Interleukin-1 family signaling (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Interleukin-1 family signaling" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">The Interleukin-1 (IL1) family of cytokines comprises 11 members, namely Interleukin-1 alpha (IL1A), Interleukin-1 beta (IL1B), Interleukin-1 receptor antagonist protein (IL1RN, IL1RA), Interleukin-18 (IL18), Interleukin-33 (IL33), Interleukin-36 receptor antagonist protein (IL36RN, IL36RA), Interleukin-36 alpha (IL36A), Interleukin-36 beta (IL36B), Interleukin-36 gamma (IL36G), Interleukin-37 (IL37) and Interleukin-38 (IL38). The genes encoding all except IL18 and IL33 are on chromosome 2. They share a common C-terminal three-dimensional structure and with apart from IL1RN they are synthesized without a hydrophobic leader sequence and are not secreted via the classical reticulum endoplasmic-Golgi pathway. IL1B and IL18, are produced as biologically inactive propeptides that are cleaved to produce the mature, active interleukin peptide. The IL1 receptor (IL1R) family comprises 10 members: Interleukin-1 receptor type 1 (IL1R1, IL1RA), Interleukin-1 receptor type 2 (IL1R2, IL1RB), Interleukin-1 receptor accessory protein (IL1RAP, IL1RAcP, IL1R3), Interleukin-18 receptor 1 (IL18R1, IL18RA) , Interleukin-18 receptor accessory protein (IL18RAP, IL18RB), Interleukin-1 receptor-like 1 (IL1RL1, ST2, IL33R), Interleukin-1 receptor-like 2 (IL1RL2, IL36R), Single Ig IL-1-related receptor (SIGIRR, TIR8), Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1, TIGGIR2) and X-linked interleukin-1 receptor accessory protein-like 2 (IL1RAPL2, TIGGIR1). Most of the genes encoding these receptors are on chromosome 2. IL1 family receptors heterodimerize upon cytokine binding. IL1, IL33 and IL36 bind specific receptors, IL1R1, IL1RL1, and IL1RL2 respectively. All use IL1RAP as a co-receptor. IL18 binds IL18R1 and uses IL18RAP as co-receptor. The complexes formed by IL1 family cytokines and their heterodimeric receptors recruit intracellular signaling molecules, including Myeloid differentiation primary response protein MyD88 (MYD88), members of he IL1R-associated kinase (IRAK) family, and TNF receptor-associated factor 6 (TRAF6), activating Nuclear factor NF-kappa-B (NFκB), as well as Mitogen-activated protein kinase 14 (MAPK14, p38), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinases (ERKs) and other Mitogen-activated protein kinases (MAPKs). View original pathway at [http://www.reactome.org/PathwayBrowser/#DIAGRAM=446652 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 446652</Comment> <Comment Source="Reactome-version">Reactome version: 75</Comment> <Comment Source="Reactome Author">Reactome Author: Ray, KP</Comment> <BiopaxRef>ba6</BiopaxRef> <BiopaxRef>d21</BiopaxRef> <BiopaxRef>bcf</BiopaxRef> <BiopaxRef>db8</BiopaxRef> <Attribute Key="reactome_id" Value="446652" /> <Graphics BoardWidth="3109.0" BoardHeight="4133.0" /> <DataNode TextLabel="IL37 " GraphId="a035f" Type="Protein" GroupRef="f957e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9011364" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="2833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="CASP1(317-404) " GraphId="a060e" 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Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008904" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000111679" /> </DataNode> <DataNode TextLabel="IKBKG " GraphId="a9aba" Type="Protein" GroupRef="daba1"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451560" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="3313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y6K9" /> </DataNode> <DataNode TextLabel="TAK1 activates NFkB&#xA;by phosphorylation&#xA;and activation of&#xA;IKKs complex" GraphId="a9e2c" Type="Pathway"> <Comment Source="Reactome">NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.</Comment> <BiopaxRef>fad</BiopaxRef> <BiopaxRef>f10</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="1705.0" CenterY="1640.0" Width="132.0" Height="96.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-445989" /> </DataNode> <DataNode TextLabel="MAP3K7 " GraphId="aa165" Type="Protein" GroupRef="c0df7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="660.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43318" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="aa1cd" Type="Protein" GroupRef="a3465"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451413" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="800.0" CenterY="2933.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="NFKB1(1-968)" GraphId="aa361" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2055.0" CenterY="1927.0" Width="108.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19838" /> </DataNode> <DataNode TextLabel="MYD88 " GraphId="aa97f" Type="Protein" GroupRef="ed581"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450120" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="3433.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99836" /> </DataNode> <DataNode TextLabel="IL1B,Myr82K-Myr83K-IL1A:IL1R1" GraphId="aaab9" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1103.0" CenterY="683.5" Width="100.0" Height="53.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-445755" /> </DataNode> <DataNode TextLabel="TRAF6 " GraphId="aada9" Type="Protein" GroupRef="ad731"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450159" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="520.0" CenterY="3233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y4K3" /> </DataNode> <DataNode TextLabel="IL1RAP-1" GraphId="ab1a2" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2807.0" CenterY="1688.5" Width="64.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="ATP" GraphId="ab2ca" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1098.0" CenterY="1999.5" Width="42.0" Height="31.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="IL37(?-218) " GraphId="ab5cf" Type="Protein" GroupRef="efb80"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9008698" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="Activated TAK&#xA;complexes" GraphId="ab5fc" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1584.0" CenterY="1992.0" Width="98.0" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-772536" /> </DataNode> <DataNode TextLabel="TAB2 " GraphId="ab7d4" Type="Protein" GroupRef="c0df7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="660.0" CenterY="3193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NYJ8" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="ab994" Type="Protein" GroupRef="e88cf"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450185" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2973.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="UBC(457-532) " GraphId="abaf5" Type="Protein" GroupRef="d243b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206877" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="NFKB1(1-433):RELA:p-S32,S36-NFKBIA:BTRC:CUL1:RBX1:SKP1" GraphId="abee3" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2562.0" CenterY="1718.5" Width="114.0" Height="67.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-206891" /> </DataNode> <DataNode TextLabel="IL1R2 " GraphId="ac7b8" Type="Protein" GroupRef="fb19a"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-445750" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P27930" /> </DataNode> <DataNode TextLabel="TAB3 " GraphId="acb37" Type="Protein" GroupRef="a4d76"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute Key="copies_num" Value="21" /> <Graphics CenterX="940.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8N5C8" /> </DataNode> <DataNode TextLabel="IL18RAP" GraphId="acb51" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2733.5" CenterY="678.0" Width="63.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95256" /> </DataNode> <DataNode TextLabel="TAB2 " GraphId="accbb" Type="Protein" GroupRef="a4d76"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute Key="copies_num" Value="18" /> <Graphics CenterX="940.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NYJ8" /> </DataNode> <DataNode TextLabel="MAP3K3 " GraphId="acdb0" Type="Protein" GroupRef="ccb8b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-507714" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="3033.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99759" /> </DataNode> <DataNode TextLabel="p-T,Y-MAPK8" GraphId="ad283" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2616.0" CenterY="2415.0" Width="114.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P45983" /> </DataNode> <DataNode TextLabel="PELI3 " GraphId="ad819" Type="Protein" GroupRef="c0c79"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450814" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="2793.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8N2H9" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="ad884" Type="Protein" GroupRef="e40d2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-202463" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="3313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="K63polyUb " GraphId="adcb4" GroupRef="e053b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948014" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="1080.0" CenterY="2913.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-450152" /> </DataNode> <DataNode TextLabel="UBB(153-228) " GraphId="addea" Type="Protein" GroupRef="b6bd1"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2340.0" CenterY="3373.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="adecf" Type="Protein" GroupRef="a4d76"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute Key="copies_num" Value="11" /> <Graphics CenterX="940.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="ae15f" Type="Protein" GroupRef="e47b7"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948065" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="3093.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="IL4, IL13" GraphId="ae1af" Type="Complex"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2357.5" CenterY="186.0" Width="59.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-6797283" /> </DataNode> <DataNode TextLabel="IL36RN" GraphId="ae593" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2997.5" CenterY="1671.0" Width="51.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBH0" /> </DataNode> <DataNode TextLabel="PTPN23 " GraphId="ae5a0" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9H3S7" /> </DataNode> <DataNode TextLabel="PSMB4 " GraphId="ae9d9" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3453.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28070" /> </DataNode> <DataNode TextLabel="IL1B " GraphId="aeacc" Type="Protein" GroupRef="ec0e9"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446864" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="2793.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01584" /> </DataNode> <DataNode TextLabel="p-S32,S36-NFKBIA " GraphId="aed00" Type="Protein" GroupRef="a3a73"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206891" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="2873.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25963" /> </DataNode> <DataNode TextLabel="UBB(153-228) " GraphId="af0e4" Type="Protein" GroupRef="c66e8"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012428" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3613.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="Myr82K-Myr83K-IL1A " GraphId="af0f1" Type="Protein" GroupRef="d2bab"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446643" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="3113.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01583" /> </DataNode> <DataNode TextLabel="p-S927,S932-NFKB1(1-968) " GraphId="af4b3" Type="Protein" GroupRef="d505e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5684270" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2340.0" CenterY="3093.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19838" /> </DataNode> <DataNode TextLabel="IL1RAP-1" GraphId="af5bc" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="226.0" CenterY="1716.5" Width="64.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="IL36B " GraphId="afe84" Type="Protein" GroupRef="aebdc"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848318" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="3073.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH7" /> </DataNode> <DataNode TextLabel="IL4 " GraphId="b02e6" Type="Protein" GroupRef="fe3f3"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-6797283" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3353.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P05112" /> </DataNode> <DataNode TextLabel="PSME4 " GraphId="b048b" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="4033.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q14997" /> </DataNode> <DataNode TextLabel="UBC(609-684) " GraphId="b0752" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="3193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="MYD88 " GraphId="b0894" Type="Protein" GroupRef="a27d7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446693" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="380.0" CenterY="2893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99836" /> </DataNode> <DataNode TextLabel="IL33 " GraphId="b09a7" Type="Protein" GroupRef="fac9c"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-448601" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="2893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95760" /> </DataNode> <DataNode TextLabel="TOLLIP " GraphId="b0d25" Type="Protein" GroupRef="e746e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446888" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="3033.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9H0E2" /> </DataNode> <DataNode TextLabel="MAP3K7 " GraphId="b0f2f" Type="Protein" GroupRef="d4948"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446878" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43318" /> </DataNode> <DataNode TextLabel="p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2" GraphId="b1304" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2331.5" CenterY="2194.0" Width="101.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5687885" /> </DataNode> <DataNode TextLabel="UBE2N " GraphId="b1481" Type="Protein" GroupRef="bd139"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948064" /> <Attribute Key="copies_num" Value="14" /> <Graphics CenterX="1080.0" CenterY="3133.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P61088" /> </DataNode> <DataNode TextLabel="IL18BP" GraphId="b1616" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2557.0" CenterY="514.0" Width="48.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95998" /> </DataNode> <DataNode TextLabel="PSME1 " GraphId="b1913" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3953.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q06323" /> </DataNode> <DataNode TextLabel="Myr82K-Myr83K-IL1A " GraphId="b1b47" Type="Protein" GroupRef="ec0e9"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446864" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="2773.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01583" /> </DataNode> <DataNode TextLabel="FBXW11 " GraphId="b1e07" Type="Protein" GroupRef="d505e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5684270" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2340.0" CenterY="3033.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UKB1" /> 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Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="IL1R1 inhibitors" GraphId="b524d" Type="Complex"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="1277.0" CenterY="606.5" Width="122.0" Height="19.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-ALL-9681804" /> </DataNode> <DataNode TextLabel="UBC(1-76) " GraphId="b53d9" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="3033.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="PTPN14 " GraphId="b552d" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2953.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15678" /> </DataNode> <DataNode TextLabel="UBC(1-76) " GraphId="b569c" Type="Protein" GroupRef="d243b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206877" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="2893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="TRAF6 " GraphId="b572b" Type="Protein" GroupRef="bc637"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-507716" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="3133.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y4K3" /> </DataNode> <DataNode TextLabel="IL36A " GraphId="b575c" Type="Protein" GroupRef="d0c31"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848325" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="2833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UHA7" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="b577b" Type="Protein" GroupRef="f1591"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948067" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="2873.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="IL37(?-218)" GraphId="b57fb" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1741.0" CenterY="322.0" Width="86.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="IL1R2 " GraphId="b5c1c" Type="Protein" GroupRef="ba7d8"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-445751" /> <Attribute 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TextLabel="hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1" GraphId="b5dc5" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1041.0" CenterY="1667.5" Width="122.0" Height="59.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-450144" /> </DataNode> <DataNode TextLabel="IL1RAPL1 " GraphId="b62dd" Type="Protein" GroupRef="e670d"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-9007912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZN1" /> </DataNode> <DataNode TextLabel="p-IRAK2 " GraphId="b632c" Type="Protein" GroupRef="a4d76"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute Key="copies_num" Value="60" /> <Graphics CenterX="940.0" CenterY="3193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43187" /> </DataNode> <DataNode TextLabel="ADP" GraphId="b66a8" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1801.0" CenterY="1901.0" Width="42.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="MYD88 " GraphId="b699a" Type="Protein" GroupRef="d2bab"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446643" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="3233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99836" /> </DataNode> <DataNode TextLabel="UBC(381-456) " GraphId="b69a7" Type="Protein" GroupRef="c66e8"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012428" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3733.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="b6b04" Type="Protein" GroupRef="efd71"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450144" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="520.0" CenterY="3453.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="RPS27A(1-76) " GraphId="b7642" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62979" /> </DataNode> <DataNode TextLabel="IL1RAP-1 " GraphId="b7929" Type="Protein" GroupRef="b92a0"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-448571" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="3073.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="b7d7c" Type="Protein" GroupRef="ec0e9"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446864" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="520.0" CenterY="2933.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="IL37 " GraphId="b7dbe" Type="Protein" GroupRef="c2fba"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012553" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2060.0" CenterY="3413.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="IL1RL1:IL33" GraphId="b7e21" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="222.5" CenterY="1665.0" Width="85.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-448601" /> </DataNode> <DataNode TextLabel="IL37(1-?):IL37(?-218):CASP1(120-197):CASP1(317-404)" GraphId="b8531" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1528.5" CenterY="260.5" Width="171.0" Height="49.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9012554" /> </DataNode> <DataNode TextLabel="PSMD5 " GraphId="b8d4f" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16401" /> </DataNode> <DataNode TextLabel="PSMA8 " GraphId="b8dc4" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="4053.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8TAA3" /> </DataNode> <DataNode TextLabel="PELI1 " GraphId="b8ec1" Type="Protein" GroupRef="c0c79"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450814" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="2753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96FA3" /> </DataNode> <DataNode TextLabel="UBB(1-76) " GraphId="b8f22" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" 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Database="Uniprot-TrEMBL" ID="Q99460" /> </DataNode> <DataNode TextLabel="IL37(?-218) " GraphId="bc916" Type="Protein" GroupRef="f92df"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012554" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="2813.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="bcd67" Type="Protein" GroupRef="e07e3"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948058" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1080.0" CenterY="3313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="IRAK4 " GraphId="bd193" Type="Protein" GroupRef="f1591"> <Attribute Key="cellular_location" Value="cytosol" 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Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="PTPN20 " GraphId="beb62" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2973.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q4JDL3" /> </DataNode> <DataNode TextLabel="PSMD11 " GraphId="beec5" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3733.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00231" /> </DataNode> <DataNode TextLabel="IL18:IL18R1:IL18RAP" GraphId="bef09" Type="Complex"> <Attribute Key="cellular_location" Value="plasma 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<Xref Database="Ensembl" ID="ENSG00000152104" /> </DataNode> <DataNode TextLabel="UBA52(1-76) " GraphId="bf33a" Type="Protein" GroupRef="d243b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206877" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="2813.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62987" /> </DataNode> <DataNode TextLabel="IRAK4" GraphId="bfc3d" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="689.5" CenterY="784.5" Width="45.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NWZ3" /> </DataNode> <DataNode TextLabel="K63polyUb-TRAF6 " GraphId="bfde8" Type="Protein" GroupRef="a4d76"> <BiopaxRef>b6a</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute 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/> </DataNode> <DataNode TextLabel="IL18R1 " GraphId="c0324" Type="Protein" GroupRef="ccd8c"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-8848366" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3173.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13478" /> </DataNode> <DataNode TextLabel="p-T342,T345,S346-IRAK4" GraphId="c0f5e" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="650.5" CenterY="1427.0" Width="203.0" Height="28.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NWZ3" /> </DataNode> <DataNode TextLabel="UBB(1-76) " GraphId="c1300" Type="Protein" GroupRef="c66e8"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012428" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" 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<Xref Database="Uniprot-TrEMBL" ID="Q9H0E2" /> </DataNode> <DataNode TextLabel="IL37(?-218):p-S423,S425-SMAD3" GraphId="c257a" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="2013.0" CenterY="205.0" Width="112.0" Height="52.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9009912" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="c2588" Type="Protein" GroupRef="c0df7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="660.0" CenterY="3133.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="IL1R1:IL1:IL1RAP:MYD88 dimer" GraphId="c2742" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="748.5" 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The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450144" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="3393.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="PSMB1 " GraphId="c2fd6" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3373.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P20618" /> </DataNode> <DataNode TextLabel="ADP" GraphId="c3039" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2112.5" CenterY="1537.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="UBA52(1-76) " GraphId="c329c" Type="Protein" GroupRef="b6bd1"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2340.0" CenterY="3313.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62987" /> </DataNode> <DataNode TextLabel="RPS27A(1-76) " GraphId="c3471" Type="Protein" GroupRef="d243b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206877" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="2793.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62979" /> </DataNode> <DataNode TextLabel="ADP" GraphId="c3648" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1842.5" CenterY="893.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="IKBKG " GraphId="c38bb" Type="Protein" GroupRef="aca42"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-168113" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="3213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y6K9" /> </DataNode> <DataNode TextLabel="TRAF6 " GraphId="c3a4a" Type="Protein" GroupRef="e8849"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450121" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="2793.0" 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GraphId="c437d" Type="Protein" GroupRef="e4299"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-445755" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2793.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P14778" /> </DataNode> <DataNode TextLabel="PTPN23 gene " GraphId="c4415" Type="Protein" GroupRef="d4437"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008904" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3473.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000076201" /> </DataNode> <DataNode TextLabel="IL18RAP " GraphId="c457d" Type="Protein" GroupRef="a138a"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-8848398" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3273.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95256" /> </DataNode> <DataNode TextLabel="CUL1 " GraphId="c45ad" Type="Protein" GroupRef="d505e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5684270" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2340.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13616" /> </DataNode> <DataNode TextLabel="RELA " GraphId="c4945" Type="Protein" GroupRef="a3a73"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206891" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="2833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q04206" /> </DataNode> <DataNode TextLabel="PELI1 " GraphId="c4ce9" Type="Protein" GroupRef="a3465"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451413" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="2853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96FA3" /> </DataNode> <DataNode TextLabel="IL1B " GraphId="c4d1e" Type="Protein" GroupRef="c10b9"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446125" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01584" /> </DataNode> <DataNode TextLabel="K63polyUb-TRAF6 " GraphId="c4e51" Type="Protein" GroupRef="e47b7"> <BiopaxRef>b6a</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948065" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1220.0" CenterY="3113.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y4K3" /> </DataNode> <DataNode TextLabel="PTPN13 " GraphId="c51b0" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12923" /> </DataNode> <DataNode TextLabel="IRAK4 " GraphId="c51c1" Type="Protein" GroupRef="e746e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446888" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="2913.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NWZ3" /> </DataNode> <DataNode TextLabel="ATP" GraphId="c554e" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1579.0" CenterY="1444.5" Width="42.0" Height="31.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="Myr82K-Myr83K-IL1A " GraphId="c5654" Type="Protein" GroupRef="c15a1"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-445758" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="3193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01583" /> </DataNode> <DataNode TextLabel="p-IRAK2" GraphId="c57e8" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="432.0" CenterY="858.5" Width="66.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43187" /> </DataNode> <DataNode TextLabel="PSMA7 " GraphId="c5920" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3353.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O14818" /> </DataNode> <DataNode TextLabel="ATP" GraphId="c5c10" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1991.0" CenterY="894.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="SKP1 " GraphId="c5d50" Type="Protein" GroupRef="d505e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5684270" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="2340.0" CenterY="2973.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P63208" /> </DataNode> <DataNode TextLabel="UBC(305-380) " GraphId="c5ff4" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="3113.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="IL18BP " GraphId="c6062" Type="Protein" GroupRef="f349a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848369" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95998" /> </DataNode> <DataNode TextLabel="ADP" GraphId="c6172" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2054.5" CenterY="892.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="hp-IRAK1:Pellino,&#xA;IRAK4:Pellino" GraphId="c6223" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1593.0" CenterY="1371.0" Width="118.0" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-451413" /> </DataNode> <DataNode TextLabel="IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1:TRAF6" GraphId="c66b9" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="236.5" CenterY="1344.5" 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GraphId="c71b9" Type="Protein" GroupRef="e746e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446888" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99836" /> </DataNode> <DataNode TextLabel="PTPN12 " GraphId="c7316" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q05209" /> </DataNode> <DataNode TextLabel="CASP1(120-297) " GraphId="c7744" Type="Protein" GroupRef="f92df"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012554" /> <Attribute 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</DataNode> <DataNode TextLabel="IL1RL2 " GraphId="c7f7c" Type="Protein" GroupRef="c7692"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-8848321" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HB29" /> </DataNode> <DataNode TextLabel="NFKB1(1-433) " GraphId="c8309" Type="Protein" GroupRef="d8bfc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206842" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="3293.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19838" /> </DataNode> <DataNode TextLabel="Ub" GraphId="c86ef" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2552.5" CenterY="1826.0" 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<Graphics CenterX="2200.0" CenterY="2873.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q01638" /> </DataNode> <DataNode TextLabel="RELA " GraphId="c9dda" Type="Protein" GroupRef="c764a"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-194047" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q04206" /> </DataNode> <DataNode TextLabel="IL36RN " GraphId="ca20d" Type="Protein" GroupRef="b5205"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8940997" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="3293.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBH0" /> </DataNode> <DataNode TextLabel="CHUK:IKBKB:IKBKG" GraphId="ca265" Type="Complex"> <Comment Source="Reactome">Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS &amp; Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.</Comment> <BiopaxRef>d4b</BiopaxRef> <BiopaxRef>a07</BiopaxRef> <BiopaxRef>dff</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1705.0" CenterY="1757.5" Width="84.0" Height="33.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-168113" /> </DataNode> <DataNode TextLabel="PSMA3 " GraphId="ca293" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3273.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25788" /> </DataNode> <DataNode TextLabel="IL1RAP-1 " GraphId="ca466" Type="Protein" GroupRef="d2bab"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-446643" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="p-PELI2 " GraphId="ca533" Type="Protein" GroupRef="bd139"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948064" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="3073.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HAT8" /> </DataNode> <DataNode TextLabel="IL1R1 " GraphId="ca7bc" Type="Protein" GroupRef="a27d7"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-446693" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="2753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P14778" /> </DataNode> <DataNode TextLabel="p-TBK1" GraphId="cab9d" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2051.5" CenterY="837.0" Width="55.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UHD2" /> </DataNode> <DataNode TextLabel="IL1RAP-1 " GraphId="cad66" Type="Protein" GroupRef="d8d19"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-446637" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="2833.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB" GraphId="cb00e" Type="Complex"> <Comment Source="Reactome">Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS &amp; Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.</Comment> <BiopaxRef>dff</BiopaxRef> <BiopaxRef>a07</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1743.0" CenterY="2079.0" Width="116.0" Height="60.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-177663" /> </DataNode> <DataNode TextLabel="UBC(457-532) " GraphId="cb573" Type="Protein" GroupRef="b6bd1"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2340.0" CenterY="3513.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="IL37 " GraphId="cb6da" Type="Protein" GroupRef="b4830"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848514" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="2953.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="IL33" GraphId="cbadf" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="105.0" CenterY="1419.0" Width="50.0" Height="16.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95760" /> </DataNode> <DataNode TextLabel="PSMB9 " GraphId="cbcda" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3553.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28065" /> </DataNode> <DataNode TextLabel="NFKB1(1-433) " GraphId="cc0c5" Type="Protein" GroupRef="a3a73"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206891" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="2853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19838" /> </DataNode> <DataNode TextLabel="IL1B " GraphId="cc313" Type="Protein" GroupRef="b4ab5"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446696" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="3233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01584" /> </DataNode> <DataNode TextLabel="Ub" GraphId="ccb20" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2076.5" CenterY="2292.0" Width="25.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-113595" /> </DataNode> <DataNode TextLabel="K63polyUb-hp-IRAK1 " GraphId="cccd9" Type="Protein" GroupRef="e07e3"> <BiopaxRef>c50</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948058" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="3213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="IL1RAP-1" GraphId="ccdb8" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1009.0" CenterY="676.5" Width="64.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="p-S207,T211-MAP2K6" GraphId="cd17d" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="982.5" CenterY="2098.5" Width="151.0" Height="27.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P52564" /> </DataNode> <DataNode TextLabel="IRAK2" GraphId="cd250" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="398.5" CenterY="788.5" Width="45.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43187" /> </DataNode> <DataNode TextLabel="IL1R1:IL1R2:IL1RN" GraphId="cd29e" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1897.0" CenterY="684.0" Width="100.0" Height="34.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-445751" /> </DataNode> <DataNode TextLabel="PTPN4 " GraphId="cd441" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2813.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P29074" /> </DataNode> <DataNode TextLabel="p-PELI1 " GraphId="cd519" Type="Protein" GroupRef="a6777"> <BiopaxRef>b35</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451425" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="3053.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96FA3" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="cd520" Type="Protein" GroupRef="a4d76"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-772536" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="2873.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="ALOX5 gene " GraphId="cd6bf" Type="Protein" GroupRef="ff406"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-6797290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000012779" /> </DataNode> <DataNode TextLabel="IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-S376,T378-IRAK1" GraphId="cd8ae" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="206.0" CenterY="1041.5" Width="160.0" Height="71.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-446689" /> </DataNode> <DataNode TextLabel="IL1F10:IL1RAPL1" GraphId="cd931" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2793.5" CenterY="2540.0" Width="79.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9007912" /> </DataNode> <DataNode TextLabel="IL1R1:IL1:IL1RAP:p-T342,T345,S346-IRAK4:MYD88 dimer:TOLLIP:p-2S,S376,T,T209,T378-IRAK1" GraphId="ce548" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="234.0" CenterY="1252.5" Width="174.0" Height="65.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-446696" /> </DataNode> <DataNode TextLabel="PTPN7 " GraphId="ce651" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="2853.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P35236" /> </DataNode> <DataNode TextLabel="IL37(?-218) " GraphId="ce925" Type="Protein" GroupRef="df691"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9009912" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="2753.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="ce9e4" Type="Protein" GroupRef="a6777"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451425" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="3033.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="TAB3 " GraphId="cec0a" Type="Protein" GroupRef="c0df7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="660.0" CenterY="3213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8N5C8" /> </DataNode> <DataNode TextLabel="NFKB1:p-S400-MAP3K8:TNIP2" GraphId="cec31" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2283.0" CenterY="2135.0" Width="102.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5687880" /> </DataNode> <DataNode TextLabel="K63polyUb-TRAF6 " GraphId="cef83" Type="Protein" GroupRef="c0df7"> <BiopaxRef>b6a</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="3093.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y4K3" /> </DataNode> <DataNode TextLabel="IL36A " GraphId="cf147" Type="Protein" GroupRef="c7692"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848321" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="2933.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UHA7" /> </DataNode> <DataNode TextLabel="IL1R1 " GraphId="cf227" Type="Protein" GroupRef="ea36c"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-446689" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="2973.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P14778" /> </DataNode> <DataNode TextLabel="IL1RL2 " GraphId="cf2f7" Type="Protein" GroupRef="b5205"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-8940997" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="3273.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HB29" /> </DataNode> <DataNode TextLabel="Interleukin-1&#xA;processing" GraphId="cf34c" Type="Pathway"> <Comment Source="Reactome">The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough &amp; Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.</Comment> <BiopaxRef>afa</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="1477.0" CenterY="566.0" Width="130.0" Height="60.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-448706" /> </DataNode> <DataNode TextLabel="K63polyUb-TRAF6 " GraphId="cf42c" Type="Protein" GroupRef="efd71"> <BiopaxRef>b6a</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450144" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="520.0" CenterY="3413.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y4K3" /> </DataNode> <DataNode TextLabel="UBC(77-152) " 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Database="Ensembl" ID="ENSG00000175354" /> </DataNode> <DataNode TextLabel="p-T342,T345,S346-IRAK4 " GraphId="d06d4" Type="Protein" GroupRef="ea36c"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446689" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="3073.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NWZ3" /> </DataNode> <DataNode TextLabel="MYD88 dimer" GraphId="d0d66" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="890.5" CenterY="771.0" Width="125.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-193932" /> </DataNode> <DataNode TextLabel="hp-IRAK1:K6-poly-Ub&#xA;oligo-TRAF6:TAK1&#xA;complex" GraphId="d0dc6" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1207.5" 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Database="Uniprot-TrEMBL" ID="O43353" /> </DataNode> <DataNode TextLabel="SHFM1 " GraphId="d17e5" Type="Protein" GroupRef="ec46a"> <BiopaxRef>bcd</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="4093.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P60896" /> </DataNode> <DataNode TextLabel="SKP1 " GraphId="d198b" Type="Protein" GroupRef="a0da6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206748" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="3393.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P63208" /> </DataNode> <DataNode TextLabel="IL1R1 " GraphId="d19ba" Type="Protein" GroupRef="fb19a"> <Attribute Key="cellular_location" 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Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="p-S177,S181-IKBKB" GraphId="d1fce" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1930.0" CenterY="1463.5" Width="136.0" Height="33.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O14920" /> </DataNode> <DataNode TextLabel="ATP" GraphId="d20ea" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2079.0" CenterY="1393.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="IL18R1:IL37,IL37(?-218):SIGIRR" GraphId="d26e5" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2042.5" CenterY="683.0" Width="131.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9008597" /> </DataNode> <DataNode TextLabel="TNIP2 " GraphId="d2716" Type="Protein" GroupRef="ccf45"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5687880" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="3453.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8NFZ5" /> </DataNode> <DataNode TextLabel="PSMD14 " GraphId="d2727" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00487" /> </DataNode> <DataNode TextLabel="Myr82K-Myr83K-IL1A " GraphId="d2779" Type="Protein" GroupRef="a27d7"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-446693" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="2773.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01583" /> </DataNode> <DataNode TextLabel="IL1RAP-1 " GraphId="d2bc9" Type="Protein" GroupRef="aebdc"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-8848318" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="3133.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NPH3-1" /> </DataNode> <DataNode TextLabel="MYD88 " GraphId="d2c50" Type="Protein" GroupRef="b4ab5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446696" /> <Attribute Key="copies_num" Value="2" /> <Graphics 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Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="UBB(153-228) " GraphId="ea2ac" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="SMAD3" GraphId="ea400" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1731.0" CenterY="444.0" Width="60.0" Height="28.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P84022" /> </DataNode> <DataNode TextLabel="PTPN6 " GraphId="ea647" Type="Protein" GroupRef="dc514"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008912" /> <Attribute Key="copies_num" Value="1" /> <Graphics 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The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450810" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="3293.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="TOLLIP " GraphId="eac8b" Type="Protein" GroupRef="ea36c"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-446689" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="3093.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9H0E2" /> </DataNode> <DataNode TextLabel="MYD88 " GraphId="ead38" Type="Protein" GroupRef="b1813"> <Attribute Key="cellular_location" 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TextLabel="IL18 gene " GraphId="f34f8" Type="Protein" GroupRef="ff406"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-6797290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000150782" /> </DataNode> <DataNode TextLabel="p-PELI1 " GraphId="f3b7e" Type="Protein" GroupRef="bd139"> <BiopaxRef>b35</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948064" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="3053.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96FA3" /> </DataNode> <DataNode TextLabel="IL18 " GraphId="f3da5" Type="Protein" GroupRef="ccd8c"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8848366" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1920.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q14116" /> </DataNode> <DataNode TextLabel="p-Pellino-1,2,(3)" GraphId="f4213" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1357.0" CenterY="1823.0" Width="112.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-450819" /> </DataNode> <DataNode TextLabel="UBC(457-532) " GraphId="f446d" Type="Protein" GroupRef="fabb5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-113595" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="3153.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" 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Database="Uniprot-TrEMBL" ID="P01583" /> </DataNode> <DataNode TextLabel="TAB1 " GraphId="f5956" Type="Protein" GroupRef="c0df7"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="660.0" CenterY="3173.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15750" /> </DataNode> <DataNode TextLabel="IL1R1:IL1R1&#xA;inhibitors" GraphId="f5a5b" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1228.5" CenterY="684.5" Width="89.0" Height="37.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9681780" /> </DataNode> <DataNode TextLabel="IL37(?-218)" GraphId="f5a89" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1880.0" CenterY="236.0" Width="86.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZH6" /> </DataNode> <DataNode TextLabel="IL36RN " GraphId="f5c33" Type="Protein" GroupRef="d6674"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8981684" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2060.0" CenterY="3193.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBH0" /> </DataNode> <DataNode TextLabel="IL1B,Myr82K-Myr83K-IL1A" GraphId="f66e2" Type="Complex"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="1391.0" CenterY="684.5" Width="100.0" Height="33.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-445744" /> </DataNode> <DataNode TextLabel="p-PELI3 " GraphId="f6c82" Type="Protein" GroupRef="bc778"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450819" /> <Attribute Key="copies_num" Value="18" /> <Graphics CenterX="1220.0" CenterY="3213.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8N2H9" /> </DataNode> <DataNode TextLabel="CASP1(317-404) " GraphId="f6cad" Type="Protein" GroupRef="c2fba"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-9012553" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="2060.0" CenterY="3373.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P29466" /> </DataNode> <DataNode TextLabel="ADP" GraphId="f6f82" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2553.5" CenterY="2166.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="f7256" Type="Protein" GroupRef="e053b"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948014" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="2873.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="PTPNs2,4,5,6,7,9,11,12,13,14,18,20,23" GraphId="f7307" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1882.5" CenterY="149.0" Width="129.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9008912" /> </DataNode> <DataNode TextLabel="IL1RN " GraphId="f730d" Type="Protein" GroupRef="ba7d8"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-445751" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="3113.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P18510" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="f7476" Type="Protein" GroupRef="e8849"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450121" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="2773.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="IL18:IL18R1" GraphId="f75bb" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2621.5" CenterY="684.0" Width="87.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-8848366" /> </DataNode> <DataNode TextLabel="IL36:IL1RL2" GraphId="f78b4" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2807.5" CenterY="1751.0" Width="79.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-8848321" /> </DataNode> <DataNode TextLabel="UBE2V1 " GraphId="f7c06" Type="Protein" GroupRef="f1591"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948067" /> <Attribute Key="copies_num" Value="38" /> <Graphics CenterX="1220.0" CenterY="2993.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13404" /> </DataNode> <DataNode TextLabel="NFKB1:RELA:p-S32,S36-NFKBIA:Ub" GraphId="f7e1c" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2197.5" CenterY="1784.0" Width="137.0" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-206877" /> </DataNode> <DataNode TextLabel="p-S400,T290-MAP3K8 " GraphId="f8011" Type="Protein" GroupRef="d505e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5684270" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="2340.0" CenterY="3113.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P41279" /> </DataNode> <DataNode TextLabel="PSMB3 " GraphId="f8087" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3433.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49720" /> </DataNode> <DataNode TextLabel="p-S218,S222-MAP2K1,p-S257,T261-MAP2K4" GraphId="f854a" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2201.0" CenterY="2546.0" Width="110.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-451654" /> </DataNode> <DataNode TextLabel="p-S176,S180-CHUK " GraphId="f8bb0" Type="Protein" GroupRef="e9696"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-177663" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="2773.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15111" /> </DataNode> <DataNode TextLabel="ADP" GraphId="f8ca5" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2705.5" CenterY="2413.0" Width="45.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="IL18" GraphId="f8d02" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="2739.0" CenterY="522.5" Width="46.0" Height="25.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q14116" /> </DataNode> <DataNode TextLabel="SQSTM1 " GraphId="f8d52" Type="Protein" GroupRef="ccb8b"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-507714" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="3013.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13501" /> </DataNode> <DataNode TextLabel="SKP1 " GraphId="f8f02" Type="Protein" GroupRef="a3ef2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1168601" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="2340.0" CenterY="3173.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P63208" /> </DataNode> <DataNode TextLabel="p-PELI1 " GraphId="f9001" Type="Protein" GroupRef="e07e3"> <BiopaxRef>b35</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-8948058" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="3233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96FA3" /> </DataNode> <DataNode TextLabel="NFKB1:p-T290-MAP3K8:TNIP2" GraphId="f9041" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2398.5" CenterY="2255.5" Width="121.0" Height="39.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5684265" /> </DataNode> <DataNode TextLabel="PSMD7 " GraphId="f98b7" Type="Protein" GroupRef="ec46a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3893.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51665" /> </DataNode> <DataNode TextLabel="PTPN5 gene " GraphId="f9924" Type="Protein" GroupRef="d4437"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9008904" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="3293.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000110786" /> </DataNode> <DataNode TextLabel="MAP3K8 " GraphId="f9ce6" Type="Protein" GroupRef="f2293"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-451638" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="2200.0" CenterY="3233.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P41279" /> </DataNode> <DataNode TextLabel="p-2S,S376,T,T209,T387-IRAK1 " GraphId="f9f41" Type="Protein" GroupRef="c0df7"> <Comment Source="Reactome">This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-450186" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="3073.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51617" /> </DataNode> <DataNode TextLabel="hp-IRAK1:3xTRAF6:3xUBE2N:UBE2V1:K63polyUb" GraphId="fa178" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1098.5" CenterY="1532.0" Width="127.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-8948014" /> </DataNode> <DataNode TextLabel="Myr82K-Myr83K-IL1A " GraphId="fa1eb" Type="Protein" GroupRef="e746e"> <Attribute Key="cellular_location" Value="extracellular 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Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-68819" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1500.0" CenterY="3773.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UNM6" /> </DataNode> <Interaction GraphId="a00b1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1441.0" Y="684.0" GraphRef="f66e2" RelX="1.0" RelY="-0.030303030303030304" /> <Point X="1488.0" Y="738.0" GraphRef="f542c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446130" /> </Interaction> <Interaction GraphId="a0bc3"> <Comment Source="Reactome">Serine/threonine protein kinase TBK1 plays a key role in regulating inflammatory responses. TBK1 activity is regulated by phosphorylation of Ser 172 within the kinase activation loop (Kishore et al. 2002). TBK1 phosphorylation is thought to be an autoactivation event. The IL 37b:IL-18R1:SIGIRR complex can suppress TBK1 activity (Nold Petry et al. 2015, Clark K et al. 2009). This event is set as a black box event instance because the precise mechanism of TBK1 suppression by IL 37b:IL-18R1:SIGIRR complex is uncertain.</Comment> <BiopaxRef>f3f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2169.0" Y="863.0" /> <Point X="2101.0" Y="862.0" /> <Anchor Position="0.0" Shape="None" GraphId="b781f" /> <Anchor Position="0.99" Shape="None" GraphId="fd853" /> <Anchor Position="0.5" Shape="None" GraphId="c6d6f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008684" /> </Interaction> <Interaction GraphId="a12af"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2328.0" Y="186.0" GraphRef="ae1af" RelX="-1.0" RelY="0.0" /> <Point X="2358.0" Y="226.0" GraphRef="ab3cc" RelX="16.0" RelY="0.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6797293" /> </Interaction> <Interaction GraphId="a159b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2410.0" Y="684.0" GraphRef="a612d" RelX="-1.0" RelY="0.0" /> <Point X="2400.0" Y="730.0" GraphRef="dd7a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848335" /> </Interaction> <Interaction GraphId="a1912"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2376.0" Y="2121.0" GraphRef="adc0c" RelX="-0.01999999999998181" RelY="0.9499999999998181" /> <Point X="2331.0" Y="2169.0" GraphRef="b1304" RelX="-0.009900990099009901" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684267" /> </Interaction> <Interaction GraphId="a1aa7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2343.0" Y="1655.0" GraphRef="dd363" RelX="0.983739837398374" RelY="0.0" /> <Point X="2475.0" Y="1780.0" GraphRef="ba4e2" RelX="0.0" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209063" /> </Interaction> <Interaction GraphId="a1bb9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2875.0" Y="1877.0" GraphRef="ebe73" RelX="-1.0" RelY="-0.02702702702702703" /> <Point X="2873.0" Y="1830.0" GraphRef="cdbe4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848316" /> </Interaction> <Interaction GraphId="a1e02"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2285.0" Y="507.0" GraphRef="b59e3" RelX="0.0" RelY="0.9499999999999886" /> <Point X="2286.0" Y="513.0" GraphRef="be780" RelX="-0.008130081300813009" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008694" /> </Interaction> <Interaction GraphId="a1e1c"> <Comment Source="Reactome">The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).</Comment> <BiopaxRef>c10</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1268.0" Y="2032.0" /> <Point X="1480.0" Y="2078.0" /> <Anchor Position="0.0" Shape="None" GraphId="db025" /> <Anchor Position="0.99" Shape="None" GraphId="dbecf" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450187" /> </Interaction> <Interaction GraphId="a2028"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1663.0" Y="1757.0" GraphRef="ca265" RelX="-1.0" RelY="-0.030303030303030304" /> <Point X="1622.0" Y="1829.0" GraphRef="f1b69" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451561" /> </Interaction> <Interaction GraphId="a3533"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1576.0" Y="1889.0" GraphRef="da07b" RelX="-0.4600000000000364" RelY="0.599999999999909" /> <Point X="1551.0" Y="1892.0" GraphRef="bb355" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451561" /> </Interaction> <Interaction GraphId="a399e"> <Comment Source="Reactome">IRAK1 and 4 interact with Pellino-1 (Jiang et al. 2003), 2 (Strellow et al. 2003) and 3 (Butler et al. 2005, 2007). Pellinos may act as scaffolding proteins, bringing signaling complexes into proximity. They are E3 ubiquitin ligases capable of ubiquitinating IRAK1, believed to mediate IL-1-stimulated formation of K63-polyubiquitinated IRAK1 in cells.&lt;br&gt;&lt;br&gt;Though not clearly demonstrated and therefore not shown here, the current models of IRAK1 involvement suggest it would be within a complex including TRAF6.</Comment> <BiopaxRef>a29</BiopaxRef> <BiopaxRef>da1</BiopaxRef> <BiopaxRef>fc0</BiopaxRef> <BiopaxRef>b66</BiopaxRef> <BiopaxRef>ace</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1713.0" Y="1372.0" /> <Point X="1658.0" Y="1369.0" /> <Anchor Position="0.0" Shape="None" GraphId="fa3f8" /> <Anchor Position="0.99" Shape="None" GraphId="e2009" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450690" /> </Interaction> <Interaction GraphId="a3b06"> <Comment Source="Reactome">Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). Like several other IL1 family members, IL1F10 is synthesized as precursors that require N terminal processing to attain full receptor agonist or antagonist function. The N terminal truncation of IL1F10 precursor occurs during apoptosis and the predicted cleavage site is at amino acid 19 (Mora et al. 2016). The proteases from apoptosis are believed to be the responsible for the cleavage process. This truncated form of IL1F10 may undergo additional processing before becoming an active interleukin. 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LineThickness="1.0"> <Point X="649.0" Y="704.0" GraphRef="b2a51" RelX="-0.5199999999999818" RelY="-0.32000000000005" /> <Point X="665.0" Y="677.0" GraphRef="ed78e" RelX="0.9801980198019802" RelY="-0.02127659574468085" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446648" /> </Interaction> <Interaction GraphId="a5c29"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="180.0" Y="1665.0" GraphRef="b7e21" RelX="-1.0" RelY="0.0" /> <Point X="160.0" Y="1710.0" GraphRef="f5d37" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448603" /> </Interaction> <Interaction GraphId="a60df"> <Comment Source="Reactome">Interleukin-1 receptor type 1 (IL1R1) is the receptor responsible for transmitting the inflammatory effects of Interleukin-1 (IL1).</Comment> <BiopaxRef>e76</BiopaxRef> <BiopaxRef>fa7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1328.0" Y="744.0" /> <Point 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ZOrder="12288" LineThickness="1.0"> <Point X="1720.0" Y="685.0" GraphRef="e28c8" RelX="-1.0" RelY="-0.04" /> <Point X="1710.0" Y="738.0" GraphRef="ab2d3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-445757" /> </Interaction> <Interaction GraphId="aaa3f"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Both full length and cleaved IL-37 can be secreted from the cytosol to the extracellular space via a mechanism dependent on caspase 1 cleavage of IL-37 (Bulau A M et al. 2014).</Comment> <BiopaxRef>a0c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2285.0" Y="412.0" /> <Point X="2285.0" Y="507.0" /> <Anchor Position="0.0" Shape="None" GraphId="b7833" /> <Anchor Position="0.99" Shape="None" GraphId="b59e3" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008694" /> </Interaction> <Interaction GraphId="aae05"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2227.0" Y="2235.0" GraphRef="fae02" RelX="0.0" RelY="-1.0" /> <Point X="2196.0" Y="2232.0" GraphRef="daf33" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684273" /> </Interaction> <Interaction GraphId="aba08"> <Comment Source="Reactome">Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation.</Comment> <BiopaxRef>e2a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2155.0" Y="2325.0" /> <Point X="2206.0" Y="2325.0" /> <Anchor Position="0.0" Shape="None" GraphId="eb2be" /> <Anchor Position="0.99" Shape="None" GraphId="c83aa" /> <Anchor Position="0.5" Shape="None" GraphId="ca685" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684250" /> </Interaction> <Interaction GraphId="aba93"> <Comment Source="Reactome">MyD88 recruits unphosphorylated IRAK1 to the signaling complex. IRAK1 is then rapidly activated and autophosphorylates in a region that is outside the kinase domain (Cao et al. 1996). Several pieces of evidence suggest that IRAK4 triggers IRAK1 activation by phosphorylating its kinase activation loop, leading to IRAK1 autophosphorylation (Suzuki et al. 2002): in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 (Li et al. 2002); IRAK1 phosphorylation by IRAK4 is independent of and precedes IRAK1 activation and autophosphorylation; IRAK1 autophosphorylation is partially inhibited in cells overexpressing a kinase-inactive IRAK4 protein (Li et al. 2002).</Comment> <BiopaxRef>c48</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="282.0" Y="902.0" /> <Point X="282.0" Y="968.0" /> <Anchor Position="0.0" Shape="None" GraphId="db43a" /> <Anchor Position="0.99" Shape="None" GraphId="b2ee9" /> <Anchor Position="0.5" Shape="None" GraphId="e0d0c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446694" /> </Interaction> <Interaction GraphId="abd7c"> <Graphics ConnectorType="Segmented" ZOrder="12288" 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Phosphorylation enhances the E3 ligase activity of Pellino-1 in conjunction with several different E2-conjugating enzymes (Ubc13-Uev1a, UbcH4, or UbcH5a/5b). Phosphorylation at any of several different sites or a combination of other sites leads to full activation of Pellino-1 E3 ubiquitin ligase activity.&lt;br&gt;&lt;br&gt;Though not shown here, the current models of IRAK1 involvement suggest it is part of a complex that includes TRAF6.</Comment> <BiopaxRef>b35</BiopaxRef> <BiopaxRef>fc0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1555.0" Y="1415.0" /> <Point X="1499.0" Y="1414.0" /> <Anchor Position="0.0" Shape="None" GraphId="a2a1d" /> <Anchor Position="0.99" Shape="None" GraphId="ec1a3" /> <Anchor Position="0.5" Shape="None" GraphId="e8a7d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450827" /> </Interaction> <Interaction GraphId="afcba"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2108.0" Y="2201.0" GraphRef="d9a43" RelX="-0.8800000000001091" RelY="-0.30999999999994543" /> <Point X="2034.0" Y="2020.0" GraphRef="dcfec" RelX="-0.01639344262295082" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684273" /> </Interaction> <Interaction GraphId="afe61"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="105.0" Y="1427.0" GraphRef="cbadf" RelX="0.0" RelY="1.0" /> <Point X="124.0" Y="1505.0" GraphRef="a85d1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448629" /> </Interaction> <Interaction GraphId="b0a0d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2194.0" Y="1900.0" GraphRef="e51a9" RelX="0.0" RelY="1.0" /> <Point X="2192.0" Y="1968.0" GraphRef="cacfb" RelX="-9.0" RelY="0.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451634" /> </Interaction> <Interaction GraphId="b0d5f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="183.0" Y="1757.0" GraphRef="d6c7c" RelX="0.22999999999998977" RelY="0.4700000000000273" /> <Point X="186.0" Y="1774.0" GraphRef="d55d6" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448603" /> </Interaction> <Interaction GraphId="b0f37"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1524.0" Y="163.0" GraphRef="db383" RelX="-0.007751937984496124" RelY="1.0" /> <Point X="1525.0" Y="198.0" GraphRef="c8f6c" RelX="0.0" RelY="-1.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012556" /> </Interaction> <Interaction GraphId="b178d"> <Comment Source="Reactome">Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). IL1F10 can bind to interleukin 1 receptor like 2 (IL1RL2, IL 36R, IL1Rrp2, IL1R6). This binding has biological consequences similar to another IL1RL2 ligand IL 36 receptor antagonist (IL 36Ra), such as suppression of IL17 and IL22 and induction of IL6 production (van de Veerdonk et al. 2012, Mora et al. 2016). Ultimately, these events lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.</Comment> <BiopaxRef>c77</BiopaxRef> <BiopaxRef>d61</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2695.0" Y="2055.0" /> <Point X="2738.0" Y="2140.0" /> <Anchor Position="0.0" Shape="None" GraphId="a0c21" /> <Anchor Position="0.99" Shape="None" GraphId="baa3b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9007901" /> </Interaction> <Interaction GraphId="b18bb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2206.0" Y="2325.0" GraphRef="c83aa" RelX="0.5100000000002183" RelY="0.0" /> <Point X="2227.0" Y="2281.0" GraphRef="fae02" RelX="0.0" RelY="0.9574468085106383" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684250" /> </Interaction> <Interaction GraphId="b1eaa"> <Comment Source="Reactome">p62, MEKK3 and TRAF6 co-localize in cytoplasmic aggregates that are thought to be centres for organizing TRAF6-regulated NF-kappaB signaling and the assembly of polyubiquinated proteins sorting to sequestosomes and proteasomes. p62/Sequestosome-1 is a scaffold protein involved in the regulation of autophagy, trafficking of proteins to the proteasome and activation of NF-kB. p62 binds the basic region of MEKK3. MEKK3 is known to bind TRAF6 in response to IL1B (Huang et al. 2004). Recently p62 was shown to be required for the association of MEKK3 with TRAF6. RNA knockdown of p62 inhibited IL1B and MEKK3 activation of NF-kB. IL1B stimulation resulted in dissociation of MEKK3 from p62:TRAF6 (Nakamura et al. 2010).</Comment> <BiopaxRef>b6b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1145.0" Y="1189.0" /> <Point X="1143.0" Y="1107.0" /> <Anchor Position="0.0" Shape="None" GraphId="cded6" /> <Anchor Position="0.99" Shape="None" GraphId="f02c2" /> <Anchor Position="0.5" Shape="None" GraphId="e3dba" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-507719" /> </Interaction> <Interaction GraphId="b211e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2127.0" Y="2592.0" GraphRef="a7e9e" RelX="0.7100000000000364" RelY="0.0" /> <Point X="2146.0" Y="2546.0" GraphRef="f854a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451649" /> </Interaction> <Interaction GraphId="b212a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1801.0" Y="2079.0" GraphRef="cb00e" RelX="1.0" RelY="0.0" /> <Point X="2348.0" Y="2048.0" GraphRef="f9ab6" RelX="0.5" RelY="-4.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684275" /> </Interaction> <Interaction GraphId="b254e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1874.0" Y="704.0" GraphRef="ffd5b" RelX="1.6400000000001" RelY="-0.34000000000003183" /> <Point X="1897.0" Y="701.0" GraphRef="cd29e" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-445757" /> </Interaction> <Interaction GraphId="b263e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1882.0" Y="865.0" GraphRef="f35e2" RelX="-0.599999999999909" RelY="0.01999999999998181" /> <Point X="1883.0" Y="837.0" GraphRef="fabbf" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9009072" /> </Interaction> <Interaction GraphId="b29b3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="433.0" Y="679.0" GraphRef="f04c9" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="380.0" Y="679.0" GraphRef="a656d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446634" /> </Interaction> <Interaction GraphId="b3699"> <Comment Source="Reactome">A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop &amp; Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008).</Comment> <BiopaxRef>c6c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="303.0" Y="1114.0" /> <Point X="302.0" Y="1174.0" /> <Anchor Position="0.0" Shape="None" GraphId="c8b62" /> <Anchor Position="0.99" Shape="None" GraphId="e60a6" /> <Anchor Position="0.5" Shape="None" GraphId="b8c06" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446701" /> </Interaction> <Interaction GraphId="b38f6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2560.0" Y="590.0" GraphRef="a90ba" RelX="-0.6199999999998909" RelY="0.5" /> <Point X="2568.0" Y="604.0" GraphRef="c7b3d" RelX="0.9764705882352941" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848392" /> </Interaction> <Interaction GraphId="b3978"> <Comment Source="Reactome">IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. &lt;br&gt;Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).</Comment> <BiopaxRef>a29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1543.0" Y="1660.0" /> <Point X="1544.0" Y="1709.0" /> <Anchor Position="0.0" Shape="None" GraphId="e9fa1" /> <Anchor Position="0.99" Shape="None" GraphId="af0d0" /> <Anchor Position="0.5" Shape="None" GraphId="c2efa" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451418" /> </Interaction> <Interaction GraphId="b40e3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2347.0" Y="2092.0" GraphRef="bf840" RelX="-0.010000000000218279" RelY="0.8000000000001819" /> <Point X="2334.0" Y="2135.0" GraphRef="cec31" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684275" /> </Interaction> <Interaction GraphId="b4647"> <Graphics ConnectorType="Segmented" 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LineThickness="1.0"> <Point X="2732.0" Y="2453.0" GraphRef="c96d8" RelX="-1.0" RelY="0.0" /> <Point X="2649.0" Y="2324.0" GraphRef="fe423" RelX="1.0" RelY="1.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008043" /> </Interaction> <Interaction GraphId="b9f24"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="320.0" Y="1344.0" GraphRef="c66b9" RelX="0.9881656804733728" RelY="-0.015873015873015872" /> <Point X="324.0" Y="1347.0" GraphRef="a7b2f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="ba15f"> <Comment Source="Reactome">Interleukin-18 binding protein (IL18BP) is a constitutively secreted protein, with an exceptionally high affinity for IL18 (400 pM) (Kim et al. 2000). It is present in the serum of healthy humans at a 20-fold molar excess compared to IL18 (Novick et al. 2001) and may blunt the Th1 response to foreign organisms, thereby reducing any autoimmune responses to a routine infection (Dinarello et al. 2013). Some studies indicate this IL18BP:IL18 complex negatively regulates IL18:IL18 receptor interaction (Kim et al. 2002, Im et al. 2002).&lt;br&gt;</Comment> <BiopaxRef>db9</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2622.0" Y="540.0" /> <Point X="2560.0" Y="590.0" /> <Anchor Position="0.0" Shape="None" GraphId="d4e4d" /> <Anchor Position="0.99" Shape="None" GraphId="a90ba" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848392" /> </Interaction> <Interaction GraphId="ba19d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1499.0" Y="1414.0" GraphRef="ec1a3" RelX="-0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="1474.0" Y="1372.0" GraphRef="e28d4" RelX="0.9844961240310077" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450827" /> </Interaction> <Interaction GraphId="ba2f9"> <Comment Source="Reactome">IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346.</Comment> <BiopaxRef>e47</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="380.0" Y="679.0" /> <Point X="308.0" Y="679.0" /> <Anchor Position="0.0" Shape="None" GraphId="a656d" /> <Anchor Position="0.99" Shape="None" GraphId="f3a0a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446634" /> </Interaction> <Interaction GraphId="ba324"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1905.0" Y="1672.0" GraphRef="b5cfe" RelX="0.0" RelY="1.0" /> <Point X="1905.0" Y="1675.0" GraphRef="f3634" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2730894" /> </Interaction> <Interaction GraphId="baca5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2768.0" Y="1751.0" GraphRef="f78b4" RelX="-1.0" RelY="0.0" /> <Point X="2758.0" Y="1728.0" GraphRef="c7486" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848314" /> </Interaction> <Interaction GraphId="bc70b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2414.0" Y="599.0" GraphRef="b07c8" RelX="0.010000000000218279" RelY="0.6100000000000136" /> <Point X="2415.0" Y="602.0" GraphRef="dbb00" RelX="-0.010309278350515464" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008587" /> </Interaction> <Interaction GraphId="bc86b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2130.0" Y="2364.0" GraphRef="e8bc6" RelX="-0.008" RelY="-1.0" /> <Point X="2182.0" Y="2324.0" GraphRef="ca685" RelX="1.5" RelY="-1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684250" /> </Interaction> <Interaction GraphId="bc955"> <Comment Source="Reactome">TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.</Comment> <BiopaxRef>b6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1073.0" Y="1560.0" /> <Point X="1042.0" Y="1635.0" /> <Anchor Position="0.0" Shape="None" GraphId="fc028" /> <Anchor Position="0.99" Shape="None" GraphId="fd9ef" /> <Anchor Position="0.5" Shape="None" GraphId="f3f53" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446877" /> </Interaction> <Interaction GraphId="bcda1"> <Comment Source="Reactome">IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2).</Comment> <BiopaxRef>cac</BiopaxRef> <BiopaxRef>d81</BiopaxRef> <BiopaxRef>dee</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2196.0" Y="2232.0" /> <Point X="2108.0" Y="2201.0" /> <Anchor Position="0.0" Shape="None" GraphId="daf33" /> <Anchor Position="0.99" Shape="None" GraphId="d9a43" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684273" /> </Interaction> <Interaction GraphId="bce60"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1284.0" Y="682.0" GraphRef="f022b" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="1267.0" Y="639.0" GraphRef="fc935" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9681763" /> </Interaction> <Interaction GraphId="bd15a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2621.0" Y="670.0" GraphRef="e94fa" RelX="-0.010000000000218279" RelY="0.6399999999999864" /> <Point X="2621.0" Y="673.0" GraphRef="f75bb" RelX="-0.011494252873563218" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848370" /> </Interaction> <Interaction GraphId="bd3fd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1579.0" Y="1429.0" GraphRef="c554e" RelX="0.0" RelY="-1.0" /> <Point X="1555.0" Y="1415.0" GraphRef="a2a1d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450827" /> </Interaction> <Interaction GraphId="bd79b"> <Comment Source="Reactome">Tyrosine protein phosphatase non receptors (PTPNs) are a family of enzymes that act in coordination with protein tyrosine kinases to control various signalling pathways downstream. This event represents the transcription and translation of the PTPN set comprising the members: 2, 4, 5, 6, 7, 9, 11, 12, 13, 14, 18, 20 and 23. This event is positively regulated by IL-37b(? 218):SMAD3 and promotes dephosphorylation and suppression of the activation of tyrosine phosphorylation-dependent signaling pathways such as ERK, p38 MAPK, JNK, PI3K, NF-κB, and STAT3 pathways. (Luo et al., 2017).</Comment> <BiopaxRef>a2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2086.0" Y="147.0" /> <Point X="1953.0" Y="147.0" /> <Anchor Position="0.0" Shape="None" GraphId="ccdfe" /> <Anchor Position="0.99" Shape="None" GraphId="fb752" /> <Anchor Position="0.5" Shape="None" GraphId="b1211" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008894" /> </Interaction> <Interaction GraphId="bde22"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="689.0" Y="773.0" GraphRef="bfc3d" RelX="-0.022222222222222223" RelY="-1.0" /> <Point X="701.0" Y="736.0" GraphRef="f51ac" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446648" /> </Interaction> <Interaction GraphId="be05d"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1F7) is a member of the IL-1 family. There are five isoforms of IL37 (a e) of which transcript IL-37 is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. (Kumar et al. 2002). Both full length and processed IL-37 can bind the Interleukin 18 receptor 1 (IL-18R1) but binding of processed IL-37 is more effective (Shi et al. 2003, Kumar et al. 2002). Subsequently, Single Ig IL-1 related receptor (SIGIRR, TIR 8,IL-1R8) is recruited and facilitates the suppression of cytokine production in several types of immune cells resulting in reduced inflammation.</Comment> <BiopaxRef>e08</BiopaxRef> <BiopaxRef>d9e</BiopaxRef> <BiopaxRef>a95</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2400.0" Y="730.0" /> <Point X="2293.0" Y="705.0" /> <Anchor Position="0.0" Shape="None" GraphId="dd7a4" /> <Anchor Position="0.99" Shape="None" GraphId="f948d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848335" /> </Interaction> <Interaction GraphId="bf248"> <Comment Source="Reactome">The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).&lt;p&gt;The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.&lt;p&gt; Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012).</Comment> <BiopaxRef>a57</BiopaxRef> <BiopaxRef>dbe</BiopaxRef> <BiopaxRef>de8</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2412.0" Y="2030.0" /> <Point X="2407.0" Y="2151.0" /> <Anchor Position="0.0" Shape="None" GraphId="f5d6f" /> <Anchor Position="0.99" Shape="None" GraphId="bbf32" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684261" /> </Interaction> <Interaction GraphId="bfb4b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2827.0" Y="2260.0" GraphRef="edc4d" RelX="0.9746835443037974" RelY="0.0" /> <Point X="2908.0" Y="2321.0" GraphRef="fdd66" RelX="0.0" RelY="0.0" /> </Graphics> <Xref 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<Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2347.0" Y="1577.0" GraphRef="c7f36" RelX="0.9862068965517241" RelY="-0.02702702702702703" /> <Point X="2338.0" Y="1613.0" GraphRef="ef803" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209125" /> </Interaction> <Interaction GraphId="c70ef"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. (Kumar et al. 2002). IL-18 binding protein (IL-18BP) binds IL-18 with high affinity inhibiting its activity (Kim et al. 2000). Both full length and processed IL-37 bind the third extracellular domain (D3) of IL-18BP. The binding of IL-18BP to IL-37 makes it unavailable for neutralization of IL-18 activity (Bufler et al. 2002). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.</Comment> <BiopaxRef>ec6</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2413.0" Y="538.0" /> <Point X="2414.0" Y="599.0" /> <Anchor Position="0.0" Shape="None" GraphId="fef43" /> <Anchor Position="0.99" Shape="None" GraphId="b07c8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008587" /> </Interaction> <Interaction GraphId="c7b77"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2719.0" Y="641.0" GraphRef="dc0bd" RelX="-1.0" RelY="0.0" /> <Point X="2622.0" Y="643.0" GraphRef="bb83c" RelX="0.5" RelY="5.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848370" /> </Interaction> <Interaction GraphId="c8259"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2245.0" Y="1968.0" GraphRef="e25fa" RelX="0.8800000000001091" RelY="0.009999999999990905" /> <Point X="2248.0" Y="1968.0" GraphRef="ede25" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451634" /> </Interaction> <Interaction GraphId="c8292"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2188.0" Y="2431.0" GraphRef="fb8f7" RelX="-0.6999999999998181" RelY="-0.13999999999987267" /> <Point X="2192.0" Y="2396.0" GraphRef="e8bc6" RelX="0.984" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684248" /> </Interaction> <Interaction GraphId="c8456"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. IL-37(? 218) can bind phosphorylated SMAD3 in A549 cells (Nold M F et al. 2010, Grimsby S et al. 2004) and may affect its function.</Comment> <BiopaxRef>f25</BiopaxRef> <BiopaxRef>eb0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1863.0" Y="326.0" /> <Point X="1943.0" Y="326.0" /> <Anchor Position="0.0" Shape="None" GraphId="f5f68" /> <Anchor Position="0.99" Shape="None" GraphId="f1143" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9009910" /> </Interaction> <Interaction GraphId="c87c3"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). However, other truncation sites in IL-37 have been suggested (Pan et al. 2001). Once processed, Caspase 1 dissociates from the protein. Caspase 1 may not be the only enzyme responsible for IL-37 processing (Sharma et al. 2008). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation. This is a black box event because the cleavage sites and the enzymes responsible for the processing of IL-37 are uncertain.</Comment> <BiopaxRef>e08</BiopaxRef> <BiopaxRef>a8f</BiopaxRef> <BiopaxRef>a0c</BiopaxRef> <BiopaxRef>d9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1554.0" Y="233.0" /> <Point X="1723.0" Y="88.0" /> <Anchor Position="0.0" Shape="None" GraphId="d217f" /> <Anchor Position="0.99" Shape="None" GraphId="e33ee" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012689" /> </Interaction> <Interaction GraphId="c921b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2831.0" Y="1915.0" GraphRef="ff196" RelX="0.0" RelY="-1.0" /> <Point X="2873.0" Y="1830.0" GraphRef="cdbe4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848316" /> </Interaction> <Interaction GraphId="c9698"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="199.0" Y="1494.0" GraphRef="ff48e" RelX="-1.0" RelY="0.0" /> <Point X="124.0" Y="1505.0" GraphRef="a85d1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448629" /> </Interaction> <Interaction GraphId="ca06f"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). However, other truncation sites in IL-37 have been suggested (Pan et al. 2001). Caspase 1 may not be the only enzyme responsible for IL-37 processing (Sharma et al. 2008). This is a black box event because the cleavage sites and the enzymes responsible for the processing of IL-37 are uncertain.</Comment> <BiopaxRef>e08</BiopaxRef> <BiopaxRef>a8f</BiopaxRef> <BiopaxRef>a0c</BiopaxRef> <BiopaxRef>d9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1524.0" Y="166.0" /> <Point X="1526.0" Y="233.0" /> <Anchor Position="0.0" Shape="None" GraphId="e5bf1" /> <Anchor Position="0.99" Shape="None" GraphId="ba9af" /> <Anchor Position="0.5" Shape="None" GraphId="c8f6c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012556" /> </Interaction> <Interaction GraphId="ca70d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2463.0" Y="620.0" GraphRef="dbb00" RelX="0.979381443298969" RelY="-0.02702702702702703" /> <Point X="2671.0" Y="783.0" GraphRef="f564a" RelX="-45.0" RelY="4.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848395" /> </Interaction> <Interaction GraphId="cb17b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2315.0" Y="2476.0" GraphRef="fb5e8" RelX="-1.0" RelY="0.0" /> <Point X="2258.0" Y="2445.0" GraphRef="d6067" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684248" /> </Interaction> <Interaction GraphId="cb659"> <Comment Source="Reactome">Interleukin-18 (IL18) binds IL18 receptor alpha chain (IL18R1), with low affinity (Torigoe et al. 1997, Kato et al. 2007).</Comment> <BiopaxRef>ab3</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2622.0" Y="606.0" /> <Point X="2621.0" Y="670.0" /> <Anchor Position="0.0" Shape="None" GraphId="c9a45" /> <Anchor Position="0.99" Shape="None" GraphId="e94fa" /> <Anchor Position="0.5" Shape="None" GraphId="de991" /> <Anchor Position="0.5" Shape="None" GraphId="bb83c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848370" /> </Interaction> <Interaction GraphId="cb6eb"> <Comment Source="Reactome">MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). 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ID="R-HSA-507719" /> </Interaction> <Interaction GraphId="cd8a9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2286.0" Y="406.0" GraphRef="d79e1" RelX="-0.009345794392523364" RelY="1.0" /> <Point X="2285.0" Y="412.0" GraphRef="b7833" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008694" /> </Interaction> <Interaction GraphId="ce104"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2801.0" Y="2031.0" GraphRef="be67f" RelX="-0.009900990099009901" RelY="-1.0" /> <Point X="2760.0" Y="1675.0" GraphRef="de644" RelX="-23.5" RelY="-3.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848314" /> </Interaction> <Interaction GraphId="ce16e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2954.0" Y="1938.0" GraphRef="dca3b" RelX="-1.0" RelY="0.0" /> <Point X="2894.0" Y="1995.0" GraphRef="c8424" RelX="0.0" RelY="0.0" /> </Graphics> <Xref 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ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2520.0" Y="1682.0" GraphRef="ea28e" RelX="1.8200000000001637" RelY="0.6900000000000546" /> <Point X="2505.0" Y="1718.0" GraphRef="abee3" RelX="-1.0" RelY="-0.014925373134328358" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209125" /> </Interaction> <Interaction GraphId="ceb7d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2157.0" Y="697.0" GraphRef="fbfc0" RelX="0.0" RelY="1.0" /> <Point X="2182.0" Y="737.0" GraphRef="d1d2f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008577" /> </Interaction> <Interaction GraphId="cef3e"> <Comment Source="Reactome">Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002).</Comment> <BiopaxRef>b3e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="366.0" Y="1291.0" /> <Point X="324.0" Y="1334.0" /> <Anchor Position="0.0" Shape="None" GraphId="eeeb3" /> <Anchor Position="0.99" Shape="None" GraphId="cf606" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446862" /> </Interaction> <Interaction GraphId="cf4e7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1025.0" Y="2061.0" GraphRef="adadb" RelX="0.0" RelY="0.6399999999998727" /> <Point X="1081.0" Y="2090.0" GraphRef="f2898" RelX="-1.0" RelY="-0.03225806451612903" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-727819" /> </Interaction> <Interaction GraphId="cfa19"> <Comment Source="Reactome">The IL1 family includes two agonists, IL1α and IL1β, and a naturally occurring receptor antagonist, IL1Ra. IL1Ra is produced locally in various tissues in response to infection or inflammation (Arend &amp; Gabay 2000). Anakinra (Kineret) is a recombinant form of IL1Ra that competitively inhibit the local inflammatory effects of IL1 (Seckinger et al. 1990) and is approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate (Drevlow et al. 1996, Cohen et al. 2002, Fleischmann et al. 2003). Isunakinra (EBI 005) is a fusion protein containing domains from IL1β and the IL1 receptor antagonist (IL1Ra or anakinra) developed as a topical therapy for dry eye disease (Goldstein et al. 2017). It blocks IL1R1 signalling with higher affinity than anakinra (Kovalchin et al. 2018). These IL1R1 inhibitors may be investigated for their role in blocking inflammatory cytokines produced in the "cytokine storm syndrome" caused by COVID-19 (Cron &amp; Chatham 2020).</Comment> <BiopaxRef>a82</BiopaxRef> <BiopaxRef>b01</BiopaxRef> <BiopaxRef>b77</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1267.0" Y="639.0" /> <Point X="1244.0" Y="663.0" /> <Anchor Position="0.0" Shape="None" GraphId="fc935" /> <Anchor Position="0.99" Shape="None" GraphId="d5186" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9681763" /> </Interaction> <Interaction GraphId="d040b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2206.0" Y="2325.0" GraphRef="c83aa" RelX="0.5100000000002183" RelY="0.0" /> <Point X="2311.0" Y="2396.0" GraphRef="ffae2" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684250" /> </Interaction> <Interaction GraphId="d10eb"> <Comment Source="Reactome">Toll-interacting protein (TOLLIP) binds to IRAK1 and IL-1RAP within the receptor complex. 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GraphId="d6343"> <Comment Source="Reactome">Interleukin-1 receptor-like 1 (IL1RL1, ST2), known for many years to be an orphan receptor within the IL1 receptor family, can bind Interleukin-33 (IL33) (Schmitz et al. 2005). The functional IL33 receptor is a heteromeric receptor complex consisting of IL1RL1 and Interleukin-1 receptor accessory protein (IL1RAP1) (Chackerian et al. 2007, Lingel et al. 2009). IL33 is found constitutively in the nucleus of endothelial cells where it can bind histone H2A-H2B (Roussel et al. 2008) leading to poorly understood intracrine gene regulatory functions (Carriere et al. 2007, Martin et al. 2013). It can be passively released from damaged cells, hence it has been termed an alarmin or damage-associated molecular pattern (DAMP), though IL33 is also released by undamaged cells (Lefrancais &amp; Cayrol 2012).</Comment> <BiopaxRef>cc6</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="124.0" Y="1505.0" /> <Point X="208.0" Y="1650.0" /> <Anchor Position="0.0" Shape="None" GraphId="a85d1" /> <Anchor Position="0.99" Shape="None" GraphId="b3de9" /> <Anchor Position="0.5" Shape="None" GraphId="e96df" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448629" /> </Interaction> <Interaction GraphId="d6775"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2130.0" Y="2364.0" GraphRef="e8bc6" RelX="-0.008" RelY="-1.0" /> <Point X="2155.0" Y="2325.0" GraphRef="eb2be" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684250" /> </Interaction> <Interaction GraphId="d6882"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2013.0" Y="1391.0" GraphRef="f2a91" RelX="1.0" RelY="0.0" /> <Point X="2039.0" Y="1436.0" GraphRef="d6527" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209087" /> </Interaction> <Interaction GraphId="d696e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2070.0" Y="1783.0" GraphRef="b84b1" RelX="-0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="2540.0" Y="1826.0" GraphRef="c86ef" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209061" /> </Interaction> <Interaction GraphId="d6d81"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2070.0" Y="1783.0" GraphRef="b84b1" RelX="-0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="1961.0" Y="1652.0" GraphRef="b5cfe" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209061" /> </Interaction> <Interaction GraphId="d7041"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1089.0" Y="1256.0" GraphRef="faf11" RelX="0.9591836734693877" RelY="-0.043478260869565216" /> <Point X="1154.0" Y="1320.0" GraphRef="cdac8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450173" /> </Interaction> <Interaction GraphId="d7067"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1098.0" Y="1557.0" GraphRef="fa178" RelX="-0.007874015748031496" RelY="1.0" /> <Point X="1073.0" Y="1560.0" GraphRef="fc028" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446877" /> </Interaction> <Interaction GraphId="d7f1a"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Truncated IL-37 can be translocated from the cytosol to the nucleus via a mechanism dependent on caspase 1 cleavage of IL-37 (Bulau A M et al. 2014). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.</Comment> <BiopaxRef>a0c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1757.0" Y="308.0" /> <Point X="1861.0" Y="250.0" /> <Anchor Position="0.0" Shape="None" GraphId="fcda6" /> <Anchor Position="0.99" Shape="None" GraphId="e4e0a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008696" /> </Interaction> <Interaction GraphId="d8888"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="890.0" Y="760.0" GraphRef="d0d66" RelX="-0.008" RelY="-1.0" /> <Point X="858.0" Y="726.0" GraphRef="b94cc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450133" /> </Interaction> <Interaction GraphId="d89b1"> <Comment Source="Reactome">Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001 IL1F10 is produced in Human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). Full length (1 – 152 amino acids) IL1F10 can bind Interleukin 1 receptor accessory protein like 1 (IL1RAPL1) (Mora et al. 2016). N-terminally truncated IL1F10 (20 – 152 amino acids) is also known to bind IL1RAPL1 but with much higher affinity. The physiological significance of full length IL1F10 binding to IL1RAPL1 is not known.</Comment> <BiopaxRef>c77</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2858.0" Y="2274.0" /> <Point X="2817.0" Y="2519.0" /> <Anchor Position="0.0" Shape="None" GraphId="b8a5a" /> <Anchor Position="0.99" Shape="None" GraphId="a8f10" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008054" /> </Interaction> <Interaction GraphId="d8f0a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1861.0" Y="250.0" GraphRef="e4e0a" RelX="1.0399999999999636" RelY="-0.5799999999999841" /> <Point X="1880.0" Y="247.0" GraphRef="f5a89" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008696" /> </Interaction> <Interaction GraphId="d923b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="416.0" Y="844.0" GraphRef="a76dd" RelX="0.7699999999999818" RelY="0.5399999999999636" /> <Point X="432.0" Y="847.0" GraphRef="c57e8" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446684" /> </Interaction> <Interaction GraphId="d9523"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2347.0" Y="524.0" GraphRef="be780" RelX="0.983739837398374" RelY="0.0" /> <Point X="2413.0" Y="538.0" GraphRef="fef43" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008587" /> </Interaction> <Interaction GraphId="d98de"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2868.0" Y="2120.0" GraphRef="b9d6c" RelX="-1.0" RelY="0.0" /> <Point X="2695.0" Y="2055.0" GraphRef="a0c21" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9007901" /> </Interaction> <Interaction GraphId="d9acb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2533.0" Y="514.0" GraphRef="b1616" RelX="-1.0" RelY="0.0" /> <Point X="2413.0" Y="538.0" GraphRef="fef43" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008587" /> </Interaction> <Interaction GraphId="d9da9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2285.0" Y="227.0" GraphRef="fdeb6" RelX="0.9789473684210527" RelY="0.0" /> <Point X="2292.0" Y="226.0" GraphRef="d9077" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6797293" /> </Interaction> <Interaction GraphId="da5ac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2101.0" Y="862.0" GraphRef="fd853" RelX="-0.6799999999998363" RelY="-0.009999999999990905" /> <Point X="2074.0" Y="892.0" GraphRef="c6172" RelX="0.9512195121951219" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008684" /> </Interaction> <Interaction GraphId="da75a"> <Comment Source="Reactome">IL1 induces the poly-ubiquitination and degradation of IRAK1. Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008). IRAK1 polyubiquitination was originally thought to tag IRAK1 for proteolysis by the proteasome, but more recently has been shown to involve K63-linked, not K48-linked polyubiquitination (Windheim et al. 2008; Conze et al. 2008), which is believed to have a scaffoling function. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitination of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008, Xiao et al. 2008). The current consensus is that Pellino proteins are the physiologically-relevant IRAK1 E3 ubiquitin ligases.</Comment> <BiopaxRef>a29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1396.0" Y="1473.0" /> <Point X="1510.0" Y="1520.0" /> <Anchor Position="0.0" Shape="None" GraphId="c3936" /> <Anchor Position="0.99" Shape="None" GraphId="cfd47" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948063" /> </Interaction> <Interaction GraphId="da92b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2109.0" Y="1927.0" GraphRef="aa361" RelX="1.0" RelY="0.0" /> <Point X="2157.0" Y="1967.0" GraphRef="ae7f7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451634" /> </Interaction> <Interaction GraphId="db659"> <Comment Source="Reactome">Pellino1, 2 and possibly 3 are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). Following ubiquitination IRAK1 dissociates.</Comment> <BiopaxRef>a29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1477.0" Y="1755.0" /> <Point X="1395.0" Y="1785.0" /> <Anchor Position="0.0" Shape="None" GraphId="cec8c" /> <Anchor Position="0.99" Shape="None" GraphId="c2d9f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948066" /> </Interaction> <Interaction GraphId="db74f"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. IL-37 can bind the Interleukin-18 receptor 1 (IL-18R1) (Shi et al. 2003, Kumar et al. 2002). Upon binding to IL-18R1, IL-37 facilitates the recruitment of Single Ig IL 1 related receptor (SIGIRR, TIR-8, IL-1R8) forming a complex (Nold Petry et al. 2015). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation.</Comment> <BiopaxRef>b46</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2182.0" Y="737.0" /> <Point X="2064.0" Y="704.0" /> <Anchor Position="0.0" Shape="None" GraphId="d1d2f" /> <Anchor Position="0.99" Shape="None" GraphId="f98b2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008577" /> </Interaction> <Interaction GraphId="db791"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="208.0" Y="1650.0" GraphRef="b3de9" RelX="0.839999999999975" RelY="1.4500000000000455" /> <Point X="222.0" Y="1653.0" GraphRef="b7e21" RelX="-0.011764705882352941" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448629" /> </Interaction> <Interaction GraphId="dbc7f"> <Comment Source="Reactome">Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008).</Comment> <BiopaxRef>fad</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1025.0" Y="1997.0" /> <Point X="1025.0" Y="2061.0" /> <Anchor Position="0.0" Shape="None" GraphId="a40df" /> <Anchor Position="0.99" Shape="None" GraphId="adadb" /> <Anchor Position="0.5" Shape="None" GraphId="c378d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-727819" /> </Interaction> <Interaction GraphId="dc04f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1041.0" Y="1256.0" GraphRef="faf11" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="366.0" Y="1291.0" GraphRef="eeeb3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446862" /> </Interaction> <Interaction GraphId="dc3f6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2392.0" Y="226.0" GraphRef="ac10d" RelX="1.0" RelY="0.0" /> <Point X="2398.0" Y="226.0" GraphRef="f5032" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6797293" /> </Interaction> <Interaction GraphId="dc8b8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1705.0" Y="1773.0" GraphRef="ca265" RelX="0.0" RelY="0.9393939393939394" /> <Point X="1744.0" Y="1832.0" GraphRef="c5970" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-168184" /> </Interaction> <Interaction GraphId="dd187"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1480.0" Y="1737.0" GraphRef="e94f1" RelX="-1.0" RelY="0.0" /> <Point X="1477.0" Y="1755.0" GraphRef="cec8c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948066" /> </Interaction> <Interaction GraphId="dd3aa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2293.0" Y="705.0" GraphRef="f948d" RelX="-1.0700000000001637" RelY="-0.25" /> <Point X="2266.0" Y="702.0" GraphRef="a64ba" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848335" /> </Interaction> <Interaction GraphId="dd4f9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1025.0" Y="2061.0" GraphRef="adadb" RelX="0.0" RelY="0.6399999999998727" /> <Point X="1057.0" Y="2098.0" GraphRef="cd17d" RelX="0.9867549668874173" RelY="-0.037037037037037035" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-727819" /> </Interaction> <Interaction GraphId="dd7a5"> <Comment Source="Reactome">In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.&lt;p&gt;This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.&lt;p&gt;IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.</Comment> <BiopaxRef>aee</BiopaxRef> <BiopaxRef>fad</BiopaxRef> <BiopaxRef>a1f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1744.0" Y="1832.0" /> <Point X="1743.0" Y="1903.0" /> <Anchor Position="0.0" Shape="None" GraphId="c5970" /> <Anchor Position="0.99" Shape="None" GraphId="a79c3" /> <Anchor Position="0.5" Shape="None" GraphId="f4935" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-168184" /> </Interaction> <Interaction GraphId="ddad5"> <Comment Source="Reactome">Signal transducer and activator of transcription 3 (STAT3) acts downstream of various cellular receptors and is primarily involved in gene transcription. STAT3 is activated by serine/threonine kinases (Rebe et al. 2013). The IL-37:IL-18R1:SIGIRR complex can facilitate the phosphorylation and activation of STAT3 (Nold Petry et al. 2015). However, the precise mechanism is unclear. 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NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).</Comment> <BiopaxRef>c93</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1622.0" Y="1829.0" /> <Point X="1576.0" Y="1889.0" /> <Anchor Position="0.0" Shape="None" GraphId="f1b69" /> <Anchor Position="0.99" Shape="None" GraphId="da07b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451561" /> </Interaction> <Interaction GraphId="deaa1"> <Comment Source="Reactome">The Interleukin-33 (IL33):Interleukin-1 receptor-like 1 (IL1RL1, ST2) complex binds the membrane-associated form of Interleukin-1 receptor accessory protein (IL1RAP-1). &lt;br&gt;&lt;br&gt;After IL33:IL1RL1 ligand binding, IL1RL1 undergoes a conformational change, which allows the recruitment of IL1RAP-1 (Lingel et al. 2009, Liu et al. 2013).</Comment> <BiopaxRef>cd2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="160.0" Y="1710.0" /> <Point X="183.0" Y="1757.0" /> <Anchor Position="0.0" Shape="None" GraphId="f5d37" /> <Anchor Position="0.99" Shape="None" GraphId="d6c7c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448603" /> </Interaction> <Interaction GraphId="def2f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2716.0" Y="522.0" GraphRef="f8d02" RelX="-1.0" RelY="-0.04" /> <Point X="2622.0" Y="606.0" GraphRef="c9a45" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848370" /> </Interaction> <Interaction GraphId="df362"> <Comment Source="Reactome">Interleukin-18/Interleukin-18 receptor 1 (IL18:IL18R1) complex binds Interleukin-18 receptor accessory protein (IL18RAP, IL18 receptor beta chain), forming a high-affinity signaling complex (Born et al. 1998, Debets et al. 2001). 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After binding to interleukin-36 IL1RL2 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways. IL1RL2 also binds Interleukin-1 family member 10 (IL38, IL1F10) (van de Veerdonk et al. 2012). The biological function of IL1F10 is thought to be inhibition of IL36 binding to IL36R (Yuan et al. 2015, Yi et al. 2016).</Comment> <BiopaxRef>e81</BiopaxRef> <BiopaxRef>d61</BiopaxRef> <BiopaxRef>ff4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2873.0" Y="1830.0" /> <Point X="2831.0" Y="1765.0" /> <Anchor Position="0.0" Shape="None" GraphId="cdbe4" /> <Anchor Position="0.99" Shape="None" GraphId="bcd69" /> <Anchor Position="0.5" Shape="None" GraphId="d9542" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848316" /> </Interaction> <Interaction GraphId="e16c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2030.0" Y="2609.0" GraphRef="f34a7" RelX="0.0" RelY="-1.0" /> <Point X="2056.0" Y="2592.0" GraphRef="aac55" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451649" /> </Interaction> <Interaction GraphId="e1750"> <Graphics ConnectorType="Segmented" ZOrder="12288" 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The TRAF6 oligomer consists of more than two molecules of TRAF6; thermodynamic data for TRAF2 strongly suggests that it is functionally a trimer (Rawlings et al. 2006). TRAF6 is represented here as a trimer, though the extent and significance of TRAF6 oligomerization is unclear. Oligomerisation may be assisted by TIFA (TRAF-interacting protein with a FHA domain; Takatsuna et al. 2003). </Comment> <BiopaxRef>ad7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1154.0" Y="1320.0" /> <Point X="1193.0" Y="1403.0" /> <Anchor Position="0.0" Shape="None" GraphId="cdac8" /> <Anchor Position="0.99" Shape="None" GraphId="c7f75" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450173" /> </Interaction> <Interaction GraphId="e68c4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1252.0" Y="1476.0" GraphRef="e4fbe" RelX="-1.0" RelY="0.0" /> <Point X="1197.0" Y="1474.0" GraphRef="d85a2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948015" /> </Interaction> <Interaction GraphId="e6b7b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1864.0" Y="361.0" GraphRef="d11de" RelX="0.9789473684210527" RelY="0.0" /> <Point X="1863.0" Y="326.0" GraphRef="f5f68" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9009910" /> </Interaction> <Interaction GraphId="e6e0e"> <Comment Source="Reactome">In human peripheral blood, monocytes Interleukin-4 (IL4) and Interleukin-13 significantly downregulate the expression of classical proinflammatory signal transducers, such as Interleukin-1 (IL1), Interleukin-6, Interleukin-8, Interleukin-18, C-C motif chemokine 2 (CCL2) and Tumor necrosis factor (TNF). Expression of Prostaglandin G/H synthase 2 (PTGS2, COX2) and Arachidonate 5-lipoxygenase (ALOX5), enzymes involved in the biosynthesis of the proinflammatory eicosanoids, is also attenuated (Chatidis et al. 2005).&lt;br&gt;This is a black box event because the mechanism of gene regulation is not fully defined.</Comment> <BiopaxRef>df1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2292.0" Y="226.0" /> <Point X="2392.0" Y="226.0" /> <Anchor Position="0.0" Shape="None" GraphId="d9077" /> <Anchor Position="0.99" Shape="None" GraphId="ac10d" /> <Anchor Position="0.5" Shape="None" GraphId="ab3cc" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6797293" /> </Interaction> <Interaction GraphId="e718d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2716.0" Y="522.0" GraphRef="f8d02" RelX="-1.0" RelY="-0.04" /> <Point X="2622.0" Y="540.0" GraphRef="d4e4d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848392" /> </Interaction> <Interaction GraphId="e780c"> <Comment Source="Reactome">Interleukin-36 receptor antagonist protein (IL36RN, IL-36Ra) binds the interleukin-36 receptor subunit IL1RL2 (Interleukin-1 receptor-like 2, IL-1Rrp2). This inhibits the activity of interleukin-36 (IL36) by preventing IL1RL2 and IL1RAP from associating to form the interleukin-36 receptor complex (Towne et al. 2015). Similarly, Interleukin-1 family member 10 (IL1F10), also referred to as Interleukin-38, binds the interleukin-36 receptor subunit IL1RL2 inhibiting IL36 signaling (van de Veerdonk et al. 2012). Homozygous and compound heterozygous mutations in IL36RN have been identified to cause generalized pustular psoriasis (GPP) (Onoufriadis et al. 2011, Marrakchi et al. 2011).</Comment> <BiopaxRef>b74</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2894.0" Y="1995.0" /> <Point X="2855.0" Y="2035.0" /> <Anchor Position="0.0" Shape="None" GraphId="c8424" /> <Anchor Position="0.99" Shape="None" GraphId="b3d6d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8940998" /> </Interaction> <Interaction GraphId="e79b2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2376.0" Y="2121.0" GraphRef="adc0c" RelX="-0.01999999999998181" RelY="0.9499999999998181" /> <Point X="2533.0" Y="2166.0" GraphRef="f6f82" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684267" /> </Interaction> <Interaction GraphId="e7a1b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2092.0" Y="148.0" GraphRef="f2473" RelX="-1.0" RelY="-0.015873015873015872" /> <Point X="2086.0" Y="147.0" GraphRef="ccdfe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008894" /> </Interaction> <Interaction GraphId="e8421"> <Comment Source="Reactome">Tpl2 (also known as Cot, officially known as MAP3K8) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1 (MAP2K4). Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007). &lt;br&gt;Positions of phosphorylations represented here are inferred from general experimental data (Zheng &amp; Guan, 1994).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2056.0" Y="2592.0" /> <Point X="2127.0" Y="2592.0" /> <Anchor Position="0.0" Shape="None" GraphId="aac55" /> <Anchor Position="0.99" Shape="None" GraphId="a7e9e" /> <Anchor Position="0.5" Shape="None" GraphId="e3d42" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451649" /> </Interaction> <Interaction GraphId="e977f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2650.0" Y="2259.0" GraphRef="e650d" RelX="0.9672131147540983" RelY="0.0" /> <Point X="2648.0" Y="2294.0" GraphRef="b8717" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008043" /> </Interaction> <Interaction GraphId="e9c00"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2197.0" Y="886.0" GraphRef="c1cb4" RelX="-1.0" RelY="0.0" /> <Point X="2169.0" Y="863.0" GraphRef="b781f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008684" /> </Interaction> <Interaction GraphId="e9cec"> <Comment Source="Reactome">MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). This complex is the minimum required for signaling (Brikos et al. 2007).</Comment> <BiopaxRef>b50</BiopaxRef> <BiopaxRef>e25</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="701.0" Y="736.0" /> <Point X="649.0" Y="704.0" /> <Anchor Position="0.0" Shape="None" GraphId="f51ac" /> <Anchor Position="0.99" Shape="None" GraphId="b2a51" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446648" /> </Interaction> <Interaction GraphId="ea320"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2648.0" Y="2352.0" GraphRef="a3be8" RelX="0.0" RelY="0.5799999999999272" /> <Point X="2683.0" Y="2413.0" GraphRef="f8ca5" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008043" /> </Interaction> <Interaction GraphId="ea439"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="790.0" Y="700.0" GraphRef="d1cd1" RelX="-0.67999999999995" RelY="-0.2599999999999909" /> <Point X="810.0" Y="679.0" GraphRef="c2742" RelX="0.984" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450133" /> </Interaction> <Interaction GraphId="ea846"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="977.0" Y="676.0" GraphRef="ccdb8" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="966.0" Y="717.0" GraphRef="f4488" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-445752" /> </Interaction> <Interaction GraphId="eafc9"> <Comment Source="Reactome">After binding of IL36 to IL1RL2, the complex associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex. The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system (Gresnigt &amp; van de Veerdonk 2013).</Comment> <BiopaxRef>bfa</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2758.0" Y="1728.0" /> <Point X="2809.0" Y="1629.0" /> <Anchor Position="0.0" Shape="None" GraphId="c7486" /> <Anchor Position="0.99" Shape="None" GraphId="e722b" /> <Anchor Position="0.5" Shape="None" GraphId="de644" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848314" /> </Interaction> <Interaction GraphId="eb1b6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1122.0" Y="1355.0" GraphRef="ecb57" RelX="0.981651376146789" RelY="-0.0196078431372549" /> <Point X="1154.0" Y="1320.0" GraphRef="cdac8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450173" /> </Interaction> <Interaction GraphId="eb1b8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2809.0" Y="1629.0" GraphRef="e722b" RelX="0.5100000000002183" RelY="-0.9900000000000091" /> <Point X="2822.0" Y="1626.0" GraphRef="f3335" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848314" /> </Interaction> <Interaction GraphId="eb3ee"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2664.0" Y="684.0" GraphRef="f75bb" RelX="0.9770114942528736" RelY="0.0" /> <Point X="2672.0" Y="728.0" GraphRef="c3379" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848395" /> </Interaction> <Interaction GraphId="ec608"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2059.0" Y="1393.0" GraphRef="d20ea" RelX="-1.0" RelY="0.0" /> <Point X="2039.0" Y="1436.0" GraphRef="d6527" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209087" /> </Interaction> <Interaction GraphId="eca5e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2775.0" Y="1688.0" GraphRef="ab1a2" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="2758.0" Y="1728.0" GraphRef="c7486" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848314" /> </Interaction> <Interaction GraphId="ed1cb"> <Comment Source="Reactome">Interleukins are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 is selectively produced by human apoptotic cells (Mora et al. 2016) and human epidermal keratinocytes (based on mRNA studies) (Boutet M A et al. 2016). IL1F10 can bind to interleukin 1 receptor like 2 (IL1RL2) and may result in the suppression of IL 17 and IL 22 and induction of IL 6 production (van de Veerdonk et al. 2012, Mora et al. 2016). IL1F10 is synthesized as precursors that require N terminal processing to attain full receptor agonist or antagonist function (Mora et al. 2016). Both full length (1 – 152 amino acids) and N terminal truncated (20 – 152 amino acids) IL1F10 can bind Interleukin 1 receptor accessory protein like 1 (IL1RAPL1) (Mora et al. 2016). The binding affinity of truncated IL1F10 is much higher than that of the full length. However, binding of the full length or truncated forms has distinct outcomes; the former induces IL6 and the latter suppresses IL6 via JNK and AP1 signaling (Mora et al. 2016).</Comment> <BiopaxRef>c77</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2908.0" Y="2321.0" /> <Point X="2811.0" Y="2432.0" /> <Anchor Position="0.0" Shape="None" GraphId="fdd66" /> <Anchor Position="0.99" Shape="None" GraphId="fb614" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008052" /> </Interaction> <Interaction GraphId="ed331"> <Comment Source="Reactome">SCF (Beta-TrCP) ubiquitinates phosphorylated I kappa B alpha.</Comment> <BiopaxRef>c4f</BiopaxRef> <BiopaxRef>a66</BiopaxRef> <BiopaxRef>d03</BiopaxRef> <BiopaxRef>e1c</BiopaxRef> <BiopaxRef>c9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2514.0" Y="1779.0" /> <Point X="2436.0" Y="1780.0" /> <Anchor Position="0.0" Shape="None" GraphId="d3aea" /> <Anchor Position="0.99" Shape="None" GraphId="dc463" /> <Anchor Position="0.5" Shape="None" GraphId="ba4e2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209063" /> </Interaction> <Interaction GraphId="ed920"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1395.0" Y="1785.0" GraphRef="c2d9f" RelX="-0.8199999999999363" RelY="0.2999999999999545" /> <Point X="1413.0" Y="1823.0" GraphRef="f4213" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948066" /> </Interaction> <Interaction GraphId="edff7"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The putative caspase 1 cleavage site is at aspartic acid 20 (Kumar et al. 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. IL-37(? 218) can bind SMAD3 (Nold M F et al. 2010, Grimsby S et al. 2004) and may affect its function.</Comment> <BiopaxRef>f25</BiopaxRef> <BiopaxRef>eb0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1774.0" Y="410.0" /> <Point X="1859.0" Y="411.0" /> <Anchor Position="0.0" Shape="None" GraphId="ba70f" /> <Anchor Position="0.99" Shape="None" GraphId="f9533" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008692" /> </Interaction> <Interaction GraphId="ee7bd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="665.0" Y="1355.0" GraphRef="c10f1" RelX="3.410000000000082" RelY="0.07999999999992724" /> <Point X="600.0" Y="784.0" GraphRef="bdef3" RelX="0.0" RelY="0.9130434782608695" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="ee8e2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1354.0" Y="1476.0" GraphRef="e4fbe" RelX="0.9805825242718447" RelY="0.0" /> <Point X="1396.0" Y="1473.0" GraphRef="c3936" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948063" /> </Interaction> <Interaction GraphId="eebc7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2497.0" Y="1957.0" GraphRef="fb3ce" RelX="-1.0" RelY="0.0" /> <Point X="2348.0" Y="2012.0" GraphRef="d4a88" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684275" /> </Interaction> <Interaction GraphId="ef04a"> <Comment Source="Reactome">Interleukin-1 receptor type 2 (IL1R2) binds Interleukin-1 but does not participate in any signaling processes. IL1R2 is thought to be a decoy receptor, removing or neutralizing Interleukin-1 that could otherwise stimulate the type 1 receptor.</Comment> <BiopaxRef>ec9</BiopaxRef> <BiopaxRef>c31</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1488.0" Y="738.0" /> <Point X="1560.0" Y="717.0" /> <Anchor Position="0.0" Shape="None" GraphId="f542c" /> <Anchor Position="0.99" Shape="None" GraphId="e3ef9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446130" /> </Interaction> <Interaction GraphId="ef165"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="573.0" Y="773.0" GraphRef="bdef3" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="573.0" Y="735.0" GraphRef="a57e6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446868" /> </Interaction> <Interaction GraphId="ef175"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="302.0" Y="1174.0" GraphRef="e60a6" RelX="-0.009999999999990905" RelY="0.599999999999909" /> <Point X="354.0" Y="1232.0" GraphRef="fc62d" RelX="-1.0" RelY="-0.03225806451612903" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446701" /> </Interaction> <Interaction GraphId="ef750"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1077.0" Y="1999.0" GraphRef="ab2ca" RelX="-1.0" RelY="-0.03225806451612903" /> <Point X="1025.0" Y="1997.0" GraphRef="a40df" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-727819" /> </Interaction> <Interaction GraphId="ef7c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1277.0" Y="615.0" GraphRef="b524d" RelX="0.0" RelY="0.8947368421052632" /> <Point X="1267.0" Y="639.0" GraphRef="fc935" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9681763" /> </Interaction> <Interaction GraphId="ef979"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2311.0" Y="2396.0" GraphRef="ffae2" RelX="-1.0" RelY="0.0" /> <Point X="2258.0" Y="2445.0" GraphRef="d6067" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684248" /> </Interaction> <Interaction GraphId="efef5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2760.0" Y="830.0" GraphRef="f4612" RelX="0.8800000000001091" RelY="1.0199999999999818" /> <Point X="2748.0" Y="851.0" GraphRef="bef09" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848395" /> </Interaction> <Interaction GraphId="f0b3b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1761.0" Y="444.0" GraphRef="ea400" RelX="1.0" RelY="0.0" /> <Point X="1774.0" Y="410.0" GraphRef="ba70f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008692" /> </Interaction> <Interaction GraphId="f14ad"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2010.0" Y="309.0" GraphRef="df0f5" RelX="-0.007751937984496124" RelY="-1.0" /> <Point X="2010.0" Y="306.0" GraphRef="c3543" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008928" /> </Interaction> <Interaction GraphId="f1680"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL 37), also known as IL 1F7, is a member of the IL 1 family. There are five isoforms of IL 37 (a e) of which transcript IL 37b is known to be functional (Sharma S et al., 2008). Like several other IL 1 family members, IL 37b is synthesized as precursors that require processing (primarily by caspase 1) to attain full receptor agonist or antagonist function (Kumar S et al., 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. Processed IL 37b can bind with phosphorylated SMAD3 in the cytosol of A549 cells (Nold M F et al., 2010, Grimsby S et al., 2004). This complex may then translocate from the cytosol to the nucleus (Nold M F et al., 2010, Dinarello et al. 2016) and may affect the function of SMAD3. These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation. This is a black box event because SMAD3 assisted IL-37 translocation to the nucleus is not fully understood.</Comment> <BiopaxRef>f25</BiopaxRef> <BiopaxRef>eb0</BiopaxRef> <BiopaxRef>e14</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2010.0" Y="306.0" /> <Point X="2012.0" Y="234.0" /> <Anchor Position="0.0" Shape="None" GraphId="c3543" /> <Anchor Position="0.99" Shape="None" GraphId="c3128" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008928" /> </Interaction> <Interaction GraphId="f17fe"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="311.0" Y="870.0" GraphRef="a3bef" RelX="-1.0" RelY="-0.03225806451612903" /> <Point X="282.0" Y="902.0" GraphRef="db43a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446694" /> </Interaction> <Interaction GraphId="f1c5a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1526.0" Y="233.0" GraphRef="ba9af" RelX="0.01999999999998181" RelY="0.6700000000000159" /> <Point X="1528.0" Y="236.0" GraphRef="b8531" RelX="-0.005847953216374269" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012556" /> </Interaction> <Interaction GraphId="f1f1d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2069.0" Y="205.0" GraphRef="c257a" RelX="1.0" RelY="0.0" /> <Point X="2011.0" Y="146.0" GraphRef="b1211" RelX="-8.5" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008894" /> </Interaction> <Interaction GraphId="f1faf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1055.0" Y="1887.0" GraphRef="a52e2" RelX="-0.010309278350515464" RelY="0.9622641509433962" /> <Point X="1040.0" Y="1924.0" GraphRef="a57e2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446870" /> </Interaction> <Interaction GraphId="f2268"> <Comment Source="Reactome">TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.</Comment> <BiopaxRef>d42</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1040.0" Y="1924.0" /> <Point X="1147.0" Y="1990.0" /> <Anchor Position="0.0" Shape="None" GraphId="a57e2" /> <Anchor Position="0.99" Shape="None" GraphId="daae9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446870" /> </Interaction> <Interaction GraphId="f28f3"> <Comment Source="Reactome">MyD88 and Tollip only bind to non-phosphorylated IRAK1 (Wesche et al. 1997) so hyper-phosphorylated IRAK1 is predisposed to release from the receptor complex, a key step in this signaling cascade. It is believed that the interaction of IRAK1 with TRAF6 enables the release of IRAK1:TRAF6 from the receptor (Gottipati et al. 2007). Though released from the receptor complex, IRAK1:TRAF6 remains associated with the membrane, perhaps due to subsequent interaction with the TAK1 complex (Dong et al. 2006).</Comment> <BiopaxRef>cca</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="324.0" Y="1347.0" /> <Point X="665.0" Y="1355.0" /> <Anchor Position="0.0" Shape="None" GraphId="a7b2f" /> <Anchor Position="0.99" Shape="None" GraphId="c10f1" /> <Anchor Position="0.5" Shape="None" GraphId="b786e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="f2a9a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="194.0" Y="1716.0" GraphRef="af5bc" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="160.0" Y="1710.0" GraphRef="f5d37" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448603" /> </Interaction> <Interaction GraphId="f2bbd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1480.0" Y="2078.0" GraphRef="dbecf" RelX="2.119999999999891" RelY="0.4600000000000364" /> <Point X="1483.0" Y="2092.0" GraphRef="eb7a4" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450187" /> </Interaction> <Interaction GraphId="f3261"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2460.0" Y="684.0" GraphRef="a612d" RelX="1.0" RelY="0.0" /> <Point X="2622.0" Y="606.0" GraphRef="c9a45" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848370" /> </Interaction> <Interaction GraphId="f33ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="686.0" Y="679.0" GraphRef="c2742" RelX="-1.0" RelY="0.0" /> <Point X="701.0" Y="736.0" GraphRef="f51ac" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446648" /> </Interaction> <Interaction GraphId="f3d06"> <Comment Source="Reactome">The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.</Comment> <BiopaxRef>d11</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1905.0" Y="1675.0" /> <Point X="1809.0" Y="2557.0" /> <Anchor Position="0.0" Shape="None" GraphId="f3634" /> <Anchor Position="0.99" Shape="None" GraphId="fb0ae" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2730894" /> </Interaction> <Interaction GraphId="f52b4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2407.0" Y="2151.0" GraphRef="bbf32" RelX="-0.0500000000001819" RelY="1.2100000000000364" /> <Point X="2398.0" Y="2236.0" GraphRef="f9041" RelX="-0.008264462809917356" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684261" /> </Interaction> <Interaction GraphId="f55da"> <Comment Source="Reactome">The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages).</Comment> <BiopaxRef>cac</BiopaxRef> <BiopaxRef>dbe</BiopaxRef> <BiopaxRef>a57</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2348.0" Y="2012.0" /> <Point X="2347.0" Y="2092.0" /> <Anchor Position="0.0" Shape="None" GraphId="d4a88" /> <Anchor Position="0.99" Shape="None" GraphId="bf840" /> <Anchor Position="0.5" Shape="None" GraphId="f9ab6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684275" /> </Interaction> <Interaction GraphId="f5a6c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="179.0" Y="1576.0" GraphRef="a7221" RelX="-1.0" RelY="0.0" /> <Point X="126.0" Y="1577.0" GraphRef="e96df" RelX="-40.0" RelY="-0.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448629" /> </Interaction> <Interaction GraphId="f5f28"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1305.0" Y="693.0" GraphRef="f022b" RelX="-0.023255813953488372" RelY="0.9130434782608695" /> <Point X="1328.0" Y="744.0" GraphRef="ca6f2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-445753" /> </Interaction> <Interaction GraphId="f6289"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="665.0" Y="1355.0" GraphRef="c10f1" RelX="3.410000000000082" RelY="0.07999999999992724" /> <Point X="650.0" Y="1413.0" GraphRef="c0f5e" RelX="-0.0049261083743842365" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="f6ca0"> <Comment Source="Reactome">The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho &amp; Tsichlis 2005). &lt;br&gt;&lt;br&gt;A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.&lt;br&gt;</Comment> <BiopaxRef>e67</BiopaxRef> <BiopaxRef>d81</BiopaxRef> <BiopaxRef>aa7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2157.0" Y="1967.0" /> <Point X="2245.0" Y="1968.0" /> <Anchor Position="0.0" Shape="None" GraphId="ae7f7" /> <Anchor Position="0.99" Shape="None" GraphId="e25fa" /> <Anchor Position="0.5" Shape="None" GraphId="cacfb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-451634" /> </Interaction> <Interaction GraphId="f7255"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="468.0" Y="1410.0" GraphRef="bbe90" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="493.0" Y="1355.0" GraphRef="b786e" RelX="-1.5" RelY="4.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="f784c"> <Comment Source="Reactome">NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro.</Comment> <BiopaxRef>e03</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2378.0" Y="2026.0" /> <Point X="2376.0" Y="2121.0" /> <Anchor Position="0.0" Shape="None" GraphId="f058b" /> <Anchor Position="0.99" Shape="None" GraphId="adc0c" /> <Anchor Position="0.5" Shape="None" GraphId="f0111" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684267" /> </Interaction> <Interaction GraphId="f7855"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="266.0" Y="852.0" GraphRef="e35b7" RelX="0.9847328244274809" RelY="0.0" /> <Point X="282.0" Y="936.0" GraphRef="e0d0c" RelX="0.0" RelY="1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446694" /> </Interaction> <Interaction GraphId="f7953"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1809.0" Y="2557.0" GraphRef="fb0ae" RelX="-0.9600000000000364" RelY="8.820000000000164" /> <Point X="1794.0" Y="2560.0" GraphRef="efea7" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2730894" /> </Interaction> <Interaction GraphId="f7d9c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1195.0" Y="1154.0" GraphRef="dc398" RelX="-1.0" RelY="0.0" /> <Point X="1145.0" Y="1154.0" GraphRef="e3dba" RelX="1.0" RelY="6.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-507719" /> </Interaction> <Interaction GraphId="f8123"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="974.0" Y="1865.0" GraphRef="e3cbd" RelX="1.0" RelY="-0.043478260869565216" /> <Point X="1026.0" Y="2031.0" GraphRef="c378d" RelX="1.0" RelY="2.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-727819" /> </Interaction> <Interaction GraphId="f8fb7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2343.0" Y="1655.0" GraphRef="dd363" RelX="0.983739837398374" RelY="0.0" /> <Point X="2338.0" Y="1613.0" GraphRef="ef803" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209125" /> </Interaction> <Interaction GraphId="f9516"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2108.0" Y="2201.0" GraphRef="d9a43" RelX="-0.8800000000001091" RelY="-0.30999999999994543" /> <Point X="2076.0" Y="2281.0" GraphRef="ccb20" RelX="-0.04" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5684273" /> </Interaction> <Interaction GraphId="f97e9"> <Comment Source="Reactome">Activated ubiquitin is transferred to a heterodimeric E2 conjugating enzyme UBE2N (Ubc13) and UBEE2V1 (Uev1A) forming an E2-Ub thioester.</Comment> <BiopaxRef>b6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1197.0" Y="1474.0" /> <Point X="1140.0" 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LineThickness="1.0"> <Point X="2436.0" Y="1780.0" GraphRef="dc463" RelX="-0.7800000000002001" RelY="0.009999999999990905" /> <Point X="2432.0" Y="1781.0" GraphRef="eb0e9" RelX="0.9863945578231292" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209063" /> </Interaction> <Interaction GraphId="fbcb0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1499.0" Y="1414.0" GraphRef="ec1a3" RelX="-0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="1479.0" Y="1433.0" GraphRef="ec8b5" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450827" /> </Interaction> <Interaction GraphId="fbd28"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1565.0" Y="110.0" GraphRef="ab695" RelX="-0.7200000000000273" RelY="0.4099999999999966" /> <Point X="1588.0" Y="138.0" GraphRef="db383" RelX="0.9844961240310077" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012542" /> </Interaction> <Interaction GraphId="fbea9"> <Comment Source="Reactome">Following the TRAF6-mediated transfer of ubiquitin from the E2 conjugating enzyme UBE2N:UBE2V1 it dissociates.</Comment> <BiopaxRef>b6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1056.0" Y="1700.0" /> <Point X="1105.0" Y="1746.0" /> <Anchor Position="0.0" Shape="None" GraphId="cb990" /> <Anchor Position="0.99" Shape="None" GraphId="fa77e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8948018" /> </Interaction> <Interaction GraphId="fc562"> <Comment Source="Reactome">Interleukin 1 family member 10 (IL1F10, IL 38) is a member of the IL1 family (Lin et al. 2001, Bensen et al. 2001). IL1F10 can bind with X linked interleukin 1 receptor accessory protein like 1 (IL 1RAPL 1) (Mora et al. 2016). Stimulated IL1RAPL1 can activate Mitogen Activated Protein Kinase 8 (MAPK8, JNK1) signaling, which is required for transcription factor AP 1 activation (Born T L et al. 2000, Khan J A et al. 2004). Full length (1 – 152 amino acids) and N terminal truncated (20 – 152 amino acids) IL1F10 can bind with IL1RAPL1. The binding affinity of truncated IL1F10 is much higher than that of the full length. Binding of truncated IL1F10 to IL1RAPL1 results in inhibition of JNK signaling, which consequently leads to IL6 suppression (Mora et al. 2016). This is represented as a black box event because the mechanism of MAPK8 activation by IL1RAPL1 is uncertain.</Comment> <BiopaxRef>c77</BiopaxRef> <BiopaxRef>fbd</BiopaxRef> <BiopaxRef>a27</BiopaxRef> <BiopaxRef>ab6</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2648.0" Y="2294.0" /> <Point X="2648.0" Y="2352.0" /> <Anchor Position="0.0" Shape="None" GraphId="b8717" /> <Anchor Position="0.99" Shape="None" GraphId="a3be8" /> <Anchor Position="0.5" Shape="None" GraphId="fe423" /> <Anchor Position="0.5" Shape="None" GraphId="a3377" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008043" /> </Interaction> <Interaction GraphId="fc66e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="308.0" Y="679.0" GraphRef="f3a0a" RelX="-0.7200000000000273" RelY="0.0" /> <Point X="305.0" Y="716.0" GraphRef="d0e19" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446634" /> </Interaction> <Interaction GraphId="fd1ee"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2347.0" Y="524.0" GraphRef="be780" RelX="0.983739837398374" RelY="0.0" /> <Point X="2400.0" Y="730.0" GraphRef="dd7a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8848335" /> </Interaction> <Interaction GraphId="fd5dc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2012.0" Y="234.0" GraphRef="c3128" RelX="0.01999999999998181" RelY="-0.7199999999999989" /> <Point X="2013.0" Y="231.0" GraphRef="c257a" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9008928" /> </Interaction> <Interaction GraphId="fd6a9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="266.0" Y="852.0" GraphRef="e35b7" RelX="0.9847328244274809" RelY="0.0" /> <Point X="282.0" Y="902.0" GraphRef="db43a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446694" /> </Interaction> <Interaction GraphId="fda91"> <Comment Source="Reactome">Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL-37, IL-1 F7) is a member of the IL-1 family. There are five isoforms of IL-37 (a-e) of which transcript IL-37b is known to be functional (Sharma et al. 2008). This isoform is represented in UniProt as the canonical form of IL-37 and in Reactome as the full length, unprocessed form of IL-37. Like several other IL-1 family members, IL-37 is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function. The processing of IL-37 begins by the binding of Caspase to the protein. This is a black box event because the precise Caspase binding site in IL-37 is unclear.</Comment> <BiopaxRef>e08</BiopaxRef> <BiopaxRef>a8f</BiopaxRef> <BiopaxRef>a0c</BiopaxRef> <BiopaxRef>d9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1637.0" Y="69.0" /> <Point X="1565.0" Y="110.0" /> <Anchor Position="0.0" Shape="None" GraphId="b0d7d" /> <Anchor Position="0.99" Shape="None" GraphId="ab695" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9012542" /> </Interaction> <Interaction GraphId="feaa4"> <Comment Source="Reactome">IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4.</Comment> <BiopaxRef>dbb</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="339.0" Y="790.0" /> <Point X="416.0" Y="844.0" /> <Anchor Position="0.0" Shape="None" GraphId="f7edf" /> <Anchor Position="0.99" Shape="None" GraphId="a76dd" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446684" /> </Interaction> <Interaction GraphId="feafa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1560.0" Y="717.0" GraphRef="e3ef9" RelX="0.7200000000000273" RelY="-0.21000000000003638" /> <Point X="1544.0" Y="687.0" GraphRef="f31c1" RelX="-1.0" RelY="-0.018867924528301886" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446130" /> </Interaction> <Interaction GraphId="fed46"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1971.0" Y="894.0" GraphRef="c5c10" RelX="-1.0" RelY="0.0" /> <Point X="1942.0" Y="863.0" GraphRef="c19e8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9009072" /> </Interaction> <Interaction GraphId="fed4d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1943.0" Y="326.0" GraphRef="f1143" RelX="0.7999999999999545" RelY="0.0" /> <Point X="1946.0" Y="327.0" GraphRef="df0f5" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9009910" /> </Interaction> <Interaction GraphId="fedce"> <Comment Source="Reactome">Human beta-TrCP forms part of the SCF E3 ubiquitin ligase complex which binds to phosphorylated residues Ser32 and Ser 36 at the IKK target motif in IKBA complex with P65:P50 heterodimer.</Comment> <BiopaxRef>c4f</BiopaxRef> <BiopaxRef>fb6</BiopaxRef> <BiopaxRef>a66</BiopaxRef> <BiopaxRef>d03</BiopaxRef> <BiopaxRef>e1c</BiopaxRef> <BiopaxRef>c9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2338.0" Y="1613.0" /> <Point X="2520.0" Y="1682.0" /> <Anchor Position="0.0" Shape="None" GraphId="ef803" /> <Anchor Position="0.99" Shape="None" GraphId="ea28e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209125" /> </Interaction> <Interaction GraphId="fefde"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1633.0" Y="1992.0" GraphRef="ab5fc" RelX="1.0" RelY="0.0" /> <Point X="1743.0" Y="1866.0" GraphRef="f4935" RelX="-0.5" RelY="-1.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-168184" /> </Interaction> <Interaction GraphId="ff20f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="665.0" Y="1355.0" GraphRef="c10f1" RelX="3.410000000000082" RelY="0.07999999999992724" /> <Point X="1014.0" Y="1355.0" GraphRef="ecb57" RelX="-1.0" RelY="-0.0196078431372549" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-446894" /> </Interaction> <Interaction GraphId="ff439"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1715.0" Y="1423.0" GraphRef="fa5b2" RelX="-1.0" RelY="0.0" /> <Point X="1713.0" Y="1372.0" GraphRef="fa3f8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-450690" /> </Interaction> <Interaction GraphId="ff60e"> <Comment Source="Reactome">The interleukin 1 receptor antagonist protein (ILRAP or IL1RN) is a member of the IL1 family that binds to IL1R1 (and with much lower affinity IL1R2) but does not elicit a signaling response. 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rdf:id="bfa"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">14734551</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">Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE.</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="d11"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17072321</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">Introduction to NF-kappaB: players, pathways, perspectives.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gilmore TD.</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="b6a"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17135271</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">Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.</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="e3c"> <bp:ID 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li S, Strelow A, Fontana EJ, Wesche H.</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="db8"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18613828</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">IL-1, IL-18, and IL-33 families of cytokines.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Arend WP, Palmer G, Gabay C.</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="e25"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17507369</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">Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Brikos C, Wait R, Begum S, O'Neill LA, Saklatvala J.</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="cac"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">22988300</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">IκB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Roget K, Ben-Addi A, Mambole-Dema A, Gantke T, Yang HT, Janzen J, Morrice N, Abbott D, Ley SC.</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="eb0"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15527767</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">Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Grimsby S, Jaensson H, Dubrovska A, Lomnytska M, Hellman U, Souchelnytskyi S.</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="bb1"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11158290</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">Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C.</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="b3e"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8837778</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">TRAF6 is a signal transducer for interleukin-1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV.</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="e03"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">12482991</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">betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, Hay RT, Ben-Neriah Y, Ley SC.</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="a27"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15123616</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">Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Khan JA, Brint EK, O'Neill LA, Tong L.</bp:AUTHORS> </bp:PublicationXref> <bp:openControlledVocabulary xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#"> <bp:TERM xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" 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