Amino acids regulate mTORC1 (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Amino acids regulate mTORC1" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">The mTORC1 complex acts as an integrator that regulates translation, lipid synthesis, autophagy, and cell growth in response to multiple inputs, notably glucose, oxygen, amino acids, and growth factors such as insulin (reviewed in Sabatini 2017, Meng et al. 2018, Kim and Guan 2019).&lt;br&gt;MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). Recruitment of mTORC1 to the lysosomal membrane is intricate and incompletely understood. At the center of the system is a complex of two small GTPases, the Rag heterodimer (RRAGA or RRAGB bound to RRAGC or RRAGD). The Rag heterodimer is tethered to the membrane by the Ragulator complex, which also binds the v-ATPase complex. The Rag heterodimer acts as a cross-regulating switch, with the binding of GTP by one subunit inhibiting the exchange of GDP for GTP by the other subunit (Shen et al. 2017). The active conformation of the Rag heterodimer that recruits mTORC1 to the lysosomal membrane is RRAGA,B:GTP:RRAGC,D:GDP while the inactive conformation, RRAGA,B:GDP:RRAGC,D:GTP, releases mTORC1 (Sancak et al. 2008, Kim et al. 2008, Sancak et al. 2010, Lawrence et al. 2018). GTPase activating proteins (GAPs) and guanyl nucleotide exchange factors (GEFs) acting upon the Rag heterodimer thereby regulate recruitment of mTORC1. RHEB:GTP at the lysosomal membrane also binds mTORC1 and directly activates mTORC1. During inactivation of mTORC1 in response to removal of amino acids, the TSC complex, a GAP for RHEB, is required in addition to the inactive Rag complex to release mTORC1 from RHEB and hence fully release mTORC1 from the lysosomal membrane (Demetriades et al. 2014).&lt;br&gt;Amino acids regulate recruitment of mTORC1 to the lysosomal membrane by at least 4 mechanisms (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017). 1) Sestrin1 (SESN1) or Sestrin2 (SESN2) binds leucine and the Sestrin1,2:leucine complex is then released from the GATOR2 complex, allowing GATOR2 to positively regulate mTORC1 activation (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016). 2) CASTOR1 in a homodimer or a heterodimer with CASTOR2 binds arginine and the CASTOR1:arginine complex is likewise released from GATOR2, allowing GATOR2 to activate mTORC1 (Chantranupong et al. 2016, Saxton et al. 2016, Gai et al. 2016, Xia et al. 2016). 3) BMT2 (SAMTOR), a negative regulator of mTORC1 activation, binds S-adenosylmethionine (SAM), a derivative of methionine (Gu et al. 2017). The binding of SAM causes BMT2 to dissociate from GATOR1, allowing the activation of mTORC1. 4) The amino acid transporter SLC38A9 binds arginine and SLC38A9 then acts as a GEF to convert RRAGA,B:GDP to the active form, RRAGA,B:GTP (Rebsamen et al. 2015, Wang et al. 2015, Wyant et al. 2017, Shen and Sabatini 2018). Amino acid starvation also regulates the assembly of the V0 and V1 subunits of v-ATPase by an uncharacterized mechanism (Stransky and Forgac 2015) and v-ATPase is required for activation of mTORC1 by amino acids (Zoncu et al. 2011). Glutamine activates mTORC1 by a mechanism that is independent of the Rag GTPases, requires ARF1, but is not yet fully elucidated (Jewell et al. 2015). 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<Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="13"/> <Graphics CenterX="380.0" CenterY="1793.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P15313"/> </DataNode> <DataNode TextLabel="LAMTOR1 " GraphId="ac7e1" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1633.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q6IAA8"/> </DataNode> <DataNode TextLabel="ATP6V1B2 " GraphId="acb0c" Type="Protein" GroupRef="ce8c2"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639277"/> <Attribute Key="copies_num" Value="12"/> <Graphics CenterX="660.0" 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Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="380.0" CenterY="1893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P36543"/> </DataNode> <DataNode TextLabel="CASTOR1:L-Arg dimer" GraphId="ad44f" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol"/> <Graphics CenterX="88.5" CenterY="745.0" Width="153.0" Height="26.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a"/> <Xref Database="Reactome" ID="R-HSA-9657636"/> </DataNode> <DataNode TextLabel="KICSTOR:GATOR1:GATOR2" GraphId="addd8" Type="Complex"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Graphics CenterX="300.0" CenterY="667.5" Width="188.0" Height="29.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a"/> <Xref 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<Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="1360.0" CenterY="1633.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8NEY4"/> </DataNode> <DataNode TextLabel="MLST8 " GraphId="af186" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1573.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9BVC4"/> </DataNode> <DataNode TextLabel="LAMTOR3 " GraphId="af1b3" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1673.0" Width="100.0" Height="20.0" ZOrder="32768" 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Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="18"/> <Graphics CenterX="1220.0" CenterY="1853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:17552"/> </DataNode> <DataNode TextLabel="ATP6V1G2 " GraphId="afcb4" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="16"/> <Graphics CenterX="1220.0" CenterY="1753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O95670"/> </DataNode> <DataNode TextLabel="ATP6V0E2 " GraphId="afed6" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="9"/> <Graphics CenterX="1360.0" 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</DataNode> <DataNode TextLabel="ATP6V1B2 " GraphId="b34aa" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="14"/> <Graphics CenterX="1220.0" CenterY="1593.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P21281"/> </DataNode> <DataNode TextLabel="LAMTOR3 " GraphId="b3679" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9UHA4"/> </DataNode> <DataNode TextLabel="MLST8 " GraphId="b3d2d" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" 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<Xref Database="ChEBI" ID="CHEBI:17552"/> </DataNode> <DataNode TextLabel="NPRL3 " GraphId="b4325" Type="Protein" GroupRef="e0c00"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640231"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1713.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q12980"/> </DataNode> <DataNode TextLabel="TCIRG1 " GraphId="b47c5" Type="Protein" GroupRef="ce8c2"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639277"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="660.0" CenterY="1313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q13488"/> </DataNode> <DataNode TextLabel="LAMTOR2 " GraphId="b4814" Type="Protein" GroupRef="ce8c2"> <Attribute Key="cellular_location" 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Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O75348"/> </DataNode> <DataNode TextLabel="MLST8 " GraphId="b52e3" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="18"/> <Graphics CenterX="1360.0" CenterY="1813.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9BVC4"/> </DataNode> <DataNode TextLabel="ATP6V1G3 " GraphId="b690a" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="1080.0" CenterY="2093.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96LB4"/> </DataNode> <DataNode TextLabel="GDP " GraphId="b6a8c" Type="Metabolite" 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<Attribute Key="complex_id" Value="R-HSA-9639277"/> <Attribute Key="copies_num" Value="16"/> <Graphics CenterX="660.0" CenterY="1753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q5VZM2"/> </DataNode> <DataNode TextLabel="ATP6V0E1 " GraphId="d4ae5" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="8"/> <Graphics CenterX="1220.0" CenterY="1513.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O15342"/> </DataNode> <DataNode TextLabel="RPTOR " GraphId="d506f" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1613.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8N122"/> </DataNode> <DataNode TextLabel="RRAGD " GraphId="d5397" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="17"/> <Graphics CenterX="1080.0" CenterY="2233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9NQL2"/> </DataNode> <DataNode TextLabel="DEPDC5 " GraphId="d5735" Type="Protein" GroupRef="fd29d"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640224"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" CenterY="1713.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O75140"/> </DataNode> <DataNode TextLabel="LAMTOR1 " GraphId="d5bc3" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1173.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q6IAA8"/> </DataNode> <DataNode TextLabel="NPRL2 " GraphId="d5e22" Type="Protein" GroupRef="ed054"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9657634"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1500.0" CenterY="1393.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8WTW4"/> </DataNode> <DataNode TextLabel="SESN2 " GraphId="d5ff5" Type="Protein" GroupRef="fbe47"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639275"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P58004"/> </DataNode> <DataNode TextLabel="LAMTOR3 " GraphId="d5ffc" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="520.0" CenterY="1253.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9UHA4"/> </DataNode> <DataNode TextLabel="SEC13 " GraphId="d6144" Type="Protein" GroupRef="fbe47"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639275"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P55735"/> </DataNode> <DataNode TextLabel="ATP6V0E2 " 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ID="Q13488"/> </DataNode> <DataNode TextLabel="FNIP1 " GraphId="d7c6a" Type="Protein" GroupRef="f15a9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640226"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="380.0" CenterY="1233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8TF40"/> </DataNode> <DataNode TextLabel="LAMTOR2 " GraphId="d8235" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y2Q5"/> </DataNode> <DataNode TextLabel="ATP6V1F " GraphId="d8824" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" 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Database="Uniprot-TrEMBL" ID="Q9Y5K8"/> </DataNode> <DataNode TextLabel="ATP6V0B " GraphId="d96d2" Type="Protein" GroupRef="ce8c2"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639277"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="660.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q99437"/> </DataNode> <DataNode TextLabel="AdoMet" GraphId="d9dce" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol"/> <Graphics CenterX="74.5" CenterY="506.0" Width="59.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:15414"/> </DataNode> <DataNode TextLabel="WDR24 " GraphId="d9f33" Type="Protein" GroupRef="e0c00"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640231"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1593.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96S15"/> </DataNode> <DataNode TextLabel="ATP6V1F " GraphId="da04e" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="12"/> <Graphics CenterX="520.0" CenterY="1613.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q16864"/> </DataNode> <DataNode TextLabel="ATP6V1G3 " GraphId="da0d0" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="18"/> <Graphics CenterX="1360.0" CenterY="1773.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96LB4"/> </DataNode> <DataNode TextLabel="LAMTOR4 " GraphId="da2b7" Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="4"/> <Graphics CenterX="380.0" CenterY="1593.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q0VGL1"/> </DataNode> <DataNode TextLabel="ATP6V1E1 " GraphId="da4f6" Type="Protein" GroupRef="c8dac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640184"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="240.0" CenterY="1673.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P36543"/> </DataNode> <DataNode TextLabel="ITFG2 " GraphId="da600" Type="Protein" GroupRef="d3800"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639274"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1373.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q969R8"/> </DataNode> <DataNode TextLabel="ATP6V1C2 " GraphId="da857" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="14"/> <Graphics CenterX="1220.0" CenterY="1633.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8NEY4"/> </DataNode> <DataNode TextLabel="RRAGB " GraphId="daaa1" Type="Protein" GroupRef="c8dac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640184"/> <Attribute Key="copies_num" Value="4"/> <Graphics CenterX="240.0" CenterY="1253.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q5VZM2"/> </DataNode> <DataNode TextLabel="ATP6V1D " GraphId="db2d4" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="1360.0" CenterY="1653.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y5K8"/> </DataNode> <DataNode TextLabel="LAMTOR3 " GraphId="db2eb" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="3"/> <Graphics CenterX="1220.0" CenterY="1353.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9UHA4"/> </DataNode> <DataNode TextLabel="ATP6V0D1 " GraphId="db3ee" Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="9"/> <Graphics CenterX="380.0" CenterY="1693.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P61421"/> </DataNode> <DataNode TextLabel="ATP6V1G2 " GraphId="db494" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="14"/> <Graphics CenterX="520.0" CenterY="1653.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O95670"/> </DataNode> <DataNode TextLabel="ATP6V1G3 " GraphId="db56c" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="100.0" CenterY="1633.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96LB4"/> </DataNode> <DataNode TextLabel="C12orf66 " GraphId="db70b" Type="Protein" GroupRef="fbe47"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639275"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1413.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96MD2"/> </DataNode> <DataNode TextLabel="KPTN " GraphId="dba50" Type="Protein" GroupRef="fbe47"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639275"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1453.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y664"/> </DataNode> <DataNode TextLabel="ATP6V0E1 " GraphId="dbc67" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="6"/> <Graphics CenterX="520.0" CenterY="1413.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O15342"/> </DataNode> <DataNode TextLabel="L-Arg " GraphId="dbc83" Type="Metabolite" GroupRef="c48b6"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640172"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="380.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:32682"/> </DataNode> <DataNode TextLabel="WDR24 " GraphId="dbe65" Type="Protein" GroupRef="af541"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639281"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" 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Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="18"/> <Graphics CenterX="1360.0" CenterY="1853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8N122"/> </DataNode> <DataNode TextLabel="RRAGA " GraphId="dc83f" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1360.0" CenterY="1213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q7L523"/> </DataNode> <DataNode TextLabel="RRAGA " GraphId="dca37" Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="380.0" CenterY="1433.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q7L523"/> </DataNode> <DataNode TextLabel="DEPDC5 " GraphId="dca96" Type="Protein" GroupRef="af541"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639281"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" CenterY="1213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O75140"/> </DataNode> <DataNode TextLabel="ATP6V1C1 " GraphId="dd12a" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="12"/> <Graphics CenterX="520.0" CenterY="1513.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P21283"/> </DataNode> <DataNode TextLabel="SESN1 " GraphId="ddbcd" Type="Protein" GroupRef="d0c75"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639290"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" CenterY="1493.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y6P5"/> </DataNode> <DataNode TextLabel="NPRL2 " GraphId="ddce0" Type="Protein" GroupRef="fbe47"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639275"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1373.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8WTW4"/> </DataNode> <DataNode TextLabel="KPTN " GraphId="ddf95" Type="Protein" GroupRef="af541"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639281"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" CenterY="1313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y664"/> </DataNode> <DataNode TextLabel="LAMTOR2 " GraphId="ddfb9" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="4"/> <Graphics CenterX="1360.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y2Q5"/> </DataNode> <DataNode TextLabel="GTP " GraphId="de327" Type="Metabolite" GroupRef="d562c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="16"/> <Graphics CenterX="1080.0" CenterY="2153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:15996"/> </DataNode> <DataNode TextLabel="ATP6V1A " GraphId="de501" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="11"/> <Graphics CenterX="1360.0" CenterY="1553.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P38606"/> </DataNode> <DataNode TextLabel="LAMTOR5 " GraphId="de63b" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="520.0" CenterY="1293.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O43504"/> </DataNode> <DataNode TextLabel="NPRL2 " GraphId="de73d" Type="Protein" GroupRef="e0c00"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640231"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="800.0" CenterY="1693.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8WTW4"/> </DataNode> <DataNode TextLabel="L-Arg " GraphId="df1aa" Type="Metabolite" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="17"/> <Graphics CenterX="520.0" CenterY="1853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:32682"/> </DataNode> <DataNode TextLabel="ATP6V0E1 " GraphId="df40b" Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="9"/> <Graphics CenterX="380.0" CenterY="1733.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O15342"/> </DataNode> <DataNode TextLabel="MTOR " GraphId="df9f8" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="3"/> <Graphics CenterX="1220.0" CenterY="1273.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P42345"/> </DataNode> <DataNode TextLabel="ATP6V1A " GraphId="dfb4e" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="8"/> <Graphics CenterX="100.0" CenterY="1413.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P38606"/> </DataNode> <DataNode TextLabel="ATP6V0E1 " GraphId="e0999" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="6"/> <Graphics CenterX="1080.0" CenterY="1833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O15342"/> </DataNode> <DataNode TextLabel="ATP6V1B1 " GraphId="e0bbb" Type="Protein" GroupRef="c8dac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640184"/> <Attribute Key="copies_num" Value="13"/> <Graphics CenterX="240.0" CenterY="1573.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P15313"/> </DataNode> <DataNode TextLabel="LAMTOR2 " GraphId="e0c2d" Type="Protein" GroupRef="c8dac"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640184"/> <Attribute Key="copies_num" Value="4"/> <Graphics CenterX="240.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9Y2Q5"/> </DataNode> <DataNode TextLabel="ATP6V0D1 " GraphId="e11ea" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="6"/> <Graphics CenterX="100.0" CenterY="1333.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P61421"/> </DataNode> <DataNode TextLabel="CASTOR2 " GraphId="e192b" Type="Protein" GroupRef="ab427"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640285"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="940.0" CenterY="1633.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="A6NHX0"/> </DataNode> <DataNode TextLabel="ATP6V1E2 " GraphId="e1c0d" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="15"/> <Graphics CenterX="1360.0" CenterY="1693.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q96A05"/> </DataNode> <DataNode TextLabel="LAMTOR1 " GraphId="e1c35" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="4"/> <Graphics CenterX="1360.0" CenterY="1313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q6IAA8"/> </DataNode> <DataNode TextLabel="RRAGA " GraphId="e1e97" Type="Protein" GroupRef="c8dac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640184"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="240.0" CenterY="1213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q7L523"/> </DataNode> <DataNode TextLabel="ATP6V0D2 " GraphId="e2417" Type="Protein" GroupRef="d0ad9"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9646465"/> <Attribute Key="copies_num" Value="9"/> <Graphics CenterX="1360.0" CenterY="1493.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8N8Y2"/> </DataNode> <DataNode TextLabel="LAMTOR5 " GraphId="e2b48" Type="Protein" GroupRef="d562c"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9645607"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1713.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O43504"/> </DataNode> <DataNode TextLabel="SLC38A9 " GraphId="e3913" Type="Protein" GroupRef="fb14d"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639283"/> <Attribute Key="copies_num" Value="17"/> <Graphics CenterX="520.0" CenterY="1833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8NBW4"/> </DataNode> <DataNode TextLabel="RRAGB " GraphId="e3989" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9640174"/> <Attribute Key="copies_num" Value="16"/> <Graphics CenterX="100.0" CenterY="1713.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q5VZM2"/> </DataNode> <DataNode TextLabel="DEPDC5 " GraphId="e3a02" Type="Protein" GroupRef="ed054"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9657634"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1500.0" 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</DataNode> <DataNode TextLabel="ATP6V0E2 " GraphId="e4a25" Type="Protein" GroupRef="e8fef"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9640192"/> <Attribute Key="copies_num" Value="9"/> <Graphics CenterX="380.0" CenterY="1753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q8NHE4"/> </DataNode> <DataNode TextLabel="DEPDC5 " GraphId="e4b52" Type="Protein" GroupRef="d3800"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-9639274"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1080.0" CenterY="1293.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O75140"/> </DataNode> <DataNode TextLabel="LAMTOR5 " GraphId="e4c22" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute 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Database="Uniprot-TrEMBL" ID="Q99437"/> </DataNode> <DataNode TextLabel="RRAGB " GraphId="f541e" Type="Protein" GroupRef="c939f"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9646467"/> <Attribute Key="copies_num" Value="17"/> <Graphics CenterX="1220.0" CenterY="1833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q5VZM2"/> </DataNode> <DataNode TextLabel="RHEB " GraphId="f55e4" Type="Protein" GroupRef="f4a43"> <Attribute Key="cellular_location" Value="lysosomal membrane"/> <Attribute Key="complex_id" Value="R-HSA-165189"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="1500.0" CenterY="1233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q15382"/> </DataNode> <DataNode TextLabel="ATP6V1H " GraphId="f5727" Type="Protein" GroupRef="db9de"> <Attribute Key="cellular_location" Value="cytosol"/> 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Upon binding S-adenosymethionine, a metabolic derivative of the amino acid methionine, SAMTOR dissociates from GATOR1 and mTORC1 activity is increased through an uncharacterized mechanism (Gu et al. 2017). GATOR1 is recruited to the lysosomal membrane by the KICSTOR complex (Wolfson et al. 2017).</Comment> <BiopaxRef>ea1</BiopaxRef> <BiopaxRef>ecc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="166.0" Y="494.0"/> <Point X="163.0" Y="453.0"/> <Anchor Position="0.0" Shape="None" GraphId="e3b5f"/> <Anchor Position="0.99" Shape="None" GraphId="abb47"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640254"/> </Interaction> <Interaction GraphId="bf763"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="402.0" Y="79.0" GraphRef="f962d" RelX="-0.003076923076923077" RelY="0.92"/> <Point X="478.0" Y="83.0" GraphRef="eaf67" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645598"/> </Interaction> <Interaction GraphId="c2c7c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="827.0" Y="800.0" GraphRef="be017" RelX="-1.0" RelY="0.0"/> <Point X="704.0" Y="813.0" GraphRef="d3139" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645608"/> </Interaction> <Interaction GraphId="c2e12"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="163.0" Y="453.0" GraphRef="abb47" RelX="-0.030000000000001137" RelY="-0.410000000000025"/> <Point X="138.0" Y="447.0" GraphRef="f214e" RelX="1.0" RelY="-0.04" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640254"/> </Interaction> <Interaction GraphId="c33cd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="203.0" Y="592.0" GraphRef="f1525" RelX="-1.0" RelY="-0.02564102564102564"/> <Point X="187.0" Y="600.0" GraphRef="b74de" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639287"/> </Interaction> <Interaction GraphId="c424c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="705.0" Y="547.0" GraphRef="e25db" RelX="-0.08000000000004093" RelY="0.6499999999999773"/> <Point X="705.0" Y="599.0" GraphRef="accd3" RelX="-0.004524886877828055" RelY="-1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640167"/> </Interaction> <Interaction GraphId="c534e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="857.0" Y="463.0" GraphRef="ec79d" RelX="-1.0" RelY="0.0"/> <Point X="713.0" Y="482.0" GraphRef="d6cc1" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640167"/> </Interaction> <Interaction GraphId="cab82"> <Comment Source="Reactome">RHEB:GTP interacts with mTORC1 and activates the kinase activity of mTORC1 (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). RHEB binds the catalytic domain of the MTOR subunit of the mTORC1 complex (Long et al. 2005, Yang et al. 2017). The interaction of RHEB with mTORC1 is independent of the guanyl nucleotide bound by RHEB while the activation of MTOR is dependent on GTP bound to RHEB (Long et al. 2005). The binding of MTOR to RHEB is dependent on amino acid sufficiency (Long et al. 2005) due to association of mTORC1 with the Rag heterodimer at the lysosomal membrane.</Comment> <BiopaxRef>dc9</BiopaxRef> <BiopaxRef>bcd</BiopaxRef> <BiopaxRef>f24</BiopaxRef> <BiopaxRef>f86</BiopaxRef> <BiopaxRef>dfa</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="697.0" Y="950.0"/> <Point X="550.0" Y="1081.0"/> <Anchor Position="0.0" Shape="None" GraphId="e5c38"/> <Anchor Position="0.99" Shape="None" GraphId="c5487"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9646468"/> </Interaction> <Interaction GraphId="cc3b6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="662.0" Y="135.0" GraphRef="afdab" RelX="1.8400000000000318" RelY="0.5199999999999818"/> <Point X="822.0" Y="138.0" GraphRef="a8486" RelX="-1.0" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645598"/> </Interaction> <Interaction GraphId="ce112"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="705.0" Y="706.0" GraphRef="c7be0" RelX="0.0" RelY="0.6100000000000136"/> <Point X="694.0" Y="737.0" GraphRef="fe68e" RelX="0.0" RelY="-1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640168"/> </Interaction> <Interaction GraphId="d15b0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="402.0" Y="79.0" GraphRef="f962d" RelX="-0.003076923076923077" RelY="0.92"/> <Point X="669.0" Y="107.0" GraphRef="ae97d" RelX="99.0" RelY="-2.0" ArrowHead="mim-catalysis"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645598"/> </Interaction> <Interaction GraphId="d1abb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="217.0" Y="752.0" GraphRef="fc6c5" RelX="0.05000000000001137" RelY="-1.6200000000000045"/> <Point X="206.0" Y="667.0" GraphRef="addd8" RelX="-1.0" RelY="-0.034482758620689655" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657619"/> </Interaction> <Interaction GraphId="d1bec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="252.0" Y="851.0" GraphRef="c8c89" RelX="-1.0" RelY="0.0"/> <Point X="212.0" Y="914.0" GraphRef="d1a31" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657619"/> </Interaction> <Interaction GraphId="d2397"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="700.0" Y="394.0" GraphRef="dc00a" RelX="-0.01999999999998181" RelY="0.8000000000000114"/> <Point X="699.0" Y="397.0" GraphRef="c35b7" RelX="-0.004405286343612335" RelY="-1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640175"/> </Interaction> <Interaction GraphId="d7b89"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="604.0" Y="50.0" GraphRef="fceec" RelX="-0.023255813953488372" RelY="1.0"/> <Point X="613.0" Y="106.0" GraphRef="d6855" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639286"/> </Interaction> <Interaction GraphId="da52f"> <Comment Source="Reactome">The Ragulator complex acts as an unconventional guanyl nucleotide exchange factor (GEF) that ejects GTP from RRAGC and, by inference, RRAGD (Shen and Sabatini 2018). (Other known GEFs cause ejection of GDP rather than GTP from their targets.) The GDP-bound form of RRAGC,D is the active form that recruits mTORC1 to the lysosomal membrane.</Comment> <BiopaxRef>c44</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="613.0" Y="106.0"/> <Point X="645.0" Y="155.0"/> <Anchor Position="0.0" Shape="None" GraphId="d6855"/> <Anchor Position="0.99" Shape="None" GraphId="de399"/> <Anchor Position="0.5" Shape="None" GraphId="f113d"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639286"/> </Interaction> <Interaction GraphId="db4d0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="254.0" Y="931.0" GraphRef="b8b78" RelX="-1.0" RelY="-0.02702702702702703"/> <Point X="224.0" Y="922.0" GraphRef="a5a29" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640237"/> </Interaction> <Interaction GraphId="dd0e4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="564.0" Y="67.0" GraphRef="f962d" RelX="0.9938461538461538" RelY="-0.04"/> <Point X="629.0" Y="125.0" GraphRef="f113d" RelX="0.0" RelY="-5.5" ArrowHead="mim-catalysis"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639286"/> </Interaction> <Interaction GraphId="dd777"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="700.0" Y="873.0" GraphRef="fc3cf" RelX="-0.03999999999996362" RelY="0.6000000000000227"/> <Point X="700.0" Y="876.0" GraphRef="cbf19" RelX="-0.004484304932735426" RelY="-1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645608"/> </Interaction> <Interaction GraphId="dd9b5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="705.0" Y="641.0" GraphRef="accd3" RelX="-0.004524886877828055" RelY="0.9534883720930233"/> <Point X="705.0" Y="645.0" GraphRef="ad064" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640168"/> </Interaction> <Interaction GraphId="deeb5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="636.0" Y="27.0" GraphRef="ef2ec" RelX="-1.0" RelY="-0.047619047619047616"/> <Point X="669.0" Y="107.0" GraphRef="f3f68" RelX="99.0" RelY="-2.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645598"/> </Interaction> <Interaction GraphId="e2f81"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="700.0" Y="914.0" GraphRef="cbf19" RelX="-0.004484304932735426" RelY="0.9487179487179487"/> <Point X="697.0" Y="950.0" GraphRef="e5c38" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9646468"/> </Interaction> <Interaction GraphId="e4ac0"> <Comment Source="Reactome">SESN2 (Sestrin2) and SESN1 (Sestrin1) each interact with the GATOR2 complex in the absence of leucine and, upon binding leucine, dissociate from the GATOR2 complex (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016). (SESN3 constitutively binds GATOR2 in the presence and absence of leucine.) When bound to GATOR2, the Sestrins appear to prevent GATOR2 from inhibiting GATOR1, a GTPase activator which negatively regulates mTORC1 activation by increasing the rate of hydrolysis of RRAGA,B:GTP to RRAGA,B:GDP. SESN1,2 complexed with GATOR2 therefore allows GATOR1 to maintain mTORC1 in the inactive state (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015). L-leucine binds SESN1,2 and causes SESN1,2 to dissociate from GATOR2, allowing GATOR2 to inhibit GATOR1 and thereby maintain RRAGA,B in the active (GTP-bound) state (Wolfson et al. 2016, Saxton et al. 2016). GATOR1 is recruited to the lysosomal membrane by the KICSTOR complex (Wolfson et al. 2017, Peng et al. 2017).&lt;br&gt;Sestrins also appear to interact with the Rag heterodimer (Peng et al. 2014) though the interaction may be indirect (Budanov 2015).</Comment> <BiopaxRef>ebc</BiopaxRef> <BiopaxRef>a83</BiopaxRef> <BiopaxRef>a07</BiopaxRef> <BiopaxRef>e94</BiopaxRef> <BiopaxRef>b58</BiopaxRef> <BiopaxRef>ecc</BiopaxRef> <BiopaxRef>d39</BiopaxRef> <BiopaxRef>f41</BiopaxRef> <BiopaxRef>aba</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="187.0" Y="600.0"/> <Point X="190.0" Y="644.0"/> <Anchor Position="0.0" Shape="None" GraphId="b74de"/> <Anchor Position="0.99" Shape="None" GraphId="d9838"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639287"/> </Interaction> <Interaction GraphId="e4cae"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="705.0" Y="706.0" GraphRef="c7be0" RelX="0.0" RelY="0.6100000000000136"/> <Point X="633.0" Y="319.0" GraphRef="bca9e" RelX="1.0" RelY="-0.04" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640168"/> </Interaction> <Interaction GraphId="e6d20"> <Comment Source="Reactome">The N-terminal domain of SLC38A9 bound to L-arginine interacts indirectly with the Ragulator complex via the Rag GTPases RRAGA and RRAGC (Wang et al. 2015, Rebsamen et al. 2015, Wyant et al. 2017, Shen and Sabatini 2018).</Comment> <BiopaxRef>c44</BiopaxRef> <BiopaxRef>cf9</BiopaxRef> <BiopaxRef>a9c</BiopaxRef> <BiopaxRef>d85</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="702.0" Y="314.0"/> <Point X="700.0" Y="394.0"/> <Anchor Position="0.0" Shape="None" GraphId="a7af6"/> <Anchor Position="0.99" Shape="None" GraphId="dc00a"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640175"/> </Interaction> <Interaction GraphId="eb14e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="645.0" Y="155.0" GraphRef="de399" RelX="0.32000000000005" RelY="0.4900000000000091"/> <Point X="647.0" Y="201.0" GraphRef="be66c" RelX="-0.0030581039755351682" RelY="-1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639286"/> </Interaction> <Interaction GraphId="eb9f7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="131.0" Y="595.0" GraphRef="f7094" RelX="0.9622641509433962" RelY="0.0"/> <Point X="187.0" Y="600.0" GraphRef="b74de" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9639287"/> </Interaction> <Interaction GraphId="ec019"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="694.0" Y="777.0" GraphRef="fe68e" RelX="0.0" RelY="1.0"/> <Point X="704.0" Y="813.0" GraphRef="d3139" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645608"/> </Interaction> <Interaction GraphId="ed1b4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="720.0" Y="941.0" GraphRef="a52a6" RelX="-1.0" RelY="0.0"/> <Point X="697.0" Y="950.0" GraphRef="e5c38" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9646468"/> </Interaction> <Interaction GraphId="edb59"> <Comment Source="Reactome">CASTOR1 in a heterodimer with CASTOR2 interacts with the GATOR2 complex via the MIOS subunit of GATOR2 (Chantranupong et al. 2016, Gai et al. 2016). The ACT domains of the CASTOR1 subunit bind L-arginine (Chantranupong et al. 2016, Saxton et al. 2016, Xia et al. 2016, Gai et al. 2016) and CASTOR1:arginine dissociates from GATOR2, which then prevents GATOR1 from activating the GTPase of RRAGA,B (Chantranupong et al. 2016). GATOR1 is recruited to the lysosomal membrane by the KICSTOR complex (Wolfson et al. 2017).</Comment> <BiopaxRef>eea</BiopaxRef> <BiopaxRef>bb7</BiopaxRef> <BiopaxRef>f58</BiopaxRef> <BiopaxRef>f3c</BiopaxRef> <BiopaxRef>ecc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="224.0" Y="922.0"/> <Point X="224.0" Y="807.0"/> <Anchor Position="0.0" Shape="None" GraphId="a5a29"/> <Anchor Position="0.99" Shape="None" GraphId="daf01"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640237"/> </Interaction> <Interaction GraphId="f0f36"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="699.0" Y="441.0" GraphRef="c35b7" RelX="-0.004405286343612335" RelY="1.0"/> <Point X="713.0" Y="482.0" GraphRef="d6cc1" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640167"/> </Interaction> <Interaction GraphId="f1e8e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="521.0" Y="1084.0" GraphRef="b1555" RelX="-0.004016064257028112" RelY="-1.0"/> <Point X="441.0" Y="584.0" GraphRef="c1381" RelX="23.0" RelY="-119.0" ArrowHead="mim-catalysis"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640195"/> </Interaction> <Interaction GraphId="f2215"> <Comment Source="Reactome">The heterodimer comprising RRAGA,B:GTP and RRAGC,D:GDP (RagA:GTP or RagB:GTP complexed with RagC:GDP or RagD:GDP) forms the active conformation of the Rag complex that recruits the mTORC1 complex from the cytosol to the lysosomal membrane (Kim et al. 2008, Sancak et al. 2008, Sancak et al. 2010) where RHEB activates the protein kinase activity of mTORC1. Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 (Zoncu et al. 2011). The active state of the RRAGA,B:RRAGC,D heterodimer is less stably associated with the Ragulator complex and appears to cycle with mTORC1 between the lysosomal membrane and the cytosol (Lawrence et al. 2018). 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RRAGA and RRAGB lack detectable GTPase activity in the absence of a GTPase activating protein (Schurmann et al. 1995). The NPRL2 subunit of the GATOR1 complex acts as a GTPase activator of RRAGA,B and thereby controls the guanyl nucleotide bound to RRAGA,B (Bar-Peled et al. 2013, Shen et al. 2019). GATOR2 antagonizes GATOR1 (Bar-Peled et al. 2013). During amino acid deficiency, Sestrins (SESN1 and SESN2) (Chantranupong et al. 2014, Parmigiani et al. 2014, Peng et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016) and CASTOR1 (Chantranupong et al. 2016, Saxton et al. 2016, Gai et al. 2016, Xia et al. 2016) bound to GATOR2 prevent GATOR2 from antagonizing GATOR1 (Bar-Peled et al. 2013). 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The GDP-bound form of RRAGC,D is the active form that recruits mTORC1 to the lysosomal membrane (Tsun et al. 2013). RRAGC,D forms a heterodimer with RRAGA,B that has two stable conformations: RRAGA,B:GTP:RRAGC,D:GDP (active) or RRAGA,B:GDP:RRAGC,D:GTP (inactive) (Shen et al. 2017). Folliculin (FLCN) complexed with FNIP1 or FNIP2 interacts with RRAGA (Petit et al. 2013) and acts as a GTPase activator (GAP) for RRAGC:GTP and RRAGD:GTP (Tsun et al. 2013). FLCN is located at the lysosomal membrane during amino acid starvation and in the cytosol during amino acid stimulation (Tsun et al. 2013).</Comment> <BiopaxRef>b17</BiopaxRef> <BiopaxRef>c8b</BiopaxRef> <BiopaxRef>ebd</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="478.0" Y="83.0"/> <Point X="662.0" Y="135.0"/> <Anchor Position="0.0" Shape="None" GraphId="eaf67"/> <Anchor Position="0.99" Shape="None" GraphId="afdab"/> <Anchor Position="0.5" Shape="None" GraphId="ae97d"/> <Anchor Position="0.5" Shape="None" GraphId="f3f68"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9645598"/> </Interaction> <Interaction GraphId="f87fb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="326.0" Y="325.0" GraphRef="e7551" RelX="-1.8400000000000318" RelY="-7.560000000000059"/> <Point X="172.0" Y="299.0" GraphRef="f2ebb" RelX="0.9428571428571428" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640195"/> </Interaction> <Interaction GraphId="f9bee"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="705.0" Y="547.0" GraphRef="e25db" RelX="-0.08000000000004093" RelY="0.6499999999999773"/> <Point X="847.0" Y="587.0" GraphRef="a93cf" RelX="-1.0" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640167"/> </Interaction> <Interaction GraphId="fa504"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="331.0" Y="592.0" GraphRef="c8c89" RelX="-0.164021164021164" RelY="-14.38888888888889"/> <Point X="441.0" Y="584.0" GraphRef="f2512" RelX="23.0" RelY="-119.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640195"/> </Interaction> <Interaction GraphId="facd3"> <Comment Source="Reactome">The CASTOR1 homodimer interacts with the GATOR2 complex via the MIOS subunit of GATOR2 (Chantranupong et al. 2016, Gai et al. 2016). The ACT domains of CASTOR1 bind L-arginine (Chantranupong et al. 2016, Saxton et al. 2016, Xia et al. 2016, Gai et al. 2016) and CASTOR1:arginine dissociates from GATOR2, which then prevents GATOR1 from activating the GTPase of RRAGA,B (Chantranupong et al. 2016). GATOR1 is recruited to the lysosomal membrane by the KICSTOR complex (Wolfson et al. 2017).</Comment> <BiopaxRef>eea</BiopaxRef> <BiopaxRef>bb7</BiopaxRef> <BiopaxRef>f58</BiopaxRef> <BiopaxRef>f3c</BiopaxRef> <BiopaxRef>ecc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="212.0" Y="914.0"/> <Point X="217.0" Y="752.0"/> <Anchor Position="0.0" Shape="None" GraphId="d1a31"/> <Anchor Position="0.99" Shape="None" GraphId="fc6c5"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9657619"/> </Interaction> <Interaction GraphId="fb1f6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="331.0" Y="592.0" GraphRef="f1525" RelX="1.0" RelY="-0.02564102564102564"/> <Point X="441.0" Y="584.0" GraphRef="f2512" RelX="23.0" RelY="-119.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640195"/> </Interaction> <Interaction GraphId="fe164"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="394.0" Y="667.0" GraphRef="addd8" RelX="1.0" RelY="-0.034482758620689655"/> <Point X="441.0" Y="584.0" GraphRef="e8218" RelX="23.0" RelY="-119.0" ArrowHead="TBar"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9640195"/> </Interaction> <Interaction GraphId="ff0ec"> <Comment Source="Reactome">Upon binding L-arginine, SLC38A9 acts as a guanyl nucleotide exchange factor (GEF) that enhances the conversion of RRAGA:GDP (RagA:GDP, and by inference RRAGB:GDP, RagB:GDP) to RRAGA:GTP, the active form (Shen and Sabatini 2018). The Ragulator complex also shows GEF activity for RRAGA,B (Bar-Peled et al. 2012). SH3BP4 inhibits loading of GTP onto RRAGB during amino acid starvation (Kim et al. 2012). 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sestrin2 inhibits mTORC1 through modulation of GATOR complexes.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kim JS, Ro SH, Kim M, Park HW, Semple IA, Park H, Cho US, Wang W, Guan KL, Karin M, Lee JH.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="e1e"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7499430</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schürmann A, Brauers A, Massmann S, Becker W, Joost HG.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b58"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">25263562</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, Spooner E, Isasa M, Gygi SP, Sabatini DM.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="ace"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">22980980</bp:ID> <bp:DB 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<bp:openControlledVocabulary xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#"><bp:TERM>regulatory pathway</bp:TERM><bp:ID>PW:0000004</bp:ID><bp:Ontology>Pathway Ontology</bp:Ontology></bp:openControlledVocabulary></Biopax> </Pathway>

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