initiation pathway - Rrag members - Rrag members --+> mTORC1 complex diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/flcn-flip label: Flcn-Flip - href: /wg/home/pathway2/molecular-pathways2/gator1-complex label: Gator1 complex - href: /wg/home/pathway2/molecular-pathways2/gator2-complex label: Gator2 complex - href: /wg/home/pathway2/molecular-pathways2/regulator-complex label: Ragulator complex - href: /wg/home/pathway2/molecular-pathways2/tsc-complex label: TSC complex - href: http://en.wikipedia.org/wiki/Arginine label: arginine - href: https://en.wikipedia.org/wiki/Leucine label: leucine references: - id: RGD:1625616 citation: Marshall S Sci STKE. 2006 Aug 1;2006(346):re7. - id: RGD:2308795 citation: Ma XM and Blenis J, Nat Rev Mol Cell Biol. 2009 May;10(5):307-18. Epub 2009 Apr 2. - id: RGD:5129888 citation: Polak P and Hall MN, Dev Cell. 2006 Oct;11(4):433-4. - id: RGD:5130004 citation: Rosner M, etal., Mutat Res. 2008 Sep-Oct;659(3):284-92. Epub 2008 Jun 11. - id: RGD:5130019 citation: Leibowitz G, etal., Diabetes Obes Metab. 2008 Nov;10 Suppl 4:157-69. - id: RGD:5130022 citation: Inoki K Diabetes Res Clin Pract. 2008 Nov 13;82 Suppl 1:S59-62. Epub 2008 Oct 15. - id: RGD:5130044 citation: Goberdhan DC and Boyd CA, Biochem Soc Trans. 2009 Feb;37(Pt 1):213-6. - id: RGD:5130045 citation: Avruch J, etal., Biochem Soc Trans. 2009 Feb;37(Pt 1):223-6. - id: RGD:5130046 citation: Sancak Y and Sabatini DM, Biochem Soc Trans. 2009 Feb;37(Pt 1):289-90. - id: RGD:5130050 citation: Dunlop EA and Tee AR, Cell Signal. 2009 Jun;21(6):827-35. Epub 2009 Jan 8. - id: RGD:5130059 citation: Polak P and Hall MN, Curr Opin Cell Biol. 2009 Apr;21(2):209-18. Epub 2009 Mar 2. - id: RGD:11535033 citation: 'Laplante M and Sabatini DM, Cell. 2012 Apr 13;149(2):274-93. doi: 10.1016/j.cell.2012.03.017.' - id: RGD:11535034 citation: 'Dibble CC and Cantley LC, Trends Cell Biol. 2015 Sep;25(9):545-55. doi: 10.1016/j.tcb.2015.06.002. Epub 2015 Jul 6.' - id: RGD:11535042 citation: 'Goberdhan DC, etal., Cell Metab. 2016 Apr 12;23(4):580-9. doi: 10.1016/j.cmet.2016.03.013.' - id: RGD:11535043 citation: 'Bar-Peled L and Sabatini DM, Trends Cell Biol. 2014 Jul;24(7):400-6. doi: 10.1016/j.tcb.2014.03.003. Epub 2014 Mar 31.' - id: RGD:11535047 citation: 'Hallett JE and Manning BD, Cell. 2016 Mar 24;165(1):15-7. doi: 10.1016/j.cell.2016.03.002.' - id: RGD:11535118 citation: 'Kennedy BK and Lamming DW, Cell Metab. 2016 Jun 14;23(6):990-1003. doi: 10.1016/j.cmet.2016.05.009.' - id: RGD:11535119 citation: 'Tan VP and Miyamoto S, J Mol Cell Cardiol. 2016 Jun;95:31-41. doi: 10.1016/j.yjmcc.2016.01.005. Epub 2016 Jan 7.' - id: RGD:11535120 citation: Lan AP, etal., Neuromolecular Med. 2016 Jun 4.